National Library of Energy BETA

Sample records for human mammary epithelial

  1. Enhanced growth medium and method for culturing human mammary epithelial cells

    DOE Patents [OSTI]

    Stampfer, Martha R.; Smith, Helene S.; Hackett, Adeline J.

    1983-01-01

    Methods are disclosed for isolating and culturing human mammary epithelial cells of both normal and malignant origin. Tissue samples are digested with a mixture including the enzymes collagenase and hyaluronidase to produce clumps of cells substantially free from stroma and other undesired cellular material. Growing the clumps of cells in mass culture in an enriched medium containing particular growth factors allows for active cell proliferation and subculture. Clonal culture having plating efficiencies of up to 40% or greater may be obtained using individual cells derived from the mass culture by plating the cells on appropriate substrates in the enriched media. The clonal growth of cells so obtained is suitable for a quantitative assessment of the cytotoxicity of particular treatment. An exemplary assay for assessing the cytotoxicity of the drug adriamycin is presented.

  2. Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Severson, Paul L.; Vrba, Lukas; Stampfer, Martha R.; Futscher, Bernard W.

    2014-11-04

    Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post-stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutationsmore » were C:G>A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. In conclusion, the results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes.« less

  3. Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations

    SciTech Connect (OSTI)

    Garbe, James C.; Vrba, Lukas; Sputova, Klara; Fuchs, Laura; Novak, Petr; Brothman, Arthur R.; Jackson, Mark; Chin, Koei; LaBarge, Mark A.; Watts, George; Futscher, Bernard W.; Stampfer, Martha R.

    2014-10-29

    Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16INK4; replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agents are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages; in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional “passenger” errors carried forward into resulting carcinomas; (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers, but not required per se; bypassing the senescence barriers by direct targeting eliminated a need for genomic errors to generate immortalization. Achieving efficient HMEC immortalization, in the absence of “passenger” genomic errors, should facilitate examination of telomerase regulation during human carcinoma progression, and exploration of agents that could prevent immortalization.

  4. Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Garbe, James C.; Vrba, Lukas; Sputova, Klara; Fuchs, Laura; Novak, Petr; Brothman, Arthur R.; Jackson, Mark; Chin, Koei; LaBarge, Mark A.; Watts, George; et al

    2014-10-29

    Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16INK4; replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agentsmore » are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages; in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional “passenger” errors carried forward into resulting carcinomas; (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers, but not required per se; bypassing the senescence barriers by direct targeting eliminated a need for genomic errors to generate immortalization. Achieving efficient HMEC immortalization, in the absence of “passenger” genomic errors, should facilitate examination of telomerase regulation during human carcinoma progression, and exploration of agents that could prevent immortalization.« less

  5. Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells

    SciTech Connect (OSTI)

    Gong, Chunhong; Zhang, Yi; Shankaran, Harish; Resat, Haluk

    2015-01-01

    Human epidermal growth factor receptors (HER, also known as ErbB) drive cellular proliferation, pro-survival and stress responses by activating several downstream kinases, in particular ERK, p38, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, first three members of HER family (HER1-3) can form homo- and hetero-dimers. Based on the considerable evidence which suggest that every receptor dimer activates intracellular signaling pathways differentially, we hypothesized that the HER dimerization pattern is a better predictor of downstream signaling than the total receptor activation levels. We validated our hypothesis using a combination of model-based analysis to quantify the HER dimerization patterns and multi-factorial experiments where HER dimerization patterns and signaling crosstalk were rationally perturbed. We have measured the activation of HER1-3 receptors and of the sentinel signaling proteins ERK, AKT, p38, JNK, STAT3 as a function of time in a panel of human mammary epithelial (HME) cells expressing different levels of HER1-3 stimulated with various ligand combinations. Our analysis using multiple ways of clustering the activation data has confirmed that the HER receptor dimer is a better predictor of the signaling through p38, ERK and AKT pathways than the total HER receptor expression and activation levels. Targeted inhibition studies to identify the causal effects allowed us to obtain a consensus regulatory interaction model, which revealed that STAT3 occupies a central role in the crosstalk between the studied pathways.

  6. Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Gong, Chunhong; Zhang, Yi; Shankaran, Harish; Resat, Haluk

    2014-10-02

    Human epidermal growth factor receptors (HER, also known as ErbB) drive cellular proliferation, pro-survival and stress responses by activating several downstream kinases, in particular ERK, p38, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, first three members of HER family (HER1-3) can form homo- and hetero-dimers. Based on the considerable evidence which suggest that every receptor dimer activates intracellular signaling pathways differentially, we hypothesized that the HER dimerization pattern is a better predictor of downstream signaling than the total receptor activation levels. We validated our hypothesis using a combination of model-based analysis tomore » quantify the HER dimerization patterns and multi-factorial experiments where HER dimerization patterns and signaling crosstalk were rationally perturbed. We have measured the activation of HER1-3 receptors and of the sentinel signaling proteins ERK, AKT, p38, JNK, STAT3 as a function of time in a panel of human mammary epithelial (HME) cells expressing different levels of HER1-3 stimulated with various ligand combinations. Our analysis using multiple ways of clustering the activation data has confirmed that the HER receptor dimer is a better predictor of the signaling through p38, ERK and AKT pathways than the total HER receptor expression and activation levels. Targeted inhibition studies to identify the causal effects allowed us to obtain a consensus regulatory interaction model, which revealed that STAT3 occupies a central role in the crosstalk between the studied pathways.« less

  7. Self-organization is a dynamic and lineage-intrinsic property of mammary epithelial cells

    SciTech Connect (OSTI)

    Chanson, L.; Brownfield, D.; Garbe, J. C.; Kuhn, I.; Stampfer, M. R.; Bissell, M. J.; LaBarge, M. A.

    2011-02-07

    Loss of organization is a principle feature of cancers; therefore it is important to understand how normal adult multilineage tissues, such as bilayered secretory epithelia, establish and maintain their architectures. The self-organization process that drives heterogeneous mixtures of cells to form organized tissues is well studied in embryology and with mammalian cell lines that were abnormal or engineered. Here we used a micropatterning approach that confined cells to a cylindrical geometry combined with an algorithm to quantify changes of cellular distribution over time to measure the ability of different cell types to self-organize relative to each other. Using normal human mammary epithelial cells enriched into pools of the two principal lineages, luminal and myoepithelial cells, we demonstrated that bilayered organization in mammary epithelium was driven mainly by lineage-specific differential E-cadherin expression, but that P-cadherin contributed specifically to organization of the myoepithelial layer. Disruption of the actomyosin network or of adherens junction proteins resulted in either prevention of bilayer formation or loss of preformed bilayers, consistent with continual sampling of the local microenvironment by cadherins. Together these data show that self-organization is an innate and reversible property of communities of normal adult human mammary epithelial cells.

  8. Proliferation of Estrogen Receptor alpha Positive Mammary Epithelial Cells is Restrained by TGFbeta1 in Adult Mice

    SciTech Connect (OSTI)

    Ewan, Kenneth B.R.; Oketch-Rabah, Hellen A.; Ravani, Shraddha A.; Shyamala, G.; Moses, Harold L.; Barcellos-Hoff, Mary Helen

    2005-03-03

    Transforming growth factor {beta}1 (TGF{beta}1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor {alpha} (ER{alpha}) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF{beta}1 is necessary for the quiescence of ER{alpha}-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF{beta}1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF{beta} signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER{alpha}. To test whether TGF{beta} was functional, we examined genetically engineered mice with different levels of TGF{beta}1. ER{alpha} co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf{beta}1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF{beta}1 via the MMTV promoter suppressed proliferation of ER{alpha} positive cells. Thus, TGF{beta}1 activation functionally restrains ER{alpha} positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF{beta}1 dysregulation may promote proliferation of ER{alpha} positive cells associated with breast cancer risk in humans.

  9. Persistence of gamma-H2AX and 53BP1 foci in proliferating and nonproliferating human mammary epithelial cells after exposure to gamma-rays or iron ions

    SciTech Connect (OSTI)

    Groesser, Torsten; Chang, Hang; Fontenay, Gerald; Chen, James; Costes, Sylvain V.; Barcellos-Hoff, Mary Helen; Parvin, Bahram; Rydberg, Bjorn

    2010-12-22

    To investigate {gamma}-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein No. 1) foci formation and removal in proliferating and non-proliferating human mammary epithelial cells (HMEC) after exposure to sparsely and densely ionizing radiation under different cell culture conditions. HMEC cells were grown either as monolayers (2D) or in extracellular matrix to allow the formation of acinar structures in vitro (3D). Foci numbers were quantified by image analysis at various time points after exposure. Our results reveal that in non-proliferating cells under 2D and 3D cell culture conditions, iron-ion induced {gamma}-H2AX foci were still present at 72 h after exposure, although 53BP1 foci returned to control levels at 48 h. In contrast in proliferating HMEC, both {gamma}-H2AX and 53BP1 foci decreased to control levels during the 24-48 h time interval after irradiation under 2D conditions. Foci numbers decreased faster after {gamma}-ray irradiation and returned to control levels by 12 h regardless of marker, cell proliferation status, and cell culture condition. Conclusions: The disappearance of radiation induced {gamma}-H2AX and 53BP1 foci in HMEC have different dynamics that depend on radiation quality and proliferation status. Notably, the general patterns do not depend on the cell culture condition (2D versus 3D). We speculate that the persistent {gamma}-H2AX foci in iron-ion irradiated non-proliferating cells could be due to limited availability of double strand break (DSB) repair pathways in G0/G1-phase, or that repair of complex DSB requires replication or chromatin remodeling.

  10. Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells

    SciTech Connect (OSTI)

    Montesano, Roberto Sarkoezi, Rita; Schramek, Herbert

    2008-09-12

    Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMPs can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here, we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hitherto unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We suggest that the ability of BMP-4 to potentiate the mitogenic activity of multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression.

  11. Stepwise DNA Methylation Changes Are Linked to Escape from Defined Proliferation Barriers and Mammary Epithelial Cell Immortalization

    SciTech Connect (OSTI)

    Novak, Petr; Jensen, Taylor J.; Garbe, James C.; Stampfer, Martha R.; Futscher, Bernard W.

    2009-04-20

    The timing and progression of DNA methylation changes during carcinogenesis are not completely understood. To develop a timeline of aberrant DNA methylation events during malignant transformation, we analyzed genome-wide DNA methylation patterns in an isogenic human mammary epithelial cell (HMEC) culture model of transformation. To acquire immortality and malignancy, the cultured finite lifespan HMEC must overcome two distinct proliferation barriers. The first barrier, stasis, is mediated by the retinoblastoma protein and can be overcome by loss of p16(INK4A) expression. HMEC that escape stasis and continue to proliferate become genomically unstable before encountering a second more stringent proliferation barrier, telomere dysfunction due to telomere attrition. Rare cells that acquire telomerase expression may escape this barrier, become immortal, and develop further malignant properties. Our analysis of HMEC transitioning from finite lifespan to malignantly transformed showed that aberrant DNA methylation changes occur in a stepwise fashion early in the transformation process. The first aberrant DNA methylation step coincides with overcoming stasis, and results in few to hundreds of changes, depending on how stasis was overcome. A second step coincides with immortalization and results in hundreds of additional DNA methylation changes regardless of the immortalization pathway. A majority of these DNA methylation changes are also found in malignant breast cancer cells. These results show that large-scale epigenetic remodeling occurs in the earliest steps of mammary carcinogenesis, temporally links DNA methylation changes and overcoming cellular proliferation barriers, and provides a bank of potential epigenetic biomarkers that mayprove useful in breast cancer risk assessment.

  12. EGF stimulates Mg{sup 2+} influx in mammary epithelial cells

    SciTech Connect (OSTI)

    Trapani, Valentina; Arduini, Daniela; Luongo, Francesca; Wolf, Federica I.

    2014-11-28

    Highlights: EGF stimulation potentiates Mg{sup 2+} influx into epithelial cells. EGF-induced Mg{sup 2+} influx does not depend on the concomitantly induced Ca{sup 2+} signal. EGF-induced Ca{sup 2+} signal is dependent on the presence of extracellular Mg{sup 2+}. New players in EGF-mediated signaling might be exploited as therapeutic targets. - Abstract: Magnesium is well established as a fundamental factor that regulates cell proliferation. However, the molecular mechanisms linking mitogenic signals, extracellular magnesium availability and intracellular effectors are still largely unknown. In the present study we sought to determine whether EGF regulates magnesium homeostasis in normal HC11 mammary epithelial cells. To this end, we measured Mg{sup 2+} and Ca{sup 2+} fluxes by confocal imaging in live cells loaded with specific fluorescent ion indicators (Mag-Fluo-4 and Fluo-4, respectively). EGF stimulation induces a rapid and sustained increase in intracellular Mg{sup 2+}, concomitantly with a rise in intracellular calcium. The increase in intracellular Mg{sup 2+} derives from an influx from the extracellular compartment, and does not depend on Ca{sup 2+}. On the contrary, the increase in intracellular Ca{sup 2+} derives from intracellular stores, and is impaired in the absence of extracellular magnesium. Inhibition of the EGF receptor tyrosine kinase by Tyrphostin AG1478 markedly inhibits EGF-induced Mg{sup 2+} and Ca{sup 2+} signals. These findings demonstrate that not only does Mg{sup 2+} influx represent an important step in the physiological response of epithelial cells to EGF, but unexpectedly the EGF-induced Mg{sup 2+} influx is essential for the Ca{sup 2+} signal to occur.

  13. Response of Human Lung Epithelial Cells to Engineered Nanoparticles...

    Office of Scientific and Technical Information (OSTI)

    Response of Human Lung Epithelial Cells to Engineered Nanoparticles. Citation Details In-Document Search Title: Response of Human Lung Epithelial Cells to Engineered Nanoparticles. ...

  14. Matrix Metalloproteinase Stromelysin-1 Triggers a Cascade of Molecular Alterations that leads to stable epithelial-to-Mesenchymal Conversion and a Premalignant Phenotype in Mammary Epithelial Cells

    SciTech Connect (OSTI)

    Lochter, A.; Galosy, S.; Muschler, J.; Freedman, N.; Werb, Z.; Bissell, M.J.

    1997-08-11

    Matrix metalloproteinases (MMPs) regulate ductal morphogenesis, apoptosis, and neoplastic progression in mammary epithelial cells. To elucidate the direct effects of MMPs on mammary epithelium, we generated functionally normal cells expressing an inducible autoactivating stromelysin-1 (SL-1) transgene. Induction of SL-1 expression resulted in cleavage of E-cadherin, and triggered progressive phenotypic conversion characterized by disappearance of E-cadherin and catenins from cell-cell contacts, downregulation of cytokeratins, upregulation of vimentin, induction of keratinocyte growth factor expression and activation, and upregulation of endogenous MMPs. Cells expressing SL-1 were unable to undergo lactogenic differentiation and became invasive. Once initiated, this phenotypic conversion was essentially stable, and progressed even in the absence of continued SL-1 expression. These observations demonstrate that inappropriate expression of SL-1 initiates a cascade of events that may represent a coordinated program leading to loss of the differentiated epithelial phenotype and gain of some characteristics of tumor cells. Our data provide novel insights into how MMPs function in development and neoplastic conversion.

  15. Analysis of differential protein expression in normal and neoplastic human breast epithelial cell lines

    SciTech Connect (OSTI)

    Williams, K.; Chubb, C.; Huberman, E.; Giometti, C.S.

    1997-07-01

    High resolution two dimensional get electrophoresis (2DE) and database analysis was used to establish protein expression patterns for cultured normal human mammary epithelial cells and thirteen breast cancer cell lines. The Human Breast Epithelial Cell database contains the 2DE protein patterns, including relative protein abundances, for each cell line, plus a composite pattern that contains all the common and specifically expressed proteins from all the cell lines. Significant differences in protein expression, both qualitative and quantitative, were observed not only between normal cells and tumor cells, but also among the tumor cell lines. Eight percent of the consistently detected proteins were found in significantly (P < 0.001) variable levels among the cell lines. Using a combination of immunostaining, comigration with purified protein, subcellular fractionation, and amino-terminal protein sequencing, we identified a subset of the differentially expressed proteins. These identified proteins include the cytoskeletal proteins actin, tubulin, vimentin, and cytokeratins. The cell lines can be classified into four distinct groups based on their intermediate filament protein profile. We also identified heat shock proteins; hsp27, hsp60, and hsp70 varied in abundance and in some cases in the relative phosphorylation levels among the cell lines. Finally, we identified IMP dehydrogenase in each of the cell lines, and found the levels of this enzyme in the tumor cell lines elevated 2- to 20-fold relative to the levels in normal cells.

  16. Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition

    SciTech Connect (OSTI)

    Andarawewa, Kumari L.; Erickson, Anna C.; Chou, William S.; Costes, Sylvain; Gascard, Philippe; Mott, Joni D.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen

    2007-04-06

    Transforming growth factor {beta}1 (TGF{beta}) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.

  17. Chlorobenzene induces oxidative stress in human lung epithelial cells in vitro

    SciTech Connect (OSTI)

    Feltens, Ralph; Moegel, Iljana; Roeder-Stolinski, Carmen; Simon, Jan-Christoph; Herberth, Gunda; Lehmann, Irina

    2010-01-01

    Chlorobenzene is a volatile organic compound (VOC) that is widely used as a solvent, degreasing agent and chemical intermediate in many industrial settings. Occupational studies have shown that acute and chronic exposure to chlorobenzene can cause irritation of the mucosa of the upper respiratory tract and eyes. Using in vitro assays, we have shown in a previous study that human bronchial epithelial cells release inflammatory mediators such as the cytokine monocyte chemoattractant protein-1 (MCP-1) in response to chlorobenzene. This response is mediated through the NF-kappaB signaling pathway. Here, we investigated the effects of monochlorobenzene on human lung cells, with emphasis on potential alterations of the redox equilibrium to clarify whether the chlorobenzene-induced inflammatory response in lung epithelial cells is caused via an oxidative stress-dependent mechanism. We found that expression of cellular markers for oxidative stress, such as heme oxygenase 1 (HO-1), glutathione S-transferase pi1 (GSTP1), superoxide dismutase 1 (SOD1), prostaglandin-endoperoxide synthase 2 (PTGS2) and dual specificity phosphatase 1 (DUSP1), were elevated in the presence of monochlorobenzene. Likewise, intracellular reactive oxygen species (ROS) were increased in response to exposure. However, in the presence of the antioxidants N-(2-mercaptopropionyl)-glycine (MPG) or bucillamine, chlorobenzene-induced upregulation of marker proteins and release of the inflammatory mediator MCP-1 are suppressed. These results complement our previous findings and point to an oxidative stress-mediated inflammatory response following chlorobenzene exposure.

  18. Theophylline prevents NAD{sup +} depletion via PARP-1 inhibition in human pulmonary epithelial cells

    SciTech Connect (OSTI)

    Moonen, Harald J.J. . E-mail: h.moonen@grat.unimaas.nl; Geraets, Liesbeth; Vaarhorst, Anika; Bast, Aalt; Wouters, Emiel F.M.; Hageman, Geja J.

    2005-12-30

    Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD{sup +}, resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD{sup +} pool, and of NAD{sup +}-dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD{sup +} levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies.

  19. Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

    SciTech Connect (OSTI)

    Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J.

    2015-07-01

    Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells provide a

  20. Quantitative proteomic analysis of human breast epithelial cells with differential telomere length

    SciTech Connect (OSTI)

    Yu, Li-Rong . E-mail: lyu@ncifcrf.gov; Chan, King C.; Tahara, Hidetoshi; Lucas, David A.; Chatterjee, Koushik; Issaq, Haleem J.; Veenstra, Timothy D. . E-mail: veenstra@ncifcrf.gov

    2007-05-18

    Telomeres play important functional roles in cell proliferation, cell cycle regulation, and genetic stability, in which telomere length is critical. In this study, quantitative proteome comparisons for the human breast epithelial cells with short and long telomeres (184-hTERT{sub L} vs. 184-hTERT{sub S} and 90P-hTERT{sub L} vs. 90P-hTERT{sub S}), resulting from transfection of the human telomerase reverse transcriptase (hTERT) gene, were performed using cleavable isotope-coded affinity tags. More than 2000 proteins were quantified in each comparative experiment, with approximately 77% of the proteins identified in both analyses. In the cells with long telomeres, significant and consistent alterations were observed in metabolism (amino acid, nucleotide, and lipid metabolism), genetic information transmission (transcription and translation regulation, spliceosome and ribosome complexes), and cell signaling. Interestingly, the DNA excision repair pathway is enhanced, while integrin and its ligands are downregulated in the cells with long telomeres. These results may provide valuable information related to telomere functions.

  1. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization

    SciTech Connect (OSTI)

    McCall, Ingrid C.; Betanzos, Abigail; Weber, Dominique A.; Nava, Porfirio; Miller, Gary W.; Parkos, Charles A.

    2009-11-15

    Phenol contamination of soil and water has raised concerns among people living near phenol-producing factories and hazardous waste sites containing the chemical. Phenol, particularly in high concentrations, is an irritating and corrosive substance, making mucosal membranes targets of toxicity in humans. However, few data on the effects of phenol after oral exposure exist. We used an in vitro model employing human intestinal epithelial cells (SK-CO15) cultured on permeable supports to examine effects of phenol on epithelial barrier function. We hypothesized that phenol disrupts epithelial barrier by altering tight junction (TJ) protein expression. The dose-response effect of phenol on epithelial barrier function was determined using transepithelial electrical resistance (TER) and FITC-dextran permeability measurements. We studied phenol-induced changes in cell morphology and expression of several tight junction proteins by immunofluorescence and Western blot analysis. Effects on cell viability were assessed by MTT, Trypan blue, propidium iodide and TUNEL staining. Exposure to phenol resulted in decreased TER and increased paracellular flux of FITC-dextran in a dose-dependent manner. Delocalization of claudin-1 and ZO-1 from TJs to cytosol correlated with the observed increase in permeability after phenol treatment. Additionally, the decrease in TER correlated with changes in the distribution of a membrane raft marker, suggesting phenol-mediated effects on membrane fluidity. Such observations were independent of effects of phenol on cell viability as enhanced permeability occurred at doses of phenol that did not cause cell death. Overall, these findings suggest that phenol may affect transiently the lipid bilayer of the cell membrane, thus destabilizing TJ-containing microdomains.

  2. Continuous human cell lines and method of making same

    DOE Patents [OSTI]

    Stampfer, Martha R.

    1989-01-01

    Substantially genetically stable continuous human cell lines derived from normal human mammary epithelial cells (HMEC) and processes for making and using the same. In a preferred embodiment, the cell lines are derived by treating normal human mammary epithelial tissue with a chemical carcinogen such as benzo[a]pyrene. The novel cell lines serve as useful substrates for elucidating the potential effects of a number of toxins, carcinogens and mutagens as well as of the addition of exogenous genetic material. The autogenic parent cells from which the cell lines are derived serve as convenient control samples for testing. The cell lines are not neoplastically transformed, although they have acquired several properties which distinguish them from their normal progenitors.

  3. Continuous human cell lines and method of making same

    DOE Patents [OSTI]

    Stampfer, M.R.

    1985-07-01

    Substantially genetically stable continuous human cell lines derived from normal human mammary epithelial cells (HMEC) and processes for making and using the same. In a preferred embodiment, the cell lines are derived by treating normal human mammary epithelial tissue with a chemical carcinogen such as benzo(a)pyrene. The novel cell lines serve as useful substrates for elucidating the potential effects of a number of toxins, carcinogens and mutagens as well as of the addition of exogenous genetic material. The autogenic parent cells from which the cell lines are derived serve as convenient control samples for testing. The cell lines are not neoplastically transformed, although they have acquired several properties which distinguish them from their normal progenitors. 2 tabs.

  4. NiO nanoparticles induce apoptosis through repressing SIRT1 in human bronchial epithelial cells

    SciTech Connect (OSTI)

    Duan, Wei-Xia; He, Min-Di; Mao, Lin; Qian, Feng-Hua; Li, Yu-Ming; Pi, Hui-Feng; Liu, Chuan; Chen, Chun-Hai; Lu, Yong-Hui; Cao, Zheng-Wang; Zhang, Lei; Yu, Zheng-Ping; Zhou, Zhou

    2015-07-15

    With application of nano-sized nickel-containing particles (Nano-Ni) expanding, the health concerns about their adverse effects on the pulmonary system are increasing. However, the mechanisms for the pulmonary toxicity of these materials remain unclear. In the present study, we focused on the impacts of NiO nanoparticles (NiONPs) on sirtuin1 (SIRT1), a NAD-dependent deacetylase, and investigated whether SIRT1 was involved in NiONPs-induced apoptosis. Although the NiONPs tended to agglomerate in fluid medium, they still entered into the human bronchial epithelial cells (BEAS-2B) and released Ni{sup 2+} inside the cells. NiONPs at doses of 5, 10, and 20 μg/cm{sup 2} inhibited the cell viability. NiONPs' produced cytotoxicity was demonstrated through an apoptotic process, indicated by increased numbers of Annexin V positive cells and caspase-3 activation. The expression of SIRT1 was markedly down-regulated by the NiONPs, accompanied by the hyperacetylation of p53 (tumor protein 53) and overexpression of Bax (Bcl-2-associated X protein). However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs-induced apoptosis and activation of p53 and Bax. Our results suggest that the repression of SIRT1 may underlie the NiONPs-induced apoptosis via p53 hyperacetylation and subsequent Bax activation. Because SIRT1 participates in multiple biologic processes by deacetylation of dozens of substrates, this knowledge of the impact of NiONPs on SIRT1 may lead to an improved understanding of the toxic mechanisms of Nano-Ni and provide a molecular target to antagonize Nano-Ni toxicity. - Highlights: • NiONPs were taken up by BEAS-2B cells and released Ni{sup 2+}. • NiONPs produced cytotoxicity was demonstrated through an apoptotic process. • NiONPs repressed SIRT1 expression and activated p53 and Bax. • Overexpression of SIRT1 attenuated NiONPs-induced apoptosis via deacetylation p53.

  5. A tool for the quantitative spatial analysis of mammary gland epithelium

    SciTech Connect (OSTI)

    Ortiz de Solorzano, Carlos; Fernandez-Gonzalez, Rodrigo

    2004-04-09

    In this paper we present a method for the spatial analysis of complex cellular systems based on a multiscale study of neighborhood relationships. A function to measure those relationships, M, is introduced. The refined Relative Neighborhood Graph is then presented as a method to establish vicinity relationships within layered cellular structures, and particularized to epithelial cell nuclei in the mammary gland. Finally, the method is illustrated with two examples that show interactions within one population of epithelial cells and between two different populations.

  6. SU-E-J-105: Stromal-Epithelial Responses to Fractionated Radiotherapy

    SciTech Connect (OSTI)

    Qayyum, M

    2014-06-01

    Purpose: The stromal-epithelial-cell interactions that are responsible for directing normal breast-tissue development and maintenance play a central role in the progression of breast cancer. In the present study, we developed three-dimensional (3-D) cell co-cultures used to study cancerous mammary cell responses to fractionated radiotherapy. In particular, we focused on the role of the reactive stroma in determining the therapeutic ratio for postsurgical treatment. Methods: Cancerous human mammary epithelial cells were cultured in a 3-D collagen matrix with human fibroblasts stimulated by various concentrations of transforming growth factor beta 1 (TGF-?1). These culture samples were designed to model the post-lumpectomy mammary stroma in the presence of residual cancer cells. We tracked over time the changes in medium stiffness, fibroblast-cell activation (conversion to cancer activated fibroblasts (CAF)), and proliferation of both cell types under a variety of fractionated radiotherapy protocols. Samples were exposed to 6 MV X-rays from a linear accelerator in daily fraction sizes of 90, 180 and 360 cGy over five days in a manner consistent with irradiation exposure during radiotherapy. Results: We found in fractionation studies with fibroblasts and CAF that higher doses per fraction may be more effective early on in deactivating cancer-harboring cellular environments. Higher-dose fraction schemes inhibit contractility in CAF and prevent differentiation of fibroblasts, thereby metabolically uncoupling tumor cells from their surrounding stroma. Yet, over a longer time period, the higher dose fractions may slow wound healing and increase ECM stiffening that could stimulate proliferation of surviving cancer cells. Conclusion: The findings suggest that dose escalation to the region with residual disease can deactivate the reactive stroma, thus minimizing the cancer promoting features of the cellular environment. Large-fraction irradiation may be used to sterilize

  7. Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

    SciTech Connect (OSTI)

    Choi, Hye Jin; Lee, Dong-Hyung; Park, Seong-Hwan; Kim, Juil; Do, Kee Hun; An, Tae Jin; Ahn, Young Sup; Park, Chung Berm; Moon, Yuseok; Medical Research Institute and Research Institute for Basic Sciences, Pusan National University, Busan

    2011-09-30

    Highlights: {yields} As a target of oncogene RhoA-linked signal, a prostaglandin metabolism is assessed. {yields} RhoA activation increases PGE{sub 2} levels and its metabolic enzyme mPGES-1. {yields} RhoA-activated NF-{kappa}B and EGR-1 are positively involved in mPGES-1 induction. -- Abstract: Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E{sub 2} (PGE{sub 2}), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE{sub 2} levels and gene expression of the rate-limiting PGE{sub 2} producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1{beta}-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1{beta}-mediated phosphorylated nuclear factor-{kappa}B and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE{sub 2} production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.

  8. Biomolecular interactions and responses of human epithelial and macrophage cells to engineered nanomaterials.

    SciTech Connect (OSTI)

    Kotula, Paul Gabriel; Brozik, Susan Marie; Achyuthan, Komandoor E.; Greene, Adrienne Celeste; Timlin, Jerilyn Ann; Bachand, George David; Bachand, Marlene; Aaron, Jesse S.; Allen, Amy; Seagrave, Jean-Clare

    2011-12-01

    Engineered nanomaterials (ENMs) are increasingly being used in commercial products, particularly in the biomedical, cosmetic, and clothing industries. For example, pants and shirts are routinely manufactured with silver nanoparticles to render them 'wrinkle-free.' Despite the growing applications, the associated environmental health and safety (EHS) impacts are completely unknown. The significance of this problem became pervasive within the general public when Prince Charles authored an article in 2004 warning of the potential social, ethical, health, and environmental issues connected to nanotechnology. The EHS concerns, however, continued to receive relatively little consideration from federal agencies as compared with large investments in basic nanoscience R&D. The mounting literature regarding the toxicology of ENMs (e.g., the ability of inhaled nanoparticles to cross the blood-brain barrier; Kwon et al., 2008, J. Occup. Health 50, 1) has spurred a recent realization within the NNI and other federal agencies that the EHS impacts related to nanotechnology must be addressed now. In our study we proposed to address critical aspects of this problem by developing primary correlations between nanoparticle properties and their effects on cell health and toxicity. A critical challenge embodied within this problem arises from the ability to synthesize nanoparticles with a wide array of physical properties (e.g., size, shape, composition, surface chemistry, etc.), which in turn creates an immense, multidimensional problem in assessing toxicological effects. In this work we first investigated varying sizes of quantum dots (Qdots) and their ability to cross cell membranes based on their aspect ratio utilizing hyperspectral confocal fluorescence microscopy. We then studied toxicity of epithelial cell lines that were exposed to different sized gold and silver nanoparticles using advanced imaging techniques, biochemical analyses, and optical and mass spectrometry methods

  9. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia

    SciTech Connect (OSTI)

    Alcaraz, Jordi; Xu, Ren; Mori, Hidetoshi; Nelson, Celeste M.; Mroue, Rana; Spencer, Virginia A.; Brownfield, Doug; Radisky, Derek C.; Bustamante, Carlos; Bissell, Mina J.

    2008-10-20

    In the mammary gland, epithelial cells are embedded in a 'soft' environment and become functionally differentiated in culture when exposed to a laminin-rich extracellular matrix gel. Here, we define the processes by which mammary epithelial cells integrate biochemical and mechanical extracellular cues to maintain their differentiated phenotype. We used single cells cultured on top of gels in conditions permissive for {beta}-casein expression using atomic force microscopy to measure the elasticity of the cells and their underlying substrata. We found that maintenance of {beta}-casein expression required both laminin signalling and a 'soft' extracellular matrix, as is the case in normal tissues in vivo, and biomimetic intracellular elasticity, as is the case in primary mammary epithelial organoids. Conversely, two hallmarks of breast cancer development, stiffening of the extracellular matrix and loss of laminin signalling, led to the loss of {beta}-casein expression and non-biomimetic intracellular elasticity. Our data indicate that tissue-specific gene expression is controlled by both the tissues unique biochemical milieu and mechanical properties, processes involved in maintenance of tissue integrity and protection against tumorigenesis.

  10. Human bronchial epithelial BEAS-2B cells, an appropriate in vitro model to study heavy metals induced carcinogenesis

    SciTech Connect (OSTI)

    Park, Youn-hee; Kim, Donghern; Dai, Jin; Zhang, Zhuo

    2015-09-15

    Occupational and environmental exposure to arsenic (III) and chromium VI (Cr(VI)) have been confirmed to cause lung cancer. Mechanisms of these metals carcinogenesis are still under investigation. Selection of cell lines to be used is essential for the studies. Human bronchial epithelial BEAS-2B cells are the cells to be utilized by most of scientists. However, due to p53 missense mutation (CCG → TCG) at codon 47 and the codon 72 polymorphism (CGC → CCC) in BEAS-2B cells, its usage has frequently been questioned. The present study has examined activity and expression of 53 and its downstream target protein p21 upon acute or chronic exposure of BEAS-2B cells to arsenic and Cr(VI). The results show that short-term exposure of BEAS-2B cells to arsenic or Cr(VI) was able to activate both p53 and p21. Chronic exposure of BEAS-2B cells to these two metals caused malignant cell transformation and tumorigenesis. In arsenic-transformed BEAS-2B cells reductions in p53 promoter activity, mRNA expression, and phosphorylation of p53 at Ser392 were observed, while the total p53 protein level remained the same compared to those in passage-matched parent ones. p21 promoter activity and expression were decreased in arsenic-transformed cells. Cr(VI)-transformed cells exhibit elevated p53 promoter activity, mRNA expression, and phosphorylation at Ser15, but reduced phosphorylation at Ser392 and total p53 protein level compared to passage-matched parent ones. p21 promoter activity and expression were elevated in Cr(VI)-transformed cells. These results demonstrate that p53 is able to respond to exposure of arsenic or Cr(VI), suggesting that BEAS-2B cells are an appropriate in vitro model to investigate arsenic or Cr(VI) induced lung cancer. - Highlights: • Short-term exposure of BEAS-2B cells to arsenic or Cr(VI) activates p53 and p21. • Chronic exposure of BEAS-2B cells to arsenic or Cr(VI) causes cell transformation and tumorigenesis. • Arsenic-transformed cells exhibit

  11. Role of reactive oxygen species in arsenic-induced transformation of human lung bronchial epithelial (BEAS-2B) cells

    SciTech Connect (OSTI)

    Zhang, Zhuo; Pratheeshkumar, Poyil; Budhraja, Amit; Son, Young-Ok; Kim, Donghern; Shi, Xianglin

    2015-01-09

    Highlights: • Short term exposure of cells to arsenic causes ROS generation. • Chronical exposure of cells to arsenic causes malignant cell transformation. • Inhibition of ROS generation reduces cell transformation by arsenic. • Arsenic-transformed cells exhibit reduced capacity of generating ROS. • Arsenic-transformed cells exhibit increased levels of antioxidants. - Abstract: Arsenic is an environmental carcinogen, its mechanisms of carcinogenesis remain to be investigated. Reactive oxygen species (ROS) are considered to be important. A previous study (Carpenter et al., 2011) has measured ROS level in human lung bronchial epithelial (BEAS-2B) cells and arsenic-transformed BEAS-2B cells and found that ROS levels were higher in transformed cells than that in parent normal cells. Based on these observations, the authors concluded that cell transformation induced by arsenic is mediated by increased cellular levels of ROS. This conclusion is problematic because this study only measured the basal ROS levels in transformed and parent cells and did not investigate the role of ROS in the process of arsenic-induced cell transformation. The levels of ROS in arsenic-transformed cells represent the result and not the cause of cell transformation. Thus question concerning whether ROS are important in arsenic-induced cell transformation remains to be answered. In the present study, we used expressions of catalase (antioxidant against H{sub 2}O{sub 2}) and superoxide dismutase 2 (SOD2, antioxidant against O{sub 2}{sup ·−}) to decrease ROS level and investigated their role in the process of arsenic-induced cell transformation. Our results show that inhibition of ROS by antioxidant enzymes decreased arsenic-induced cell transformation, demonstrating that ROS are important in this process. We have also shown that in arsenic-transformed cells, ROS generation was lower and levels of antioxidants are higher than those in parent cells, in a disagreement with the previous

  12. Nitrative DNA damage induced by multi-walled carbon nanotube via endocytosis in human lung epithelial cells

    SciTech Connect (OSTI)

    Guo, Feiye; Ma, Ning; Horibe, Yoshiteru; Kawanishi, Shosuke; Murata, Mariko; Hiraku, Yusuke

    2012-04-15

    Carbon nanotube (CNT) has a promising usage in the field of material science for industrial purposes because of its unique physicochemical property. However, intraperitoneal administration of CNT was reported to cause mesothelioma in experimental animals. Chronic inflammation may contribute to carcinogenesis induced by fibrous materials. 8-Nitroguanine is a mutagenic DNA lesion formed during inflammation and may play a role in CNT-induced carcinogenesis. In this study, we examined 8-nitroguanine formation in A549 human lung alveolar epithelial cells treated with multi-walled CNT (MWCNT) by fluorescent immunocytochemistry. Both MWCNTs with diameter of 2030 nm (CNT20) and 4070 nm (CNT40) significantly induced 8-nitroguanine formation at 5 and 10 ?g/ml (p < 0.05), which persisted for 24 h, although there was no significant difference in DNA-damaging abilities of these MWCNTs. MWCNTs significantly induced the expression of inducible nitric oxide synthase (iNOS) for 24 h (p < 0.05). MWCNTs also significantly increased the level of nitrite, a hydrolysis product of oxidized NO, in the culture supernatant at 4 and 8 h (p < 0.05). MWCNT-induced 8-nitroguanine formation and iNOS expression were largely suppressed by inhibitors of iNOS (1400 W), nuclear factor-?B (Bay11-7082), actin polymerization (cytochalasin D), caveolae-mediated endocytosis (methyl-?-cyclodextrin, MBCD) and clathrin-mediated endocytosis (monodansylcadaverine, MDC). Electron microscopy revealed that MWCNT was mainly located in vesicular structures in the cytoplasm, and its cellular internalization was reduced by MBCD and MDC. These results suggest that MWCNT is internalized into cells via clathrin- and caveolae-mediated endocytosis, leading to inflammatory reactions including iNOS expression and resulting nitrative DNA damage, which may contribute to carcinogenesis. Highlights: ?Multi-walled carbon nanotube (MWCNT) caused DNA damage in A549 cells. ?MWCNT formed 8-nitroguanine, a DNA lesion associated

  13. Long-term low-dose ?-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway

    SciTech Connect (OSTI)

    Liu, Weili; Xiao, Linlin; Dong, Chen; He, Mingyuan; Pan, Yan; Xie, Yuexia; Tu, Wenzhi; Fu, Jiamei; Shao, Chunlin

    2014-05-09

    Highlights: Multi-exposures of 25 mGy ?-ray enhanced cell proliferation, adhesion, and invasion. MAPK/Akt but not JNK/P66 was positively correlated with cell invasive phenotypes. LDR of ?-irradiation triggers cell malignant transformation through MAPK/Akt. - Abstract: Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cells Beas-2B were fractionally irradiated with 0.025 Gy ?-particles for 8 times in total and then further cultured for 12 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 12 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of ?-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway.

  14. Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development

    SciTech Connect (OSTI)

    Thomasset, N.; Lochter, A.; Sympson, C.J.; Lund, L.R.; Williams, D.R.; Behrendtsen, O.; Werb, Z.; Bissell, M.J.

    1998-04-24

    Extracellular matrix and extracellular matrix-degrading matrix metalloproteinases play a key role in interactions between the epithelium and the mesenchyme during mammary gland development and disease. In patients with breast cancer, the mammary mesenchyme undergoes a stromal reaction, the etiology of which is unknown. We previously showed that targeting of an autoactivating mutant of the matrix metalloproteinase stromelysin-1 to mammary epithelia of transgenic mice resulted in reduced mammary function during pregnancy and development of preneoplastic and neoplastic lesions. Here we examine the cascade of alterations before breast tumor formation in the mammary gland stroma once the expression of the stromelysin-1 transgene commences. Beginning in postpubertal virgin animals, low levels of transgene expression in mammary epithelia led to increased expression of endogenous stromelysin-1 in stromal fibroblasts and up-regulation of other matrix metalloproteinases, without basement membrane disruption. These changes were accompanied by the progressive development of a compensatory reactive stroma, characterized by increased collagen content and vascularization in glands from virgin mice. This remodeling of the gland affected epithelial-mesenchymal communication as indicated by inappropriate expression of tenascin-C starting by day 6 of pregnancy. This, together with increased transgene expression, led to basement membrane disruption starting by day 15 of pregnancy. We propose that the highly reactive stroma provides a prelude to breast epithelial tumors observed in these animals. Epithelial development depends on an exquisite series of inductive and instructive interactions between the differentiating epithelium and the mesenchymal (stromal) compartment. The epithelium, which consists of luminal and myoepithelial cells, is separated from the stroma by a basement membrane (BM), which plays a central role in mammary gland homeostasis and gene expression. In vivo, stromal

  15. Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Nguyen, David H.; Ouyang, Haoxu; Mao, Jian-Hua; Hlatky, Lynn; Barcellos-Hoff, M. H.

    2014-12-01

    Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53-null mammary tissue fragments and monitored for one year. Tumors arose sooner from adultmore » hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80% JH vs. 70% AH), but JH tumors were significantly more ER-immunoreactive (P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. Lastly, these data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.« less

  16. Cytochrome P450 2A13 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1-induced DNA damage

    SciTech Connect (OSTI)

    Yang, Xuejiao; Zhang, Zhan; Wang, Xichen; Wang, Yun; Zhang, Xiaoming; Lu, Huiyuan; Wang, Shou-Lin

    2013-07-15

    Cytochrome P450 2A13 (CYP2A13) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 (AFB1). Our previous study suggested that CYP2A13 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells (BEAS-2B). However, the role of CYP2A13 in AFB1-induced DNA damage is unclear. Using BEAS-2B cells that stably express CYP2A13 (B-2A13), CYP1A2 (B-1A2), and CYP2A6 (B-2A6), we compared their effects in AFB1-induced DNA adducts, DNA damage, and cell cycle changes. BEAS-2B cells that were transfected with vector (B-vector) were used as a control. The results showed that AFB1 (580 nM) dose- and time-dependently induced DNA damage in B-2A13 cells. AFB1 at 10 and 80 nM significantly augmented this effect in B-2A13 and B-1A2 cells, respectively. B-2A6 cells showed no obvious DNA damage, similar to B-vector cells and the vehicle control. Similarly, compared with B-vector, B-1A2 or B-2A6 cells, B-2A13 cells showed more sensitivity in AFB1-induced ?H2AX expression, DNA adduct 8-hydroxy-deoxyguanosine formation, and S-phase cell-cycle arrest. Furthermore, AFB1 activated the proteins related to DNA damage responses, such as ATM, ATR, Chk2, p53, BRCA1, and H2AX, rather than the proteins related to DNA repair. These effects could be almost completely inhibited by 100 ?M nicotine (a substrate of CYP2A13) or 1 ?M 8-methoxypsoralen (8-MOP; an inhibitor of CYP enzyme). Collectively, these findings suggest that CYP2A13 plays an important role in low-concentration AFB1-induced DNA damage, possibly linking environmental airborne AFB1 to genetic injury in human respiratory system. - Highlights: CYP2A13 plays a critical role in low concentration of AFB1-induced DNA damage. B-2A13 cells were more sensitive to AFB1 than B-1A2 cells and B-2A6 cells. AFB1 dose- and time-dependently induced DNA damage in B-2A13 cells AFB1-induced DNA adducts and damage can be inhibited by nicotine and 8-MOP.

  17. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    SciTech Connect (OSTI)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2014-12-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  18. Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

    SciTech Connect (OSTI)

    Luo, Fei; Xu, Yuan; Ling, Min; Zhao, Yue; Xu, Wenchao; Liang, Xiao; Jiang, Rongrong; Wang, Bairu; Bian, Qian; Liu, Qizhan

    2013-11-15

    Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3 days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis. - Highlights: Arsenite evokes IL-6 secretion. IL-6 autocrine mediates STAT3 signaling and up-regulates miR-21expression. Inflammation is involved in arsenite-induced EMT.

  19. Epithelialmesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanism in lung epithelial cells

    SciTech Connect (OSTI)

    Ding, Song-Ze; Yang, Yu-Xiu; Li, Xiu-Ling; Michelli-Rivera, Audrey; Han, Shuang-Yin; Wang, Lei; Pratheeshkumar, Poyil; Wang, Xin; Lu, Jian; Yin, Yuan-Qin; Budhraja, Amit; Hitron, Andrew J.

    2013-05-15

    Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelialmesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology. Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhancement the binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention. - Graphical abstract: Epithelialmesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanisms in lung epithelial cells. - Highlights: We study if Cr(VI) might induce EMT and invasion in epithelial cells. Cr(VI) induces EMT by altering E-cadherin and vimentin expression. It also increases cell invasion and promotes oncogenic transformation. Catalase reduces Cr(VI)-induced EMT, invasion and

  20. A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Vrba, Lukas; Garbe, James C.; Stampfer, Martha R.; Futscher, Bernard W.

    2015-10-19

    Immortality is an essential characteristic of human carcinoma cells. We recently developed an efficient, reproducible method that immortalizes human mammary epithelial cells (HMEC) in the absence of gross genomic changes by targeting 2 critical senescence barriers. Consistent transcriptomic changes associated with immortality were identified using microarray analysis of isogenic normal finite pre-stasis, abnormal finite post-stasis, and immortal HMECs from 4 individuals. A total of 277 genes consistently changed in cells that transitioned from post-stasis to immortal. Gene ontology analysis of affected genes revealed biological processes significantly altered in the immortalization process. These immortalization-associated changes showed striking similarity to the genemore » expression changes seen in The Cancer Genome Atlas (TCGA) clinical breast cancer data. The most dramatic change in gene expression seen during the immortalization step was the downregulation of an unnamed, incompletely annotated transcript that we called MORT, for mortality, since its expression was closely associated with the mortal, finite lifespan phenotype. We show here that MORT (ZNF667-AS1) is expressed in all normal finite lifespan human cells examined to date and is lost in immortalized HMEC. MORT gene silencing at the mortal/immortal boundary was due to DNA hypermethylation of its CpG island promoter. This epigenetic silencing is also seen in human breast cancer cell lines and in a majority of human breast tumor tissues. The functional importance of DNA hypermethylation in MORT gene silencing is supported by the ability of 5-aza-2'- deoxycytidine to reactivate MORT expression. Analysis of TCGA data revealed deregulation of MORT expression due to DNA hypermethylation in 15 out of the 17 most common human cancers. In conclusion, the epigenetic silencing of MORT in a large majority of the common human cancers suggests a potential fundamental role in cellular immortalization during human

  1. Nesfatin-1 inhibits ovarian epithelial carcinoma cell proliferation in vitro

    SciTech Connect (OSTI)

    Xu, Yang; Pang, Xiaoyan; Dong, Mei; Wen, Fang Zhang, Yi

    2013-11-01

    Highlights: Nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest. Nesfatin-1 enhances HO-8910 cell apoptosis. Nesfatin-1 inhibits HO-8910 cell proliferation via mTOR and RhoA/ROCK signaling pathway. The first report of nesfatin-1-mediated proliferation in ovarian epithelial carcinoma. -- Abstract: Nesfatin-1, an 82-amino-acid peptide derived from a 396-amino-acid precursor protein nucleobindin 2 (NUCB2), was originally identified in hypothalamic nuclei involved in the regulation of food intake. It was recently reported that nesfatin-1 is a novel depot specific adipokine preferentially produced by subcutaneous tissue, with obesity- and food deprivation-regulated expression. Although a relation between ovarian cancer mortality and obesity has been previously established, a role of nesfatin-1 in ovarian epithelial carcinoma remains unknown. The aim of the present study is to examine the effect of nesfatin-1 on ovary carcinoma cells proliferation. We found that nesfatin-1 inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, this inhibition could be abolished by nesfatin-1 neutralizing antibody. Nesfatin-1 enhances HO-8910 cell apoptosis, activation of mammalian target of rapamycin (mTOR) and RhoA/ROCK signaling pathway block the effects of nesfatin-1-induced apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation by nesfatin-1. In conclusion, the present study demonstrated that nesfatin-1 can inhibit the proliferation in human ovarian epithelial carcinoma cell line HO-8910 cells through inducing apoptosis via mTOR and RhoA/ROCK signaling pathway. This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients.

  2. Alveolocapillary model system to study alveolar re-epithelialization

    SciTech Connect (OSTI)

    Willems, Coen H.M.P.; Zimmermann, Luc J.I.; Sanders, Patricia J.L.T.; Wagendorp, Margot; Kloosterboer, Nico; Cohen Tervaert, Jan Willem; Duimel, Hans J.Q.; Verheyen, Fons K.C.P.; Iwaarden, J. Freek van

    2013-01-01

    In the present study an in vitro bilayer model system of the pulmonary alveolocapillary barrier was established to investigate the role of the microvascular endothelium on re-epithelialization. The model system, confluent monolayer cultures on opposing sides of a porous membrane, consisted of a human microvascular endothelial cell line (HPMEC-ST1.6R) and an alveolar type II like cell line (A549), stably expressing EGFP and mCherry, respectively. These fluorescent proteins allowed the real time assessment of the integrity of the monolayers and the automated analysis of the wound healing process after a scratch injury. The HPMECs significantly attenuated the speed of re-epithelialization, which was associated with the proximity to the A549 layer. Examination of cross-sectional transmission electron micrographs of the model system revealed protrusions through the membrane pores and close contact between the A549 cells and the HPMECs. Immunohistochemical analysis showed that these close contacts consisted of heterocellular gap-, tight- and adherens-junctions. Additional analysis, using a fluorescent probe to assess gap-junctional communication, revealed that the HPMECs and A549 cells were able to exchange the fluorophore, which could be abrogated by disrupting the gap junctions using connexin mimetic peptides. These data suggest that the pulmonary microvascular endothelium may impact the re-epithelialization process. -- Highlights: ? Model system for vital imaging and high throughput screening. ? Microvascular endothelium influences re-epithelialization. ? A549 cells form protrusions through membrane to contact HPMEC. ? A549 cells and HPMECs form heterocellular tight-, gap- and adherens-junctions.

  3. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    SciTech Connect (OSTI)

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Snijders, Antoine M.; Mao, Jian-Hua

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGF?1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGF?1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

  4. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; et al

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genesmore » involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.« less

  5. Annexin A9 (ANXA9) biomarker and therapeutic target in epithelial cancer

    DOE Patents [OSTI]

    Hu, Zhi; Kuo, Wen-Lin; Neve, Richard M.; Gray, Joe W.

    2012-06-12

    Amplification of the ANXA9 gene in human chromosomal region 1q21 in epithelial cancers indicates a likelihood of both in vivo drug resistance and metastasis, and serves as a biomarker indicating these aspects of the disease. ANXA9 can also serve as a therapeutic target. Interfering RNAs (iRNAs) (such as siRNA and miRNA) and shRNA adapted to inhibit ANXA9 expression, when formulated in a therapeutic composition, and delivered to cells of the tumor, function to treat the epithelial cancer.

  6. Enhancement of cancer stem-like and epithelial?mesenchymal transdifferentiation property in oral epithelial cells with long-term nicotine exposure: Reversal by targeting SNAIL

    SciTech Connect (OSTI)

    Yu, Cheng-Chia; School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan ; Chang, Yu-Chao; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan

    2013-02-01

    Cigarette smoking is one of the major risk factors in the development and further progression of tumorigenesis, including oral squamous cell carcinoma (OSCC). Recent studies suggest that interplay cancer stem-like cells (CSCs) and epithelial?mesenchymal transdifferentiation (EMT) properties are responsible for the tumor maintenance and metastasis in OSCC. The aim of the present study was to investigate the effects of long-term exposure with nicotine, a major component in cigarette, on CSCs and EMT characteristics. The possible reversal regulators were further explored in nicotine-induced CSCs and EMT properties in human oral epithelial (OE) cells. Long-term exposure with nicotine was demonstrated to up-regulate ALDH1 population in normal gingival and primary OSCC OE cells dose-dependently. Moreover, long-term nicotine treatment was found to enhance the self-renewal sphere-forming ability and stemness gene signatures expression and EMT regulators in OE cells. The migration/cell invasiveness/anchorage independent growth and in vivo tumor growth by nude mice xenotransplantation assay was enhanced in long-term nicotine-stimulated OE cells. Knockdown of Snail in long-term nicotine-treated OE cells was found to reduce their CSCs properties. Therapeutic delivery of Si-Snail significantly blocked the xenograft tumorigenesis of long-term nicotine-treated OSCC cells and largely significantly improved the recipient survival. The present study demonstrated that the enrichment of CSCs coupled EMT property in oral epithelial cells induced by nicotine is critical for the development of OSCC tumorigenesis. Targeting Snail might offer a new strategy for the treatment of OSCC patients with smoking habit. -- Highlights: ? Sustained nicotine treatment induced CSCs properties of oral epithelial cells. ? Long-term nicotine treatment enhance EMT properties of oral epithelial cells. ? Long-term nicotine exposure increased tumorigenicity of oral epithelial cells. ? Si-Snail blocked

  7. A 3-D Model of Signaling and Transport Pathways in Epithelial Cells

    SciTech Connect (OSTI)

    Quong, A A; Westbrook, C K

    2005-04-01

    A 3-dimensional computer model was developed to simulate the spatial and chemical evolution of calcium ions inside an array of human epithelial kidney cells. This is a prototype model, intended to develop a methodology to incorporate much more complex interactions of metabolic and other processes within many types of cells and lead to increased ability to predict cellular responses to disease as well as to chemical and biological warfare situations. Preliminary tests of the model are described.

  8. Biomolecular interactions and responses of human epithelial and...

    Office of Scientific and Technical Information (OSTI)

    of inhaled nanoparticles to cross the blood-brain barrier; Kwon et al., 2008, J. Occup. ... AND NANOTECHNOLOGY; ASPECT RATIO; BLOOD-BRAIN BARRIER; CELL MEMBRANES; CHEMISTRY; ...

  9. Cell shape regulates global histone acetylation in human mammaryepithelial cells

    SciTech Connect (OSTI)

    Le Beyec, Johanne; Xu, Ren; Lee, Sun-Young; Nelson, Celeste M.; Rizki, Aylin; Alcaraz, Jordi; Bissell, Mina J.

    2007-02-28

    Extracellular matrix (ECM) regulates cell morphology and gene expression in vivo; these relationships are maintained in three-dimensional (3D) cultures of mammary epithelial cells. In the presence of laminin-rich ECM (lrECM), mammary epithelial cells round up and undergo global histone deacetylation, a process critical for their functional differentiation. However, it remains unclear whether lrECM-dependent cell rounding and global histone deacetylation are indeed part of a common physical-biochemical pathway. Using 3D cultures as well as nonadhesive and micropatterned substrata, here we showed that the cell 'rounding' caused by lrECM was sufficient to induce deacetylation of histones H3 and H4 in the absence of biochemical cues. Microarray and confocal analysis demonstrated that this deacetylation in 3D culture is associated with a global increase in chromatin condensation and a reduction in gene expression. Whereas cells cultured on plastic substrata formed prominent stress fibers, cells grown in 3D lrECM or on micropatterns lacked these structures. Disruption of the actin cytoskeleton with cytochalasin D phenocopied the lrECM-induced cell rounding and histone deacetylation. These results reveal a novel link between ECM-controlled cell shape and chromatin structure, and suggest that this link is mediated by changes in the actin cytoskeleton.

  10. IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

    SciTech Connect (OSTI)

    Zhu, Yingting; Tissue Tech Inc, Miami, FL 33173 ; Zhu, Min; Lance, Peter

    2012-11-15

    COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.

  11. Increasing cell culture population doublings for long-term growth of finite life span human cell cultures

    DOE Patents [OSTI]

    Stampfer, Martha R; Garbe, James C

    2015-02-24

    Cell culture media formulations for culturing human epithelial cells are herein described. Also described are methods of increasing population doublings in a cell culture of finite life span human epithelial cells and prolonging the life span of human cell cultures. Using the cell culture media disclosed alone and in combination with addition to the cell culture of a compound associated with anti-stress activity achieves extended growth of pre-stasis cells and increased population doublings and life span in human epithelial cell cultures.

  12. Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells

    SciTech Connect (OSTI)

    Zhu, Yingting; Tissue Tech Inc., Miami, FL 33173 ; Zhu, Min; Lance, Peter

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Human colonic cancer associated fibroblasts are major sources of COX-2 and PGE{sub 2}. Black-Right-Pointing-Pointer The fibroblasts interact with human colonic epithelial cancer cells. Black-Right-Pointing-Pointer Activation of COX-2 signaling in the fibroblasts affects behavior of the epithelia. Black-Right-Pointing-Pointer Protein Kinase C controls the activation of COX-2 signaling. -- Abstract: COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.

  13. A chemically defined culture medium containing Rho kinase inhibitor Y-27632 for the fabrication of stratified squamous epithelial cell grafts

    SciTech Connect (OSTI)

    Aslanova, Afag; Takagi, Ryo; Yamato, Masayuki; Okano, Teruo; Yamamoto, Masakazu

    2015-05-01

    With the development of a culture method for stratified squamous epithelial cells, tissue-engineered epithelial cell sheets have been successfully applied as clinical cell grafts. However, the implementation of these cell sheets without the use of any animal-derived materials is highly desirable. In this study, Rho-associated protein kinase inhibitor Y-27632 was used to develop a chemically defined culture medium for the fabrication of stratified epithelial cell grafts consisting of human epidermal and oral keratinocytes, and the proliferation activity, cell morphology, and gene expressions of the keratinocytes were analyzed. The results of a colorimetric assay indicated that Y-27632 significantly promoted the proliferation of the keratinocytes in culture media both with and without fetal bovine serum (FBS), although there were no indications of Y-27632 efficacy on cell morphology and stratification of the keratinocytes in culture medium without any animal-derived materials. The results of quantitative RT-PCR revealed that gene expressions correlated with cell adhesion, cell–cell junction, proliferation markers, and stem/progenitor markers in cultured keratinocytes were not strongly affected by the addition of Y-27632 to the culture medium. Moreover, gene expressions of differentiation markers in stratified keratinocytes cultured in medium without FBS were nearly identical to those of keratinocytes co-cultured with 3T3 feeder cells. Interestingly, the expressions of differentiation markers in cultured stratified keratinocytes were suppressed by FBS, whereas they were reconstructed by either co-culture of a 3T3 feeder layer or addition of Y-27632 into the culture medium containing FBS. These findings indicate that Y-27632 is a useful supplement for the development of a chemically defined culture medium for fabrication of stratified epithelial cell grafts for clinical applications for the purpose of developing the culture medium with a lower risk of pathogen

  14. Sensitive Targeted Quantification of ERK Phosphorylation Dynamics and Stoichiometry in Human Cells without Affinity Enrichment

    SciTech Connect (OSTI)

    Shi, Tujin; Gao, Yuqian; Gaffrey, Matthew J.; Nicora, Carrie D.; Fillmore, Thomas L.; Chrisler, William B.; Gritsenko, Marina A.; Wu, Chaochao; He, Jintang; Bloodsworth, Kent J.; Zhao, Rui; Camp, David G.; Liu, Tao; Rodland, Karin D.; Smith, Richard D.; Wiley, H. S.; Qian, Weijun

    2014-12-17

    Mass spectrometry-based targeted quantification is a promising technology for site-specific quantification of posttranslational modifications (PTMs). However, a major constraint of most targeted MS approaches is the limited sensitivity for quantifying low-abundance PTMs, requiring the use of affinity reagents to enrich specific PTMs. Herein, we demonstrate the direct site-specific quantification of ERK phosphorylation isoforms (pT, pY, pTpY) and their relative stoichiometries using a highly sensitive targeted MS approach termed high-pressure, high-resolution separations with intelligent selection and multiplexing (PRISM). PRISM provides effective enrichment of target peptides within a given fraction from complex biological matrix with minimal sample losses, followed by selected reaction monitoring (SRM) quantification. The PRISM-SRM approach enabled direct quantification of ERK phosphorylation in human mammary epithelial cells (HMEC) from as little as 25 µg tryptic peptides from whole cell lysates. Compared to immobilized metal-ion affinity chromatography, PRISM provided >10-fold improvement in signal intensities, presumably due to the better peptide recovery of PRISM for handling small size samples. This approach was applied to quantify ERK phosphorylation dynamics in HMEC treated by different doses of EGF at both the peak activation (10 min) and steady state (2 h). At 10 min, the maximal ERK activation was observed with 0.3 ng/mL dose, whereas the maximal steady state level of ERK activation at 2 h was at 3 ng/ml dose, corresponding to 1200 and 9000 occupied receptors, respectively. At 10 min, the maximally activated pTpY isoform represented ~40% of total ERK, falling to less than 10% at 2 h. The time course and dose-response profiles of individual phosphorylated ERK isoforms indicated that singly phosphorylated pT-ERK never increases significantly, while the increase of pY-ERK paralleled that of pTpY-ERK. This data supports for a processive, rather than

  15. Sensitive Targeted Quantification of ERK Phosphorylation Dynamics and Stoichiometry in Human Cells without Affinity Enrichment

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Shi, Tujin; Gao, Yuqian; Gaffrey, Matthew J.; Nicora, Carrie D.; Fillmore, Thomas L.; Chrisler, William B.; Gritsenko, Marina A.; Wu, Chaochao; He, Jintang; Bloodsworth, Kent J.; et al

    2014-12-17

    Mass spectrometry-based targeted quantification is a promising technology for site-specific quantification of posttranslational modifications (PTMs). However, a major constraint of most targeted MS approaches is the limited sensitivity for quantifying low-abundance PTMs, requiring the use of affinity reagents to enrich specific PTMs. Herein, we demonstrate the direct site-specific quantification of ERK phosphorylation isoforms (pT, pY, pTpY) and their relative stoichiometries using a highly sensitive targeted MS approach termed high-pressure, high-resolution separations with intelligent selection and multiplexing (PRISM). PRISM provides effective enrichment of target peptides within a given fraction from complex biological matrix with minimal sample losses, followed by selected reactionmore » monitoring (SRM) quantification. The PRISM-SRM approach enabled direct quantification of ERK phosphorylation in human mammary epithelial cells (HMEC) from as little as 25 µg tryptic peptides from whole cell lysates. Compared to immobilized metal-ion affinity chromatography, PRISM provided >10-fold improvement in signal intensities, presumably due to the better peptide recovery of PRISM for handling small size samples. This approach was applied to quantify ERK phosphorylation dynamics in HMEC treated by different doses of EGF at both the peak activation (10 min) and steady state (2 h). At 10 min, the maximal ERK activation was observed with 0.3 ng/mL dose, whereas the maximal steady state level of ERK activation at 2 h was at 3 ng/ml dose, corresponding to 1200 and 9000 occupied receptors, respectively. At 10 min, the maximally activated pTpY isoform represented ~40% of total ERK, falling to less than 10% at 2 h. The time course and dose-response profiles of individual phosphorylated ERK isoforms indicated that singly phosphorylated pT-ERK never increases significantly, while the increase of pY-ERK paralleled that of pTpY-ERK. This data supports for a processive, rather than

  16. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition

    SciTech Connect (OSTI)

    Gudjonsson, Thorarinn; Ronnov-Jessen, Lone; Villadsen, Rene; Rank, Fritz; Bissell, Mina J.; Petersen, Ole William

    2001-10-04

    The signals that determine the correct polarity of breast epithelial structures in vivo are not understood. We have shown previously that luminal epithelial cells can be polarized when cultured within a reconstituted basement membrane gel. We reasoned that such cues in vivo may be given by myoepithelial cells. Accordingly, we used an assay where luminal epithelial cells are incorrectly polarized to test this hypothesis. We show that culturing human primary luminal epithelial cells within collagen-I gels leads to formation of structures with no lumina and with reverse polarity as judged by dual stainings for sialomucin, epithelial specific antigen or occludin. No basement membrane is deposited, and {beta}4-integrin staining is negative. Addition of purified human myoepithelial cells isolated from normal glands corrects the inverse polarity, and leads to formation of double-layered acini with central lumina. Among the laminins present in the human breast basement membrane (laminin-1, -5 and -10/11), laminin-1 was unique in its ability to substitute for myoepithelial cells in polarity reversal. Myoepithelial cells were purified also from four different breast cancer sources including a biphasic cell line. Three out of four samples either totally lacked the ability to interact with luminal epithelial cells, or conveyed only correction of polarity in a fraction of acini. This behavior was directly related to the ability of the tumor myoepithelial cells to produce {alpha}-1 chain of laminin. In vivo, breast carcinomas were either negative for laminin-1 (7/12 biopsies) or showed a focal, fragmented deposition of a less intensely stained basement membrane (5/12 biopsies). Dual staining with myoepithelial markers revealed that tumorassociated myoepithelial cells were either negative or weakly positive for expression of laminin-1, establishing a strong correlation between loss of laminin-1 and breast cancer. We conclude that the double-layered breast acinus may be

  17. Hyaluronan in human malignancies

    SciTech Connect (OSTI)

    Sironen, R.K.; Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio ; Tammi, M.; Tammi, R.; Auvinen, P.K.; Anttila, M.; Department of Gynecology and Obstetrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio ; Kosma, V-M.

    2011-02-15

    Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of hyaluronan in tumor growth and metastasis. A high stromal hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced hyaluronan content. In addition to the stroma-cancer cell interaction, hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, hyaluronan synthases and hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.

  18. Cellular morphometry of the bronchi of human and dog lungs

    SciTech Connect (OSTI)

    Robbins, E.S.

    1992-09-01

    Quantitative data of the human bronchial epithelial cells at possible risk for malignant transformation in lung cancer is crucial for accurate radon dosimetry and risk analysis. The locations and other parameters of the nuclei which may be damaged by [alpha] particles must be determined and compared in different airway generations, among smokers, non-smokers and ex-smokers, between men and women and in people of different ages. This proposal includes extended morphometric studies on electron micrographs of human epithelium of defined airway generations and in parallel on electron micrographs of the dog bronchial lining. The second part of this proposal describes studies to quantitate the cycling bronchial epithelial population(s) using proliferation markers and immunocytochemistry on frozen and paraffin sections and similar labeling of isolated bronchial epithelial cells sorted flow cytometry.

  19. A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

    SciTech Connect (OSTI)

    Castillo-Lluva, Sonia; Hontecillas-Prieto, Lourdes; Blanco-Gómez, Adrian; del Mar Sáez-Freire, María; García-Cenador, Begona; García-Criado, Javier; Pérez-Andrés, Martín; Orfao, Alberto; Cañamero, Marta; Mao, Jian-Hua; Gridley, Thomas; Castellanos-Martín, Andres; Pérez-Losada, Jesus

    2015-06-22

    Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. In conclusion, our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

  20. A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Castillo-Lluva, Sonia; Hontecillas-Prieto, Lourdes; Blanco-Gómez, Adrian; del Mar Sáez-Freire, María; García-Cenador, Begona; García-Criado, Javier; Pérez-Andrés, Martín; Orfao, Alberto; Cañamero, Marta; Mao, Jian-Hua; et al

    2015-06-22

    Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2more » oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. In conclusion, our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.« less

  1. Exposure to Ionizing Radiation Causes Long-Term Increase in Serum Estradiol and Activation of PI3K-Akt Signaling Pathway in Mouse Mammary Gland

    SciTech Connect (OSTI)

    Suman, Shubhankar; Johnson, Michael D.; Fornace, Albert J.; Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC ; Datta, Kamal

    2012-10-01

    Purpose: Exposure to ionizing radiation is an established risk factor for breast cancer. Radiation exposure during infancy, childhood, and adolescence confers the highest risk. Although radiation is a proven mammary carcinogen, it remains unclear where it acts in the complex multistage process of breast cancer development. In this study, we investigated the long-term pathophysiologic effects of ionizing radiation at a dose (2 Gy) relevant to fractionated radiotherapy. Methods and Materials: Adolescent (6-8 weeks old; n = 10) female C57BL/6J mice were exposed to 2 Gy total body {gamma}-radiation, the mammary glands were surgically removed, and serum and urine samples were collected 2 and 12 months after exposure. Molecular pathways involving estrogen receptor-{alpha} (ER{alpha}) and phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling were investigated by immunohistochemistry and Western blot. Results: Serum estrogen and urinary levels of the oncogenic estrogen metabolite (16{alpha}OHE1) were significantly increased in irradiated animals. Immunostaining for the cellular proliferative marker Ki-67 and cyclin-D1 showed increased nuclear accumulation in sections of mammary glands from irradiated vs. control mice. Marked increase in p85{alpha}, a regulatory sub-unit of the PI3K was associated with increase in Akt, phospho-Akt, phospho-BAD, phospho-mTOR, and c-Myc in irradiated samples. Persistent increase in nuclear ER{alpha} in mammary tissues 2 and 12 months after radiation exposure was also observed. Conclusions: Taken together, our data not only support epidemiologic observations associating radiation and breast cancer but also, specify molecular events that could be involved in radiation-induced breast cancer.

  2. YY1 modulates taxane response in epithelial ovarian cancer

    SciTech Connect (OSTI)

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2008-10-10

    The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1

  3. Link Alpha M

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    m A B C D E F G H I J K L M N O P Q R S T U V W Y Z Filter by alpha... A B C D E F G H I J K L M N O P Q R S T U V W Y Z Macintosh User Group (LBNL-MUG) Mail Services (Facilities Dep't.) Malware/Virus Protection and Prevention Mammary: Human Mammary Epithelial Cell (HMEC) Map: Berkeley Lab Global Talent Map Map: Lab Shuttle Bus Map Maps: Berkeley Lab Interactive Site Map Maps: Berkeley Lab Printable Site Map Massage Material Safety Data Sheets (Safety Data Sheets, SDS) Material Transfer

  4. Human Resources | Argonne National Laboratory

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources

  5. Cellular morphometry of the bronchi of human and dog lungs. Annual progress report, April 1, 1992--March 31, 1993

    SciTech Connect (OSTI)

    Robbins, E.S.

    1992-09-01

    Quantitative data of the human bronchial epithelial cells at possible risk for malignant transformation in lung cancer is crucial for accurate radon dosimetry and risk analysis. The locations and other parameters of the nuclei which may be damaged by {alpha} particles must be determined and compared in different airway generations, among smokers, non-smokers and ex-smokers, between men and women and in people of different ages. This proposal includes extended morphometric studies on electron micrographs of human epithelium of defined airway generations and in parallel on electron micrographs of the dog bronchial lining. The second part of this proposal describes studies to quantitate the cycling bronchial epithelial population(s) using proliferation markers and immunocytochemistry on frozen and paraffin sections and similar labeling of isolated bronchial epithelial cells sorted flow cytometry.

  6. Mechanisms of disease: epithelial-mesenchymal transition and back again: does cellular plasticity fuel neoplastic progression?

    SciTech Connect (OSTI)

    Bissell, Mina J; Turley, Eva A.; Veiseh, Mandana; Radisky, Derek C.; Bissell, Mina J.

    2008-02-13

    Epithelial-mesenchymal transition (EMT) is a conversion that facilitates organ morphogenesis and tissue remodeling in physiological processes such as embryonic development and wound healing. A similar phenotypic conversion is also detected in fibrotic diseases and neoplasia, which is associated with disease progression. EMT in cancer epithelial cells often seems to be an incomplete and bi-directional process. In this Review, we discuss the phenomenon of EMT as it pertains to tumor development, focusing on exceptions to the commonly held rule that EMT promotes invasion and metastasis. We also highlight the role of the RAS-controlled signaling mediators, ERK1, ERK2 and PI3-kinase, as microenvironmental responsive regulators of EMT.

  7. Sox5 induces epithelial to mesenchymal transition by transactivation of Twist1

    SciTech Connect (OSTI)

    Pei, Xin-Hong; Lv, Xin-Quan; Li, Hui-Xiang

    2014-03-28

    Highlights: • Depletion of Sox5 inhibits breast cancer proliferation, migration, and invasion. • Sox5 transactivates Twist1 expression. • Sox5 induces epithelial to mesenchymal transition through transactivation of Twist1 expression. - Abstract: The epithelial to mesenchymal transition (EMT), a highly conserved cellular program, plays an important role in normal embryogenesis and cancer metastasis. Twist1, a master regulator of embryonic morphogenesis, is overexpressed in breast cancer and contributes to metastasis by promoting EMT. In exploring the mechanism underlying the increased Twist1 in breast cancer cells, we found that the transcription factor SRY (sex-determining region Y)-box 5(Sox5) is up-regulation in breast cancer cells and depletion of Sox5 inhibits breast cancer cell proliferation, migration, and invasion. Furthermore, depletion of Sox5 in breast cancer cells caused a dramatic decrease in Twist1 and chromosome immunoprecipitation assay showed that Sox5 can bind directly to the Twist1 promoter, suggesting that Sox5 transactivates Twist1 expression. We further demonstrated that knockdown of Sox5 up-regulated epithelial phenotype cell biomarker (E-cadherin) and down-regulated mesenchymal phenotype cell biomarkers (N-cadherin, Vimentin, and Fibronectin 1), resulting in suppression of EMT. Our study suggests that Sox5 transactivates Twist1 expression and plays an important role in the regulation of breast cancer progression.

  8. Evaluation of Common Angling-Induced Sources of Epithelial Damage for Popular Freshwater Sport Fish using Fluorescein

    SciTech Connect (OSTI)

    Colotelo, Alison HA; Cooke, Steven J.

    2011-05-01

    Angling is a popular recreational activity across the globe and a large proportion of fish captured by anglers are released due to voluntary or mandatory catch-and-release practices. The handling associated with hook removal and return of the fish to their environment can cause physical damage to the epidermal layer of the fish which may affect the condition and survival of released fish. This study investigated possible sources of epithelial damage associated with several different handling methods (i.e. landing net types, interactions with different boat floor surfaces, tournament procedures) commonly used in recreational angling for two popular freshwater sport fish species, largemouth bass (Micropterus salmoides) and northern pike (Esox lucius). Epithelial damage was examined using fluorescein, a non-toxic dye, which has been shown to detect latent epithelial damage. Northern pike exhibited extensive epithelial damage after exposure to several of the induced treatments (i.e., interaction with a carpeted surface, knotted nylon net, and line rolling) but relatively little epithelial damage when exposed to others (i.e., knotless rubber nets, smooth boat surfaces, or lip gripping devices). Largemouth bass did not show significant epithelial damage for any of the treatments, with the exception of fish caught in a semi-professional live release tournament. The detection of latent injuries using fluorescein can be an important management tool as it provides visual examples of potential damage that can be caused by different handling methods. Such visualizations can be used to encourage fish friendly angler behaviour and enhance the survival and welfare of released fish. It can also be used to test new products that are intended to or claim to reduce injury to fish that are to be released. Future research should evaluate the relationship between different levels of epithelial damage and mortality across a range of environmental conditions.

  9. Comparative Evaluation of Four Presumptive Tests for Blood to Detect Epithelial Injury on Fish

    SciTech Connect (OSTI)

    Colotelo, Alison HA; Smokorowski, Karen; Haxton, Tim; Cooke, Steven J.

    2014-06-01

    Current methods of fish epithelial injury detection are limited to gross macroscopic examination that has a subjective bias as well as an inability to reliably quantify the degree of injury. Fluorescein, a presumptive test for blood, has been shown to have the capability to detect and quantify fish epithelial injury. However, there are several other presumptive tests for blood (Bluestar*, phenolphthalein, and HemastixH) that may have benefits over the use of fluorescein, particularly for field research on wild fish. This study investigated the capabilities of these four tests to detect and quantify a variety of injuries commonly encountered by fish (abrasion, cuts, fin frays, and punctures) using the freshwater bluegill Lepomis macrochirus as a model. Fluorescein was consistently found to be the most reliable (i.e., detected the highest proportion of true positive results and rarely detected false positive reactions) of the four presumptive tests for blood compared. Further testing was conducted to examine the reliability of fluorescein. By 24 h after an injury was inflicted, the injury was no longer detectable by fluorescein, and when fluorescein was applied to an injured fish, the fluorescein was no longer detectable 3 h after application. In a comparison of two common anaesthetics used in fisheries research, there was no significant difference in the proportion of injury detected when 3- aminobenzoic acid ethyl ester methanesulfate (tricaine) was used compared with a clove oil and ethanol (1:9) solution. In summary, fluorescein was the most reliable presumptive test for blood examined in this study for the detection and quantification of recent (hours) fish epithelial injury.

  10. 14-3-3{sigma} controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway

    SciTech Connect (OSTI)

    Xin, Ying; Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 ; Lu, Qingxian; Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 ; Li, Qiutang; Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202

    2010-02-19

    14-3-3{sigma} (also called stratifin) is specifically expressed in the stratified squamous epithelium and its function was recently shown to be linked to epidermal stratification and differentiation in the skin. In this study, we investigated its role in corneal epithelium cell proliferation and differentiation. We showed that the 14-3-3{sigma} mutation in repeated epilation (Er) mutant mice results in a dominant negative truncated protein. Primary corneal epithelial cells expressing the dominant negative protein failed to undergo high calcium-induced cell cycle arrest and differentiation. We further demonstrated that blocking endogenous 14-3-3{sigma} activity in corneal epithelial cells by overexpressing dominative negative 14-3-3{sigma} led to reduced Notch activity and Notch1/2 transcription. Significantly, expression of the active Notch intracellular domain overcame the block in epithelial cell differentiation in 14-3-3{sigma} mutant-expressing corneal epithelial cells. We conclude that 14-3-3{sigma} is critical for regulating corneal epithelial proliferation and differentiation by regulating Notch signaling activity.

  11. Silencing heme oxygenase-1 gene expression in retinal pigment epithelial cells inhibits proliferation, migration and tube formation of cocultured endothelial cells

    SciTech Connect (OSTI)

    Zhang, Wenjie; Zhang, Xiaomei; Lu, Hong; Matsukura, Makoto; Zhao, Jien; Shinohara, Makoto

    2013-05-10

    Highlights: •HO-1 is highly induced in RPE cells by hypoxia. •Inhibition of HO-1 activity and knockdown of HO-1 expression inhibit VEGF expression in RPE cells under hypoxia. •Knockdown of HO-1 in RPE cells inhibits angiogenesis of endothelial cells in vitro. -- Abstract: Heme oxygenase-1 (HO-1) plays an important role in the vasculature and in the angiogenesis of tumors, wounds and other environments. Retinal pigment epithelial (RPE) cells and choroidal endothelial cells (CECs) are the main cells involved in choroidal neovascularization (CNV), a process in which hypoxia plays an important role. Our aim was to evaluate the role of human RPE-cell HO-1 in the angiogenic activities of cocultured endothelial cells under hypoxia. Small interfering RNA (siRNA) for HO-1 was transfected into human RPE cell line ARPE-19, and zinc protoporphyrin (ZnPP) was used to inhibit HO-1 activity. Knockdown of HO-1 expression and inhibition of HO-1 activity resulted in potent reduction of the expression of vascular endothelial growth factor (VEGF) under hypoxia. Furthermore, knockdown of HO-1 suppressed the proliferation, migration and tube formation of cocultured endothelial cells. These findings indicated that HO-1 might have an angiogenic effect in CNV through modulation of VEGF expression and might be a potential target for treating CNV.

  12. Estrogen inhibits cell cycle progression and retinoblastoma phosphorylation in rhesus ovarian surface epithelial cell culture

    SciTech Connect (OSTI)

    Wright, Jay W.; Stouffer, Richard L.; Rodland, Karin D.

    2003-10-31

    Estrogen promotes the growth of some ovarian cancer cells at nanomolar concentrations, but has been shown to inhibit growth of normal ovarian surface epithelial (OSE) cells at micromolar concentrations (1?g/ml). OSE cells express the estrogen receptor (ER)-?, and are the source of 90% of various cancers. The potential sensitivity of OSE cells to estrogen stresses the importance of understanding the estrogen-dependent mechanisms at play in OSE proliferation and transformation, as well as in anticancer treatment. We investigated the effects of estradiol on cell proliferation in vitro, and demonstrate an intracellular locus of action of estradiol in cultured rhesus ovarian surface epithelial (RhOSE) cells. We show that ovarian and breast cells are growth-inhibited by micromolar concentration of estradiol and that this inhibition correlates with estrogen receptor expression. We further show that normal rhesus OSE cells do not activate ERK or Akt in response to estradiol nor does estradiol block the ability of serum to stimulate ERK or induce cyclin D expression. Contrarily, estradiol inhibits serum-dependent retinoblastoma protein (Rb) phosphorylation and blocks DNA synthesis. This inhibition does not formally arrest cells and is reversible within hours of estrogen withdrawal. Our data are consistent with growth inhibition by activation of Rb and indicate that sensitivity to hormone therapy in anticancer treatment can be modulated by cell cycle regulators downstream of the estrogen receptor.

  13. Long-term Survival Outcomes Following Internal Mammary Node Irradiation in Stage II-III Breast Cancer: Results of a Large Retrospective Study With 12-Year Follow-up

    SciTech Connect (OSTI)

    Chang, Jee Suk; Park, Won; Kim, Yong Bae; Lee, Ik Jae; Keum, Ki Chang; Lee, Chang Geol; Choi, Doo Ho; Suh, Chang-Ok; Huh, Seung Jae

    2013-08-01

    Purpose: To examine the effect of internal mammary node irradiation (IMNI) on disease-free survival (DFS) and overall survival (OS) in breast cancer patients treated with modified radical mastectomy and postoperative radiation therapy. Methods and Materials: Between 1994 and 2002, 396 patients with stage II-III breast cancer were treated with postmastectomy radiation therapy with (n=197) or without (n=199) IMNI. Patients who received neoadjuvant chemotherapy were excluded. IMNI was administered at the clinical discretion of the treating physician. Median RT dose was 50.4 Gy (range, 45.0-59.4 Gy) in 28 fractions, with inclusion of the supraclavicular fossa in 96% of patients. Adjuvant chemotherapy was administered to 99.7% of the patients and endocrine therapy to 53%. Results: The median follow-up was 149 months (range, 124-202). IMNI patients had more advanced nodal stage and non-high grade tumors than those without IMNI (P<.001). Otherwise, disease and treatment characteristics were well balanced. The 10-year DFS with and without IMNI was 65% and 57%, respectively (P=.05). Multivariate analysis demonstrated that IMNI was an independent, positive predictor of DFS (hazard ratio [HR], 0.70; P=.02). Benefits of IMNI in DFS were seen most apparently in N2 patients (HR, 0.44; 95% confidence interval [CI], 0.26-0.74) and inner/central tumors (HR, 0.55; 95% CI, 0.34-0.90). The 10-year OS with and without IMNI was 72% and 66%, respectively (P=.62). The 10-year DFS and OS were 61%, and 69%, respectively. Conclusions: Internal mammary node irradiation significantly improved DFS in postmastectomy breast cancer patients. Pending long-term results from randomized trials, treatment of internal mammary nodes should be considered in postmastectomy radiation therapy.

  14. Low doses ionizing radiation enhances the invasiveness of breast cancer cells by inducing epithelial-mesenchymal transition

    SciTech Connect (OSTI)

    Zhang, Xin; Li, Xiaoyan; Zhang, Ning; Yang, Qifeng; Moran, Meena S.

    2011-08-19

    Highlights: {yields} Low doses ionizing irradiation would enhance the invasiveness of breast cancer cells by inducing EMT. {yields} Low doses ionizing radiation induced morphologic changes in breast cancer cells. {yields} Low doses ionizing radiation led to upregulation of mesenchymal markers and down-regulation of epithelial markers. {yields} Low doses ionizing radiation increased migration and invasion of breast cancer cells. -- Abstract: Epithelial-mesenchymal transition (EMT) is a process cellular morphologic and molecular alterations facilitate cell invasion. We hypothesized that low dose ionizing irradiation (LDIR) enhances the invasiveness of breast cancer cells by inducing EMT. The effects of LDIR on cellular morphology and the EMT markers of MCF-7 breast cancer cells were analyzed by western blot/RT-PCR and migration/invasion was examined using the transwell assay. We found that LDIR led to the phenotypic changes of EMT in MCF-7 cells and down-regulation of epithelial differentiation markers and transcriptional induction of mesenchymal markers. Furthermore, the radiated cells demonstrated enhanced migration/invasion MCF-7 cells compared with non-radiated cells. In summary, LDIR promotes the invasiveness of breast cancer cells through epithelial to mesenchymal transition. These findings may ultimately provide a new targeted approach for improving the therapeutic effectiveness of radiation in breast cancer.

  15. Pinkbar is an epithelial-specific BAR domain protein that generates planar membrane structures

    SciTech Connect (OSTI)

    Pyklinen, Anette; Boczkowska, Malgorzata; Zhao, Hongxia; Saarikangas, Juha; Rebowski, Grzegorz; Jansen, Maurice; Hakanen, Janne; Koskela, Essi V.; Pernen, Johan; Vihinen, Helena; Jokitalo, Eija; Salminen, Marjo; Ikonen, Elina; Dominguez, Roberto; Lappalainen, Pekka

    2013-05-29

    Bin/amphipysin/Rvs (BAR)-domain proteins sculpt cellular membranes and have key roles in processes such as endocytosis, cell motility and morphogenesis. BAR domains are divided into three subfamilies: BAR- and F-BAR-domain proteins generate positive membrane curvature and stabilize cellular invaginations, whereas I-BAR-domain proteins induce negative curvature and stabilize protrusions. We show that a previously uncharacterized member of the I-BAR subfamily, Pinkbar, is specifically expressed in intestinal epithelial cells, where it localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions. Notably, the BAR domain of Pinkbar does not induce membrane tubulation but promotes the formation of planar membrane sheets. Structural and mutagenesis analyses reveal that the BAR domain of Pinkbar has a relatively flat lipid-binding interface and that it assembles into sheet-like oligomers in crystals and in solution, which may explain its unique membrane-deforming activity.

  16. Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism

    SciTech Connect (OSTI)

    Ahluwalia, Amrita [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States)] [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Jones, Michael K. [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States) [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Medicine, University of California, Irvine, CA (United States); Szabo, Sandor [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States) [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Pathology, University of California, Irvine, CA (United States); Tarnawski, Andrzej S., E-mail: amrita.ahluwalia@va.gov [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Medicine, University of California, Irvine, CA (United States)

    2013-08-09

    Highlights: Malignant colonic epithelial cells express VEGF and its receptors. Cultured colon cancer cells secrete VEGF into the medium. Inhibition of VEGF receptor significantly decreases colon cancer cell proliferation. VEGF is critical for colon cancer cell growth. -- Abstract: Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. Material and methods: We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n = 43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. Results: Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. Conclusions: Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is independent of

  17. Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; Linderman, Jennifer J.; Moore, Bethany B.; Kirschner, Denise E.

    2016-06-23

    Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited withmore » enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic

  18. The effect of retinal pigment epithelial cell patch size on growth factor expression

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Vargis, Elizabeth A.; Peterson, Cristen B.; Morrell-Falvey, Jennifer L.; Retterer, Scott T.; Collier, Charles Patrick

    2014-01-30

    The spatial organization of retinal pigment epithelial (RPE) cells grown in culture was controlled using micropatterning techniques in order to examine the effect of patch size on cell health and differentiation. Understanding this effect is a critical step in the development of multiplexed high throughput fluidic assays and provides a model for replicating disease states associated with the deterioration of retinal tissue during age-related macular degeneration (AMD). Microcontact printing of fibronectin on polystyrene and glass substrates was used to promote cell attachment, forming RPE patches of controlled size and shape. These colonies mimic the effect of atrophy and loss-of-function thatmore » occurs in the retina during degenerative diseases such as AMD. After 72 hours of cell growth, levels of vascular endothelial growth factor (VEGF), an important biomarker of AMD, were measured. Cells were counted and morphological indicators of cell viability and tight junction formation were assessed via fluorescence microscopy. As a result, up to a twofold increase of VEGF expression per cell was measured as colony size decreased, suggesting that the local microenvironment of, and connections between, RPE cells influences growth factor expression leading to the initiation and progression of diseases such as AMD.« less

  19. Controlling Retinal Pigment Epithelial Cell Patch Size Influences Growth Factor Expression

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Vargis, Elizabeth A; Peterson, Cristen B; Morrell-Falvey, Jennifer L; Retterer, Scott T; Collier, Pat

    2014-01-01

    The spatial organization of retinal pigment epithelial (RPE) cells grown in culture was controlled using micropatterning techniques in order to examine the effect of patch size on cell health and differentiation. Understanding this effect is a critical step in the development of multiplexed high throughput fluidic assays and provides a model for replicating disease states associated with the deterioration of retinal tissue during age-related macular degeneration (AMD). Microcontact printing of fibronectin on polystyrene and glass substrates was used to promote cell attachment, forming RPE patches of controlled size and shape. These colonies mimic the effect of atrophy and loss-of-function thatmore » occurs in the retina during degenerative diseases such as AMD. After 72 hours of cell growth, levels of vascular endothelial growth factor (VEGF), an important biomarker of AMD, were measured. Cells were counted and morphological indicators of cell viability and tight junction formation were assessed via fluorescence microscopy. Up to a twofold increase of VEGF expression per cell was measured as colony size decreased, suggesting that the local microenvironment of, and connections between, RPE cells influences growth factor expression leading to the initiation and progression of diseases such as AMD.« less

  20. ORISE: Protecting Human Subjects

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Protecting Human Subjects Protecting Human Subjects The U.S. Department of Energy (DOE) Human Subjects Research Program exists to ensure that all research conducted at DOE ...

  1. Human Resources Specialist (Human Resources Development)

    Broader source: Energy.gov [DOE]

    This position is located in the Leadership and Organizational Development group of Learning and Development (NHT), Human Capital Management (NH), Chief Administrative Officer (N). Human Capital...

  2. 3,5,4?-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/?-catenin signaling cascades and reversal of epithelialmesenchymal transition

    SciTech Connect (OSTI)

    Tsai, Jie-Heng; Hsu, Li-Sung; Lin, Chih-Li; Hong, Hui-Mei; Pan, Min-Hsiung; Way, Tzong-Der; Chen, Wei-Jen

    2013-11-01

    The molecular basis of epithelialmesenchymal transition (EMT) functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor-initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. We have recently verified the antitumor activity of 3,5,4?-trimethoxystilbene (MR-3), a naturally methoxylated derivative of resveratrol, in colorectal cancer xenografts via an induction of apoptosis. The effect of MR-3 on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored. We found that MR-3 significantly increased epithelial marker E-cadherin expression and triggered a cobblestone-like morphology of MCF-7 cells, while reciprocally decreasing the expression of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of ?-catenin, accompanied with the downregulation of ?-catenin target genes and the increment of membrane-bound ?-catenin. These results suggest the involvement of Wnt/?-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3? activity by inhibiting the phosphorylation of Akt, the event required for ?-catenin destruction via a proteasome-mediated system. Overall, these findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and consequently, ?-catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. - Highlights: MR-3 blocked MCF-7 cell invasion by inducing a reversal of EMT. Wnt/?-catenin signaling is involved in MR-3-induced EMT reversion of MCF-7

  3. COMMD1 regulates the delta epithelial sodium channel ({delta}ENaC) through trafficking and ubiquitination

    SciTech Connect (OSTI)

    Chang, Tina; Ke, Ying; Ly, Kevin; McDonald, Fiona J.

    2011-08-05

    Highlights: {yields} The COMM domain of COMMD1 mediates binding to {delta}ENaC. {yields} COMMD1 reduces the cell surface population of {delta}ENaC. {yields} COMMD1 increases the population of {delta}ENaC-ubiquitin. {yields} Both endogenous and transfected {delta}ENaC localize with COMMD1 and transferrin suggesting they are located in early/recycling endosomes. -- Abstract: The delta subunit of the epithelial sodium channel ({delta}ENaC) is a member of the ENaC/degenerin family of ion channels. {delta}ENaC is distinct from the related {alpha}-, {beta}- and {gamma}ENaC subunits, known for their role in sodium homeostasis and blood pressure control, as {delta}ENaC is expressed in brain neurons and activated by external protons. COMMD1 (copper metabolism Murr1 domain 1) was previously found to associate with and downregulate {delta}ENaC activity. Here, we show that COMMD1 interacts with {delta}ENaC through its COMM domain. Co-expression of {delta}ENaC with COMMD1 significantly reduced {delta}ENaC surface expression, and led to an increase in {delta}ENaC ubiquitination. Immunocytochemical and confocal microscopy studies show that COMMD1 promoted localization of {delta}ENaC to the early/recycling endosomal pool where the two proteins were localized together. These results suggest that COMMD1 downregulates {delta}ENaC activity by reducing {delta}ENaC surface expression through promoting internalization of surface {delta}ENaC to an intracellular recycling pool, possibly via enhanced ubiquitination.

  4. Human-machine interactions

    DOE Patents [OSTI]

    Forsythe, J. Chris; Xavier, Patrick G.; Abbott, Robert G.; Brannon, Nathan G.; Bernard, Michael L.; Speed, Ann E.

    2009-04-28

    Digital technology utilizing a cognitive model based on human naturalistic decision-making processes, including pattern recognition and episodic memory, can reduce the dependency of human-machine interactions on the abilities of a human user and can enable a machine to more closely emulate human-like responses. Such a cognitive model can enable digital technology to use cognitive capacities fundamental to human-like communication and cooperation to interact with humans.

  5. ORISE: Human Subjects Protection

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Subjects Protection The Oak Ridge Institute for Science and Education (ORISE) ... U.S. Department of Energy (DOE) laboratories involved in human subjects research projects. ...

  6. Jefferson Lab Human Resources

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources The Human Resources team is fully integrated with Jefferson Lab's mission, committed to providing quality customer service based on expertise, innovation and ...

  7. Human Reliability Assessment

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    ... Signup SlideShare Human Reliability Assessment HomeStationary PowerNuclear EnergyNuclear Energy Safety TechnologiesRisk and Safety AssessmentHuman Reliability Assessment ...

  8. Decoupling Internalization, Acidification and Phagosmal-Endosomal/Iysosomal Phagocytosis of Internalin A coated Beads in epithelial cells

    SciTech Connect (OSTI)

    Blanchette, C D; Woo, Y; Thomas, C; Shen, N; Sulchek, T A; Hiddessen, A L

    2008-12-22

    Phagocytosis has been extensively examined in 'professional' phagocytic cells using pH sensitive dyes. However, in many of the previous studies, a separation between the end of internalization, beginning of acidification and completion of phagosomal-endosomal/lysosomal fusion was not clearly established, and in several cases, it was treated as a one-step process. In addition, very little work has been done to systematically examine phagosomal maturation in 'non-professional' phagocytic cells, such as epithelial cells. Therefore, in this study, we developed a simple and novel method to decouple and accurately measure particle internalization, phagosomal acidification and phagosomal-endosomal/lysosomal fusion in Madin-Darby Canine Kidney (MDCK) and Caco-2 epithelial cells. Our method was developed using a pathogen mimetic system consisting of polystyrene beads coated with Internalin A (InlA), a membrane surface protein from Listeria monocytogenes known to trigger receptor-mediated internalization. We achieved independent measurements of the rates of internalization, phagosomal acidification and phagosomal-endosomal/lysosomal fusion in epithelial cells by combining the InlA-coated beads (InlA-beads) with antibody quenching, pH sensitive dyes and endosomal/lysosomal dyes, as follows: the rate of InlA bead internalization was measured via antibody quenching of a pH independent dye (Alexa488) conjugated to InlA-beads, the rate at which phagosomes containing internalized InlA beads became acidified was measured using a pH dependent dye (FITC) conjugated to the beads and the rate of phagosomal-endosomal/lysosomal fusion was measured using a combination of unlabeled InlA-beads and an endosomal/lysosomal dye. By performing these independent measurements under identical experimental conditions, we were able to decouple the three processes and establish time scales for each. In a separate set of experiments, we also exploited the phagosomal acidification process to demonstrate

  9. Protective effects of pulmonary epithelial lining fluid on oxidative stress and DNA single-strand breaks caused by ultrafine carbon black, ferrous sulphate and organic extract of diesel exhaust particles

    SciTech Connect (OSTI)

    Chuang, Hsiao-Chi; Cheng, Yi-Ling; Lei, Yu-Chen; Chang, Hui-Hsien; Cheng, Tsun-Jen

    2013-02-01

    Pulmonary epithelial lining fluid (ELF) is the first substance to make contact with inhaled particulate matter (PM) and interacts chemically with PM components. The objective of this study was to determine the role of ELF in oxidative stress, DNA damage and the production of proinflammatory cytokines following physicochemical exposure to PM. Ultrafine carbon black (ufCB, 15 nm; a model carbonaceous core), ferrous sulphate (FeSO{sub 4}; a model transition metal) and a diesel exhaust particle (DEP) extract (a model organic compound) were used to examine the acellular oxidative potential of synthetic ELF and non-ELF systems. We compared the effects of exposure to ufCB, FeSO{sub 4} and DEP extract on human alveolar epithelial Type II (A549) cells to determine the levels of oxidative stress, DNA single-strand breaks and interleukin-8 (IL-8) production in ELF and non-ELF systems. The effects of ufCB and FeSO{sub 4} on the acellular oxidative potential, cellular oxidative stress and DNA single-strand breakage were mitigated significantly by the addition of ELF, whereas there was no decrease following treatment with the DEP extract. There was no significant effect on IL-8 production following exposure to samples that were suspended in ELF/non-ELF systems. The results of the present study indicate that ELF plays an important role in the initial defence against PM in the pulmonary environment. Experimental components, such as ufCB and FeSO{sub 4}, induced the production of oxidative stress and led to DNA single-strand breaks, which were moderately prevented by the addition of ELF. These findings suggest that ELF plays a protective role against PM-driven oxidative stress and DNA damage. -- Highlights: ► To determine the role of ELF in ROS, DNA damage and IL-8 after exposure to PM. ► ufCB, FeSO{sub 4} and DEP extract were used to examine the protective effects of ELF. ► PM-driven oxidative stress and DNA single-strand breakage were mitigated by ELF. ► The findings

  10. ARM - Human Causes

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Study Hall About ARM Global Warming FAQ Just for Fun Meet our Friends Cool Sites Teachers Teachers' Toolbox Lesson Plans Human Causes Some of the human activities which can cause ...

  11. Human Genome: DOE Origins

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Genome Research: DOE Origins Resources with Additional Information Charles DeLisi Charles DeLisi The genesis of the Department of Energy (DOE) human genome project took place ...

  12. Dummy Run of Quality Assurance Program in a Phase 3 Randomized Trial Investigating the Role of Internal Mammary Lymph Node Irradiation in Breast Cancer Patients: Korean Radiation Oncology Group 08-06 Study

    SciTech Connect (OSTI)

    Chung, Yoonsun; Kim, Jun Won; Shin, Kyung Hwan; Kim, Su Ssan; Ahn, Sung-Ja; Park, Won; Lee, Hyung-Sik; Kim, Dong Won; Lee, Kyu Chan; Suh, Hyun Suk; Kim, Jin Hee; Shin, Hyun Soo; Kim, Yong Bae; Suh, Chang-Ok

    2015-02-01

    Purpose: The Korean Radiation Oncology Group (KROG) 08-06 study protocol allowed radiation therapy (RT) technique to include or exclude breast cancer patients from receiving radiation therapy to the internal mammary lymph node (IMN). The purpose of this study was to assess dosimetric differences between the 2 groups and potential influence on clinical outcome by a dummy run procedure. Methods and Materials: All participating institutions were asked to produce RT plans without irradiation (Arm 1) and with irradiation to the IMN (Arm 2) for 1 breast-conservation treatment case (breast-conserving surgery [BCS]) and 1 mastectomy case (modified radical mastectomy [MRM]) whose computed tomography images were provided. We assessed interinstitutional variations in IMN delineation and evaluated the dose-volume histograms of the IMN and normal organs. A reference IMN was delineated by an expert panel group based on the study guidelines. Also, we analyzed the potential influence of actual dose variation observed in this study on patient survival. Results: Although physicians intended to exclude the IMN within the RT field, the data showed almost 59.0% of the prescribed dose was delivered to the IMN in Arm 1. However, the mean doses covering the IMN in Arm 1 and Arm 2 were significantly different for both cases (P<.001). Due to the probability of overdose in Arm 1, the estimated gain in 7-year disease-free survival rate would be reduced from 10% to 7.9% for BCS cases and 7.1% for MRM cases. The radiation doses to the ipsilateral lung, heart, and coronary artery were lower in Arm 1 than in Arm 2. Conclusions: Although this dummy run study indicated that a substantial dose was delivered to the IMN, even in the nonirradiation group, the dose differences between the 2 groups were statistically significant. However, this dosimetric profile should be studied further with actual patient samples and be taken into consideration when analyzing clinical outcomes according to IMN

  13. Report: EM Human Capital Initiatives

    Office of Environmental Management (EM)

    HUMAN CAPITAL September 25, 2008 Submitted by the EMAB Human Capital Subcommittee Background: The enhancement of the Office of Environmental Management's (EM) human capital has ...

  14. Corporate Human Resources Information Services (CHIRS) PIA, Office of Human

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Capitol Management | Department of Energy Corporate Human Resources Information Services (CHIRS) PIA, Office of Human Capitol Management Corporate Human Resources Information Services (CHIRS) PIA, Office of Human Capitol Management Corporate Human Resources Information Services (CHIRS) PIA, Office of Human Capitol Management Corporate Human Resources Information Services (CHIRS) PIA, Office of Human Capitol Management (80.67 KB) More Documents & Publications MOX Services Unclassified

  15. Exploring the potential role of tungsten carbide cobalt (WC-Co) nanoparticle internalization in observed toxicity toward lung epithelial cells in vitro

    SciTech Connect (OSTI)

    Armstead, Andrea L.; Arena, Christopher B.; Li, Bingyun

    2014-07-01

    Tungsten carbide cobalt (WC-Co) has been recognized as a workplace inhalation hazard in the manufacturing, mining and drilling industries by the National Institute of Occupational Safety and Health. Exposure to WC-Co is known to cause “hard metal lung disease” but the relationship between exposure, toxicity and development of disease remain poorly understood. To better understand this relationship, the present study examined the role of WC-Co particle size and internalization on toxicity using lung epithelial cells. We demonstrated that nano- and micro-WC-Co particles exerted toxicity in a dose- and time-dependent manner and that nano-WC-Co particles caused significantly greater toxicity at lower concentrations and shorter exposure times compared to micro-WC-Co particles. WC-Co particles in the nano-size range (not micron-sized) were internalized by lung epithelial cells, which suggested that internalization may play a key role in the enhanced toxicity of nano-WC-Co particles over micro-WC-Co particles. Further exploration of the internalization process indicated that there may be multiple mechanisms involved in WC-Co internalization such as actin and microtubule based cytoskeletal rearrangements. These findings support our hypothesis that WC-Co particle internalization contributes to cellular toxicity and suggest that therapeutic treatments inhibiting particle internalization may serve as prophylactic approaches for those at risk of WC-Co particle exposure. - Highlights: • Hard metal (WC-Co) particle toxicity was established in lung epithelial cells. • Nano-WC-Co particles caused greater toxicity than micro-WC-Co particles. • Nano- and micro-WC-Co particles were capable of inducing cellular apoptosis. • Nano-WC-Co particles were internalized by lung epithelial cells. • WC-Co particle internalization was mediated by actin dynamics.

  16. Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and ?-catenin signaling pathway

    SciTech Connect (OSTI)

    Li, Hongzhong; Huang, Jing; Yang, Bing; Xiang, Tingxiu; Yin, Xuedong; Peng, Weiyan; Cheng, Wei; Wan, Jingyuan; Luo, Fuling; Li, Hongyuan; Ren, Guosheng

    2013-10-01

    Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelialmesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of ?-catenin pathway. Subsequent experiments showed that inhibiting ?-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active ?-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. - Highlights: Mangiferin inhibits growth and metastatic potential in breast cancer cells. Mangiferin down-regulates MMP-7 and -9 in breast cancer cells. Mangiferin induces the reversal of EMT in metastatic breast cancer cells. Mangiferin inhibits the activation of ?-catenin pathway in breast cancer cells. Inhibiting ?-catenin is responsible for the antitumor activity of mangiferin.

  17. Cellular interactions via conditioned media induce in vivo nephron generation from tubular epithelial cells or mesenchymal stem cells

    SciTech Connect (OSTI)

    Machiguchi, Toshihiko Nakamura, Tatsuo

    2013-06-07

    Highlights: We have attempted in vivo nephron generation using conditioned media. Vascular and tubular cells do cross-talks on cell proliferation and tubular changes. Tubular cells suppress these changes in mesenchymal stem cells. Tubular cells differentiate mesenchymal stem cells into tubular cells. Nephrons can be created from implanted tubular cells or mesenchymal stem cells. -- Abstract: There are some successful reports of kidney generation by utilizing the natural course of kidney development, namely, the use of an artificially treated metanephros, blastocyst or ureteric bud. Under a novel concept of cellular interactions via conditioned media (CMs), we have attempted in vivo nephron generation from tubular epithelial cells (TECs) or mesenchymal stem cells (MSCs). Here we used 10 CMs of vascular endothelial cells (VECs) and TECs, which is the first to introduce a CM into the field of organ regeneration. We first present stimulative cross-talks induced by these CMs between VECs and TECs on cell proliferation and morphological changes. In MSCs, TEC-CM suppressed these changes, however, induced cytokeratin expression, indicating the differentiation of MSCs into TECs. As a result, glomerular and tubular structures were created following the implantation of TECs or MSCs with both CMs. Our findings suggest that the cellular interactions via CMs might induce in vivo nephron generation from TECs or MSCs. As a promoting factor, CMs could also be applied to the regeneration of other organs and tissues.

  18. Human Genome: DOE Origins

    Office of Scientific and Technical Information (OSTI)

    of the Department of Energy; DOE Technical Report; 1988 Mapping and Sequencing the Human Genome; DOE Technical Report; 1988 Understanding our Genetic Inheritance: The U.S....

  19. Jefferson Lab Human Resources

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    ... Sponsor click on this link to nominate a student: SPONSOR NOMINATION FORM If you have any questions please contact: Human Resources Jefferson Science Associates 628 Hofstadter Rd., ...

  20. Jefferson Lab Human Resources

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    JLab Diversity Policies 200 Human Resources 202 Equal Employment Opportunity and Affirmative Action 203 Employment 208 Employee Performance and Conduct 209 Staff Development 210 ...

  1. Jefferson Lab Human Resources

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources Consultants Cassandra Andrews, HR Consultant, Employee Relations & Recruitment (757) 269-7068, candrews@jlab.org Kelly Allmon, HR Consultant, Recruitment & ...

  2. Metaproteomics Reveals Functional Shifts in Microbial and Human Proteins During Infant Gut Colonization Case

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Young, Jacque C.; Pan, Chongle; Adams, Rachel M.; Brooks, Brandon; Banfield, Jillian F.; Morowitz, Michael J.; Robert L. Hettich

    2015-01-01

    The microbial colonization of the human gastrointestinal tract plays an important role in establishing health and homeostasis. However, the time-dependent functional signatures of microbial and human proteins during early colonization of the gut have yet to be determined. Thus, we employed shotgun proteomics to simultaneously monitor microbial and human proteins in fecal samples from a preterm infant during the first month of life. Microbial community complexity and functions increased over time, with compositional changes that were consistent with previous metagenomic and rRNA gene data indicating three distinct colonization phases. Overall microbial community functions were established relatively early in development andmore » remained stable. Human proteins detected included those responsible for epithelial barrier function and antimicrobial activity. Some neutrophil-derived proteins increased in abundance early in the study period, suggesting activation of the innate immune system. Moreover, abundances of cytoskeletal and mucin proteins increased later in the time course, suggestive of subsequent adjustment to the increased microbial load. Our study provides the first snapshot of coordinated human and microbial protein expression in the infant gut during early development.« less

  3. Metaproteomics Reveals Functional Shifts in Microbial and Human Proteins During Infant Gut Colonization Case

    SciTech Connect (OSTI)

    Young, Jacque C.; Pan, Chongle; Adams, Rachel M.; Brooks, Brandon; Banfield, Jillian F.; Morowitz, Michael J.; Robert L. Hettich

    2015-01-01

    The microbial colonization of the human gastrointestinal tract plays an important role in establishing health and homeostasis. However, the time-dependent functional signatures of microbial and human proteins during early colonization of the gut have yet to be determined. Thus, we employed shotgun proteomics to simultaneously monitor microbial and human proteins in fecal samples from a preterm infant during the first month of life. Microbial community complexity and functions increased over time, with compositional changes that were consistent with previous metagenomic and rRNA gene data indicating three distinct colonization phases. Overall microbial community functions were established relatively early in development and remained stable. Human proteins detected included those responsible for epithelial barrier function and antimicrobial activity. Some neutrophil-derived proteins increased in abundance early in the study period, suggesting activation of the innate immune system. Moreover, abundances of cytoskeletal and mucin proteins increased later in the time course, suggestive of subsequent adjustment to the increased microbial load. Our study provides the first snapshot of coordinated human and microbial protein expression in the infant gut during early development.

  4. Protection of Human Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2000-05-15

    To establish DOE procedures and responsibilities for implementing the policy and requirements set forth in 10 CFR Part 745, Protection of Human Subjects, ad in DOE P 443.1, Policy on the Protection of Human Subjects. Cancels DOE O 1300.3. Canceled by DOE O 443.1A.

  5. Protection of Human Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2007-12-20

    The order establishes Department of Energy (DOE) procedures and responsibilities for implementing the policy and requirements set forth in 10 Code of Federal Regulations (CFR) Part 745, Protection of Human Subjects; and in DOE P 443.1A, Protection of Human Subjects, dated 12-20-07. Cancels DOE O 443.1. Canceled by DOE O 443.1B.

  6. The human genome project

    SciTech Connect (OSTI)

    Yager, T.D.; Zewert, T.E.; Hood, L.E. )

    1994-04-01

    The Human Genome Project (HGP) is a coordinated worldwide effort to precisely map the human genome and the genomes of selected model organisms. The first explicit proposal for this project dates from 1985 although its foundations (both conceptual and technological) can be traced back many years in genetics, molecular biology, and biotechnology. The HGP has matured rapidly and is producing results of great significance.

  7. Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro

    SciTech Connect (OSTI)

    Zhang, Huiying; Department of Environmental and Molecular Toxicology, College of Agriculture and Life Sciences, NC State University, Raleigh, NC 27695 ; Newman, Donna R.; Bonner, James C.; Sannes, Philip L.

    2012-11-15

    Environmental exposure to cadmium is known to cause damage to alveolar epithelial cells of the lung, impair their capacity to repair, and result in permanent structural alterations. Cell surface heparan sulfate proteoglycans (HSPGs) can modulate cell responses to injury through their interactions with soluble effector molecules. These interactions are often sulfate specific, and the removal of sulfate groups from HS side chains could be expected to influence cellular injury, such as that caused by exposure to cadmium. The goal of this study was to define the role 6-O-sulfate plays in cellular responses to cadmium exposure in two pulmonary epithelial cancer cell lines (H292 and A549) and in normal human primary alveolar type II (hAT2) cells. Sulfate levels were modified by transduced transient over-expression of 6-O-endosulfatase (HSulf-1), a membrane-bound enzyme which specifically removes 6-O-sulfate groups from HSPG side chains. Results showed that cadmium decreased cell viability and activated apoptosis pathways at low concentrations in hAT2 cells but not in the cancer cells. HSulf-1 over-expression, on the contrary, decreased cell viability and activated apoptosis pathways in H292 and A549 cells but not in hAT2 cells. When combined with cadmium, HSulf-1 over-expression further decreased cell viability and exacerbated the activation of apoptosis pathways in the transformed cells but did not add to the toxicity in hAT2 cells. The finding that HSulf-1 sensitizes these cancer cells and intensifies the injury induced by cadmium suggests that 6-O-sulfate groups on HSPGs may play important roles in protection against certain environmental toxicants, such as heavy metals. -- Highlights: ? Primary human lung alveolar type 2 (hAT2) cells and H292 and A549 cells were used. ? Cadmium induced apoptosis in hAT2 cells but not in H292 or A549 cells. ? HSulf-1exacerbates apoptosis induced by cadmium in H292 and A549 but not hAT2 cells.

  8. EGFR tyrosine kinase inhibitory peptide attenuates Helicobacter pylori-mediated hyper-proliferation in AGS enteric epithelial cells

    SciTech Connect (OSTI)

    Himaya, S.W.A.; Dewapriya, Pradeep; Kim, Se-Kwon

    2013-06-15

    Helicobacter pylori infection is one of the most critical causes of stomach cancer. The current study was conducted to explore the protective effects of an isolated active peptide H-P-6 (Pro-Gln-Pro-Lys-Val-Leu-Asp-Ser) from microbial hydrolysates of Chlamydomonas sp. against H. pylori-induced carcinogenesis. The peptide H-P-6 has effectively suppressed H. pylori-induced hyper-proliferation and migration of gastric epithelial cells (AGS). However, the peptide did not inhibit the viability of the bacteria or invasion into AGS cells. Therefore, the effect of the peptide on regulating H. pylori-induced molecular signaling was investigated. The results indicated that H. pylori activates the EGFR tyrosine kinase signaling and nuclear translocation of the ?-catenin. The EGFR activation has led to the up-regulation of PI3K/Akt signaling pathway. Moreover, the nuclear translocation levels of ?-catenin were significantly increased as a result of Akt mediated down-regulation of GSK3/? protein levels in the cytoplasm. Both of these consequences have resulted in increased expression of cell survival and migration related genes such as c-Myc, cyclin-D, MMP-2 and matrilysin. Interestingly, the isolated peptide potently inhibited H. pylori-mediated EGFR activation and thereby down-regulated the subsequent P13K/Akt signaling leading to ?-catenin nuclear translocation. The effect of the peptide was confirmed with the use of EGFR tyrosine kinase inhibitor AG1487 and molecular docking studies. Collectively this study identifies a potent peptide which regulates the H. pylori-induced hyper-proliferation and migration of AGS cells at molecular level. - Highlights: Chlamydomonas sp. derived peptide H-P-6 inhibits H. pylori-induced pathogenesis. H-P-6 suppresses H. pylori-induced hyper-proliferation and migration of AGS cells. The peptide inhibits H. pylori-induced EGFR activation.

  9. BENZO[a]PYRENE DIOL EPOXIDE PERTURBATION OF CELL CYCLE KINETICS OF SYNCHRONIZED MOUSE LIVER EPITHELIAL CELLS

    SciTech Connect (OSTI)

    Pearlman, A.L.; Navsky, B.N.; Bartholomew, J.C

    1980-07-01

    A cell cycle synchronization system is described for the analysis of the perturbation of cell cycle kinetics and the cycle-phase specificity of chemicals and other agents. We used the system to study the effects of ({+-})r-7, t-8-dihydroxy-t-9, 10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide) upon the cell cycle of mouse liver epithelial cells(NMuLi). BaP diol epoxide(0.6 uM) was added to replated cultures of NMuLi cells that had been synchronized in various stages of the cell cycle by centrifugal elutriation. DNA histograms were obtained by flow cytometry as a function of time after replating. The data were analyzed by a computer modeling routine and reduced to a few graphs illustrating the 'net effects' of the BaP diol epoxide relative to controls. BaP diol epoxide slowed S-phase traversal in all samples relative to their respective control. Traversal through G{sub 2}M was also slowed by at least 50%. BaP diol epoxide had no apparent effect upon G{sub 1} traversal by cycling cells, but delayed the recruitment of quiescent G{sub 0} cells by about 2 hrs. The methods described constitute a powerful new approach for probing the cell cycle effects of a wide variety of agents. The present system appears to be extremely sensitive and capable of characterizing the action of agents on each phase of the cell cycle. The methods are automatable and would allow for the assay and possible differential characterization of mutagens and carcinogens.

  10. Apical polarity in three-dimensional culture systems: where to now?

    SciTech Connect (OSTI)

    Inman, J.L.; Bissell, Mina

    2010-01-21

    Delineation of the mechanisms that establish and maintain the polarity of epithelial tissues is essential to understanding morphogenesis, tissue specificity and cancer. Three-dimensional culture assays provide a useful platform for dissecting these processes but, as discussed in a recent study in BMC Biology on the culture of mammary gland epithelial cells, multiple parameters that influence the model must be taken into account.

  11. Human Genome Project

    SciTech Connect (OSTI)

    Block, S.; Cornwall, J.; Dally, W.; Dyson, F.; Fortson, N.; Joyce, G.; Kimble, H. J.; Lewis, N.; Max, C.; Prince, T.; Schwitters, R.; Weinberger, P.; Woodin, W. H.

    1998-01-04

    The study reviews Department of Energy supported aspects of the United States Human Genome Project, the joint National Institutes of Health/Department of Energy program to characterize all human genetic material, to discover the set of human genes, and to render them accessible for further biological study. The study concentrates on issues of technology, quality assurance/control, and informatics relevant to current effort on the genome project and needs beyond it. Recommendations are presented on areas of the genome program that are of particular interest to and supported by the Department of Energy.

  12. Human Reliability Program Overview

    SciTech Connect (OSTI)

    Bodin, Michael

    2012-09-25

    This presentation covers the high points of the Human Reliability Program, including certification/decertification, critical positions, due process, organizational structure, program components, personnel security, an overview of the US DOE reliability program, retirees and academia, and security program integration.

  13. Protection of Human Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2007-12-20

    The Policy is to establish DOE-specific principles for the protection of human subjects involved in DOE research. Cancels DOE P 443.1. Canceled by DOE O 443.1B

  14. Protection of Human Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2000-05-15

    The purpose of this Policy is to establish DOE-specific policy for the protection of human subjects involved in DOE research. Canceled by DOE P 443.1A.

  15. Human Resource Management Delegation

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    1996-06-28

    The notice is to clarifies and updates existing Human Resource Management Delegation Authorities and the levels to which they are delegated. Expired 6-28-97. Does not cancel any directives.

  16. Structural studies of human Naked2: A biologically active intrinsically unstructured protein

    SciTech Connect (OSTI)

    Hu Tianhui; Krezel, Andrzej M.; Li Cunxi; Coffey, Robert J. . E-mail: robert.coffey@vanderbilt.edu

    2006-12-01

    Naked1 and 2 are two mammalian orthologs of Naked Cuticle, a canonical Wnt signaling antagonist in Drosophila. Naked2, but not Naked1, interacts with transforming growth factor-{alpha} (TGF{alpha}) and escorts TGF{alpha}-containing vesicles to the basolateral membrane of polarized epithelial cells. Full-length Naked2 is poorly soluble. Since most functional domains, including the Dishevelled binding region, EF-hand, vesicle recognition, and membrane targeting motifs, reside in the N-terminal half of the protein, we expressed and purified the first 217 residues of human Naked2 and performed a functional analysis of this fragment. Its circular dichroism (CD) and nuclear magnetic resonance (NMR) spectra showed no evidence of secondary and/or tertiary structure. The fragment did not bind calcium or zinc. These results indicate that the N-terminal half of Naked2 behaves as an intrinsically unstructured protein.

  17. ORISE: Protecting Human Subjects Website

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Protecting Human Subjects Website Institutions that engage in human subjects research are required by federal policy to establish an institutional review board (IRB) to ensure that ...

  18. Human Resources | The Ames Laboratory

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources The mission of the Human Resource Department is to support the goals of The Ames Laboratory by providing support services which promote a work environmnent ...

  19. Human Genome Research: Decoding DNA

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Genome Research: Decoding DNA Resources with Additional Information Charles DeLisi ... role in proposing and initiating the Human Genome Program in 1986. The U.S. ...

  20. ORISE: Human Subjects Research Database

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Subjects Research Database Section 10, Part 745 of the Code of Federal Regulations ... on all research projects that involve human subjects and that are funded by DOE, ...

  1. New light on human evolution

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    light on human evolution New light on human evolution Scientists recently unearthed 8 million-year-old gorilla fossils from the Chorora Formation in Ethiopia, which indicate the ...

  2. Human Capital - DOE Directives, Delegations, and Requirements

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Capital by Website Administrator Back

  3. A bioinformatics prediction approach towards analyzing the glycosylation, co-expression and interaction patterns of epithelial membrane antigen (EMA/MUC1)

    SciTech Connect (OSTI)

    Kalra, Rajkumar S. Wadhwa, Renu

    2015-02-27

    Epithelial membrane antigen (EMA or MUC1) is a heavily glycosylated, type I transmembrane glycoprotein commonly expressed by epithelial cells of duct organs. It has been shown to be aberrantly glycosylated in several diseases including cancer. Protein sequence based annotation and analysis of glycosylation profile of glycoproteins by robust computational and comprehensive algorithms provides possible insights to the mechanism(s) of anomalous glycosylation. In present report, by using a number of bioinformatics applications we studied EMA/MUC1 and explored its trans-membrane structural domain sequence that is widely subjected to glycosylation. Exploration of different extracellular motifs led to prediction of N and O-linked glycosylation target sites. Based on the putative O-linked target sites, glycosylated moieties and pathways were envisaged. Furthermore, Protein network analysis demonstrated physical interaction of EMA with a number of proteins and confirmed its functional involvement in cell growth and proliferation pathways. Gene Ontology analysis suggested an involvement of EMA in a number of functions including signal transduction, protein binding, processing and transport along with glycosylation. Thus, present study explored potential of bioinformatics prediction approach in analyzing glycosylation, co-expression and interaction patterns of EMA/MUC1 glycoprotein.

  4. Reprogramming of cell junction modules during stepwise epithelial to mesenchymal transition and accumulation of malignant features in vitro in a prostate cell model

    SciTech Connect (OSTI)

    Ke, Xi-song; Department of Microbiology, Haukeland, University Hospital, Bergen ; Li, Wen-cheng; Urological Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 ; Hovland, Randi; Department of Molecular Biology, University of Bergen, Bergen ; Qu, Yi; Liu, Run-hui; McCormack, Emmet; Thorsen, Frits; Olsen, Jan Roger; Molven, Anders; Department of Pathology, Haukeland University Hospital, Bergen ; Kogan-Sakin, Ira; Rotter, Varda; Akslen, Lars A.; Department of Pathology, Haukeland University Hospital, Bergen ; Oyan, Anne Margrete; Department of Microbiology, Haukeland, University Hospital, Bergen ; Kalland, Karl-Henning; Department of Microbiology, Haukeland, University Hospital, Bergen

    2011-01-15

    Epithelial to mesenchymal transition (EMT) is pivotal in tumor metastasis. Our previous work reported an EMT model based on primary prostate epithelial cells (EP156T) which gave rise to cells with mesenchymal phenotype (EPT1) without malignant transformation. To promote prostate cell transformation, cells were maintained in saturation density cultures to select for cells overriding quiescence. Foci formed repeatedly following around 8 weeks in confluent EPT1 monolayers. Only later passage EPT1, but not EP156T cells of any passage, could form foci. Cells isolated from the foci were named EPT2 and formed robust colonies in soft agar, a malignant feature present neither in EP156T nor in EPT1 cells. EPT2 cells showed additional malignant traits in vitro, including higher ability to proliferate following confluence, higher resistance to apoptosis and lower dependence on exogenous growth factors than EP156T and EPT1 cells. Microarray profiling identified gene sets, many of which belong to cell junction modules, that changed expression from EP156T to EPT1 cells and continued to change from EPT1 to EPT2 cells. Our findings provide a novel stepwise cell culture model in which EMT emerges independently of transformation and is associated with subsequent accumulation of malignant features in prostate cells. Reprogramming of cell junction modules is involved in both steps.

  5. Human MSH2 protein

    DOE Patents [OSTI]

    Chapelle, A. de la; Vogelstein, B.; Kinzler, K.W.

    1997-01-07

    The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error{sup +} (RER{sup +}) tumor cells. 19 figs.

  6. Human MSH2 protein

    DOE Patents [OSTI]

    de la Chapelle, Albert; Vogelstein, Bert; Kinzler, Kenneth W.

    1997-01-01

    The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

  7. Human Resources | The Ames Laboratory

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Budget Human Resources The Human Resources function in NNSA is a vital partnership between all levels of NNSA management. It requires effective collaboration with the Service Center's Office of Human Capital Management Services. The Headquarters' Office of Human Capital Management Programs is organized into the following five divisions. Policy and Planning The Policy and Planning Division will be responsible for the development, implementation, and oversight of, human resources management

  8. Human Reliability Program Handbook

    Broader source: Energy.gov [DOE]

    The Human Reliability Program is a security and safety reliability program designed to ensure that individuals who occupy positions affording access to certain materials, nuclear explosive devices, facilities, and programs meet the highest standards of reliability and physical and mental suitability.

  9. The effect of DDT and its metabolite (DDE) on prostaglandin secretion from epithelial cells and on contractions of the smooth muscle of the bovine oviduct in vitro

    SciTech Connect (OSTI)

    Wrobel, Michal H.; Mlynarczuk, Jaroslaw; Kotwica, Jan

    2012-03-01

    The insecticide DDT and its metabolite (DDE), due to their lipolytic nature and resistance to biodegradation, are accumulated in the living tissues. In cows, DDT and DDE were found to affect prostaglandin (PG) secretion from the endometrium and contractions of the myometrium. In this study, the impact of both xenobiotics (0.1, 1, 10 or 100 ng/ml) on the function of epithelial cells and muscle strips of bovine oviducts from 1 to 5 day of the oestrous cycle was examined. Therefore the concentration of PGE2 and PGFM (a metabolite of PGF2α) in culture media, mRNA expression of genes involved in PGs synthesis in epithelial cells and the force and amplitude of strips contractions were measured after 2 and 24 or 48 h of incubation. Neither DDT nor DDE affected the viability of cells after 48 h (P > 0.05). Both DDT and DDE increased the concentrations of PGFM in culture medium and secretion of PGE2 after only 2 h of cell culture (P < 0.05). Similar effects were seen for the influence of DDE on amount of PGFM after 48 h, while DDT decreased secretion of PGE2 (P < 0.05). DDT after 2 h increased (P < 0.05) mRNA expression of PGF2α synthase (PGFS), while both xenobiotics decreased (P < 0.05) mRNA expression of cyclooxygenase-2 (COX-2) after 24 h. DTT also increased the force of isthmus contractions after 2 h, as did both xenobiotics after 48 h (P < 0.05). Moreover, after 2 and 48 h, DDE stimulated the amplitude of contractions of the isthmus as well as the ampulla, (P < 0.05). The effect of both compounds on oviduct contractions was diminished by indomethacin, which blocks PG synthesis. We conclude that oviductal secretion of prostaglandins is affected, by DDT and DDE. The influence of these xenobiotics on PGF2α and PGE2 secretion and ratio may be part of the mechanism by which both DDT and its metabolite disturb the contractions of oviductal muscle. -- Highlights: ► DDT and its metabolite – DDE are accumulated in the living tissues. ► The insecticides affected PGF2

  10. Human Factors Engineering Analysis Tool

    Energy Science and Technology Software Center (OSTI)

    2002-03-04

    HFE-AT is a human factors engineering (HFE) software analysis tool (AT) for human-system interface design of process control systems, and is based primarily on NUREG-0700 guidance.

  11. Global Warming and Human Health

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    American Geophysical Union Global Warming and Human Health WHEN: Jul 27, 2015 5:30 PM - ... Event Description The main reason we are concerned about human-induced climate change is ...

  12. ORISE: Protecting Human Subjects Website

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Protecting Human Subjects Website Institutions that engage in human subjects research are required by federal policy to establish an institutional review board (IRB) to ensure that risks to human subjects in research are minimal and to provide protection with respect to the rights and welfare of research subjects. The Oak Ridge Institute for Science and Education (ORISE) administers the Oak Ridge Sitewide Institutional Review Board (ORSIRB) and manages the ORISE Human Subjects website. The

  13. Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells

    SciTech Connect (OSTI)

    Shibuya, Akiko; Onda, Kenji; Kawahara, Hirofumi; Uchiyama, Yuka; Nakayama, Hiroko; Omi, Takamasa; Nagaoka, Masayoshi; Matsui, Hirofumi; Hirano, Toshihiko

    2010-07-30

    Research highlights: {yields} Sofalcone increases HO-1 in gastric epithelial cells. {yields} The induction of HO-1 by sofalcone treatment follows the activation of Nrf2. {yields} The production of VEGF by sofalcone treatment is mediated by HO-1 induction. -- Abstract: Sofalcone, 2'-carboxymethoxy-4,4-bis(3-methyl-2-butenyloxy)chalcone, is an anti-ulcer agent that is classified as a gastric mucosa protective agent. Recent studies indicate heat shock proteins such as HSP32, also known as heme-oxygenase-1(HO-1), play important roles in protecting gastrointestinal tissues from several stresses. We have previously reported that sofalcone increases the expression of HO-1 in adipocytes and pre-adipocytes, although the effect of sofalcone on HO-1 induction in gastrointestinal tissues is not clear. In the current study, we investigated the effects of sofalcone on the expression of HO-1 and its functional role in rat gastric epithelial (RGM-1) cells. We found that sofalcone increased HO-1 expression in RGM-1 cells in both time- and concentration-dependent manners. The HO-1 induction was associated with the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in RGM-1 cells. We also observed that sofalcone increased vascular endothelial growth factor (VEGF) production in the culture medium. Treatment of RGM-1 cells with an HO-1 inhibitor (tin-protoporphyrin), or HO-1 siRNA inhibited sofalcone-induced VEGF production, suggesting that the effect of sofalcone on VEGF expression is mediated by the HO-1 pathway. These results suggest that the gastroprotective effects of sofalcone are partly exerted via Nrf2-HO-1 activation followed by VEGF production.

  14. Protection of Human Research Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2011-03-17

    The Order establishes DOE-specific policy and principles for the protection of human subjects involved in DOE research, and DOE procedures and responsibilities for implementing the policy and requirements set forth in Title 45 Code of Federal Regulations (CFR) Part 46, Protection of Human Subjects, and 10 CFR Part 745, Protection of Human Subjects. Supersedes DOE O 443.1B.

  15. Human Capital Management Accountability Program

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2008-08-01

    The Order establishes requirements, roles and responsibilities for the Human Capital Management Accountability Program (HCMAP) for human resources programs and personnel and ensures that human capital activities are regulatory and procedurally compliant with Federal statutes and Departmental policies. Does not cancel other directives.

  16. Human portable preconcentrator system

    DOE Patents [OSTI]

    Linker, Kevin L.; Bouchier, Francis A.; Hannum, David W.; Rhykerd, Jr., Charles L.

    2003-01-01

    A preconcentrator system and apparatus suited to human portable use wherein sample potentially containing a target chemical substance is drawn into a chamber and through a pervious screen. The screen is adapted to capture target chemicals and then, upon heating, to release those chemicals into the chamber. Chemicals captured and then released in this fashion are then carried to a portable chemical detection device such as a portable ion mobility spectrometer. In the preferred embodiment, the means for drawing sample into the chamber comprises a reversible fan which, when operated in reverse direction, creates a backpressure that facilitates evolution of captured target chemicals into the chamber when the screen is heated.

  17. HUMAN MACHINE COOPERATIVE TELEROBOTICS

    SciTech Connect (OSTI)

    William R. Hamel; Spivey Douglass; Sewoong Kim; Pamela Murray; Yang Shou; Sriram Sridharan; Ge Zhang; Scott Thayer; Rajiv V. Dubey

    2003-06-30

    The remediation and deactivation and decommissioning (D&D) of nuclear waste storage tanks using telerobotics is one of the most challenging tasks faced in environmental cleanup. Since a number of tanks have reached the end of their design life and some of them have leaks, the unstructured, uncertain and radioactive environment makes the work inefficient and expensive. However, the execution time of teleoperation consumes ten to hundred times that of direct contact with an associated loss in quality. Thus, a considerable effort has been expended to improve the quality and efficiency of telerobotics by incorporating into teleoperation and robotic control functions such as planning, trajectory generation, vision, and 3-D modeling. One example is the Robot Task Space Analyzer (RTSA), which has been developed at the Robotics and Electromechanical Systems Laboratory (REMSL) at the University of Tennessee in support of the D&D robotic work at the Oak Ridge National Laboratory and the National Energy Technology Laboratory. This system builds 3-D models of the area of interest in task space through automatic image processing and/or human interactive manual modeling. The RTSA generates a task plan file, which describes the execution of a task including manipulator and tooling motions. The high level controller of the manipulator interprets the task plan file and executes the task automatically. Thus, if the environment is not highly unstructured, a tooling task, which interacts with environment, will be executed in the autonomous mode. Therefore, the RTSA not only increases the system efficiency, but also improves the system reliability because the operator will act as backstop for safe operation after the 3-D models and task plan files are generated. However, unstructured conditions of environment and tasks necessitate that the telerobot operates in the teleoperation mode for successful execution of task. The inefficiency in the teleoperation mode led to the research

  18. Human Genome Program

    SciTech Connect (OSTI)

    Not Available

    1993-01-01

    The DOE Human Genome program has grown tremendously, as shown by the marked increase in the number of genome-funded projects since the last workshop held in 1991. The abstracts in this book describe the genome research of DOE-funded grantees and contractors and invited guests, and all projects are represented at the workshop by posters. The 3-day meeting includes plenary sessions on ethical, legal, and social issues pertaining to the availability of genetic data; sequencing techniques, informatics support; and chromosome and cDNA mapping and sequencing.

  19. PIA - Human Resources Information System (HRIS) | Department...

    Broader source: Energy.gov (indexed) [DOE]

    Information System (HRIS) PIA - Human Resources Information System (HRIS) (232.73 KB) More Documents & Publications PIA - INL PeopleSoft - Human Resource System PIA - Human ...

  20. Project ATHENA creates surrogate human organ systems

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Project ATHENA creates surrogate human organ systems Project ATHENA creates surrogate human organ systems The development of miniature surrogate human organs, coupled with highly ...

  1. Contractor Human Resources | National Nuclear Security Administration...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Contractor Human Resources The Contractor Human Resources mission is to provide expert advice and assistance to our customers in order to ensure quality Contractor Human Resource ...

  2. New human resources division leader selected

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    New Human Resources division leader selected New human resources division leader selected Donna J. Hampton has been named the new Human Resources Division leader. March 15, 2011 ...

  3. ORISE: Human Subjects Protection Resource Protection Book

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Subjects Protection Resource Book The Human Subjects Protection Resource Book synthesizes information currently available on the protection of human subjects in research, the ...

  4. Human subjects research handbook: Protecting human research subjects. Second edition

    SciTech Connect (OSTI)

    1996-01-30

    This handbook serves as a guide to understanding and implementing the Federal regulations and US DOE Orders established to protect human research subjects. Material in this handbook is directed towards new and continuing institutional review board (IRB) members, researchers, institutional administrators, DOE officials, and others who may be involved or interested in human subjects research. It offers comprehensive overview of the various requirements, procedures, and issues relating to human subject research today.

  5. Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

    SciTech Connect (OSTI)

    Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet; Quistgaard, Esben M.; Nordlund, Par; Thanabalu, Thirumaran; Torres, Jaume

    2015-08-15

    The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target.

  6. Human portable preconcentrator system

    SciTech Connect (OSTI)

    Linker, Kevin L.; Brusseau, Charles A.; Hannum, David W.; Puissant, James G.; Varley, Nathan R.

    2003-08-12

    A preconcentrator system and apparatus suited to human portable use wherein sample potentially containing a target chemical substance is drawn into a chamber and through a pervious screen. The screen is adapted to capture target chemicals and then, upon heating, to release those chemicals into the chamber. Chemicals captured and then released in this fashion are then carried to a portable chemical detection device such as a portable ion mobility spectrometer. In the preferred embodiment, the means for drawing sample into the chamber comprises a reversible fan which, when operated in reverse direction, creates a backpressure that facilitates evolution of captured target chemicals into the chamber when the screen is heated. The screen can be positioned directly in front of the detector prior to heating to improve detection capability.

  7. Human-computer interface

    DOE Patents [OSTI]

    Anderson, Thomas G.

    2004-12-21

    The present invention provides a method of human-computer interfacing. Force feedback allows intuitive navigation and control near a boundary between regions in a computer-represented space. For example, the method allows a user to interact with a virtual craft, then push through the windshield of the craft to interact with the virtual world surrounding the craft. As another example, the method allows a user to feel transitions between different control domains of a computer representation of a space. The method can provide for force feedback that increases as a user's locus of interaction moves near a boundary, then perceptibly changes (e.g., abruptly drops or changes direction) when the boundary is traversed.

  8. Human Reliability Program Workshop

    SciTech Connect (OSTI)

    Landers, John; Rogers, Erin; Gerke, Gretchen

    2014-05-18

    A Human Reliability Program (HRP) is designed to protect national security as well as worker and public safety by continuously evaluating the reliability of those who have access to sensitive materials, facilities, and programs. Some elements of a site HRP include systematic (1) supervisory reviews, (2) medical and psychological assessments, (3) management evaluations, (4) personnel security reviews, and (4) training of HRP staff and critical positions. Over the years of implementing an HRP, the Department of Energy (DOE) has faced various challenges and overcome obstacles. During this 4-day activity, participants will examine programs that mitigate threats to nuclear security and the insider threat to include HRP, Nuclear Security Culture (NSC) Enhancement, and Employee Assistance Programs. The focus will be to develop an understanding of the need for a systematic HRP and to discuss challenges and best practices associated with mitigating the insider threat.

  9. Human Performance Modeling for Dynamic Human Reliability Analysis

    SciTech Connect (OSTI)

    Boring, Ronald Laurids; Joe, Jeffrey Clark; Mandelli, Diego

    2015-08-01

    Part of the U.S. Department of Energy’s (DOE’s) Light Water Reac- tor Sustainability (LWRS) Program, the Risk-Informed Safety Margin Charac- terization (RISMC) Pathway develops approaches to estimating and managing safety margins. RISMC simulations pair deterministic plant physics models with probabilistic risk models. As human interactions are an essential element of plant risk, it is necessary to integrate human actions into the RISMC risk framework. In this paper, we review simulation based and non simulation based human reliability analysis (HRA) methods. This paper summarizes the founda- tional information needed to develop a feasible approach to modeling human in- teractions in RISMC simulations.

  10. PIA - Human Resources - Personal Information Change Request ...

    Energy Savers [EERE]

    Human Resources - Personal Information Change Request - Idaho National Engineering Laboratory PIA - Human Resources - Personal Information Change Request - Idaho National...

  11. Careers/ Human Resources | Princeton Plasma Physics Lab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources Employment Opportunities Directory Environment, Safety & Health Furth Plasma Physics Library Lab Leadership Organization Chart Technology Transfer Careers Human ...

  12. ORISE: Human Subjects Research Database

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Subjects Research Database Section 10, Part 745 of the Code of Federal Regulations and U.S. Department of Energy (DOE) Orders 443.1 and 481.1 require the maintenance of information on all research projects that involve human subjects and that are funded by DOE, conducted in DOE facilities, performed by DOE personnel or involve DOE or contract personnel. The Oak Ridge Institute for Science and Education (ORISE) maintains the Human Subjects Research Database (HSRD) for the Office of

  13. Quantum physics and human values

    SciTech Connect (OSTI)

    Stapp, H.P.

    1989-09-01

    This report discusses the following concepts: the quantum conception of nature; the quantum conception of man; and the impact upon human values. (LSP).

  14. Human Genome Research: Decoding DNA

    Office of Scientific and Technical Information (OSTI)

    ... Speeding Up the Process of Gene Discovery Engineered Enzyme Accelerates DNA Sequencing Putting a Virus to Practical Use DOE Joint Genome Institute The Human Genome Project: ...

  15. Protection of Human Research Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2015-07-20

    Changes are made to harmonize the definitions in this Order with those in the Federal regulations for the protection of human subjects (10 CFR Part 745), specifically, splitting the definition "human subject research" into "research" and "human subject," and adopting, verbatim, the definitions of "research" and "human subject" from 10 CFR Part 745 and adding the definition of "generalizable," since the determination of whether a project is "research" in 10 CFR Part 745 hinges on whether the work being conducted is generalizable. Small corrections and updates have been made to the references, links, and organization titles.

  16. Simulating human behavior for national security human interactions.

    SciTech Connect (OSTI)

    Bernard, Michael Lewis; Hart, Dereck H.; Verzi, Stephen J.; Glickman, Matthew R.; Wolfenbarger, Paul R.; Xavier, Patrick Gordon

    2007-01-01

    This 3-year research and development effort focused on what we believe is a significant technical gap in existing modeling and simulation capabilities: the representation of plausible human cognition and behaviors within a dynamic, simulated environment. Specifically, the intent of the ''Simulating Human Behavior for National Security Human Interactions'' project was to demonstrate initial simulated human modeling capability that realistically represents intra- and inter-group interaction behaviors between simulated humans and human-controlled avatars as they respond to their environment. Significant process was made towards simulating human behaviors through the development of a framework that produces realistic characteristics and movement. The simulated humans were created from models designed to be psychologically plausible by being based on robust psychological research and theory. Progress was also made towards enhancing Sandia National Laboratories existing cognitive models to support culturally plausible behaviors that are important in representing group interactions. These models were implemented in the modular, interoperable, and commercially supported Umbra{reg_sign} simulation framework.

  17. Proliferation of rhesus ovarian surface epithelial cells in culture: Lack of mitogenic response to steroid or gonadotropic hormones

    SciTech Connect (OSTI)

    Wright, Jay W.; Toth-Fejel, Suellen; Stouffer, Richard L.; Rodland, Karin D.

    2002-06-30

    Ovarian cancer is the most lethal gynecological cancer and approximately 90% of ovarian cancers derive from the ovarian surface epithelium (OSE), yet the biology of the OSE is poorly understood. Factors associated with increased risk of non-hereditary ovarian cancer include the formation of inclusion cysts, effects of reproductive hormones cytokeratin, vimentin, N-cadherin, E-cadherin, estrogen receptor-a, and progesterone receptor. We show that these cells activate MAP Kinase and proliferate in response to extracellular calcium, as do human and rat OSE. In contrast, the gonadotropic hormones FSH (4-400 IU/L), LH (8.5-850 IU/l), and hCG (10-1000 IU/l) fail to stimulate proliferation. We find that concentrations of progesterone and estrogen normally present in follicles just prior to ovulation ( ~1000 ng/ml) significantly decrease the number of mitotically active RhOSE cells as determined by PCNA labelling, total cell count, and 3H-thymidine uptake, while lower steroid concentrations have no effect.

  18. The Human Genome Diversity Project

    SciTech Connect (OSTI)

    Cavalli-Sforza, L.

    1994-12-31

    The Human Genome Diversity Project (HGD Project) is an international anthropology project that seeks to study the genetic richness of the entire human species. This kind of genetic information can add a unique thread to the tapestry knowledge of humanity. Culture, environment, history, and other factors are often more important, but humanity`s genetic heritage, when analyzed with recent technology, brings another type of evidence for understanding species` past and present. The Project will deepen the understanding of this genetic richness and show both humanity`s diversity and its deep and underlying unity. The HGD Project is still largely in its planning stages, seeking the best ways to reach its goals. The continuing discussions of the Project, throughout the world, should improve the plans for the Project and their implementation. The Project is as global as humanity itself; its implementation will require the kinds of partnerships among different nations and cultures that make the involvement of UNESCO and other international organizations particularly appropriate. The author will briefly discuss the Project`s history, describe the Project, set out the core principles of the Project, and demonstrate how the Project will help combat the scourge of racism.

  19. Human Reliability Analysis for Digital Human-Machine Interfaces

    SciTech Connect (OSTI)

    Ronald L. Boring

    2014-06-01

    This paper addresses the fact that existing human reliability analysis (HRA) methods do not provide guidance on digital human-machine interfaces (HMIs). Digital HMIs are becoming ubiquitous in nuclear power operations, whether through control room modernization or new-build control rooms. Legacy analog technologies like instrumentation and control (I&C) systems are costly to support, and vendors no longer develop or support analog technology, which is considered technologically obsolete. Yet, despite the inevitability of digital HMI, no current HRA method provides guidance on how to treat human reliability considerations for digital technologies.

  20. Human Genome Education Program

    SciTech Connect (OSTI)

    Richard Myers; Lane Conn

    2000-05-01

    The funds from the DOE Human Genome Program, for the project period 2/1/96 through 1/31/98, have provided major support for the curriculum development and field testing efforts for two high school level instructional units: Unit 1, ''Exploring Genetic Conditions: Genes, Culture and Choices''; and Unit 2, ''DNA Snapshots: Peaking at Your DNA''. In the original proposal, they requested DOE support for the partial salary and benefits of a Field Test Coordinator position to: (1) complete the field testing and revision of two high school curriculum units, and (2) initiate the education of teachers using these units. During the project period of this two-year DOE grant, a part-time Field-Test Coordinator was hired (Ms. Geraldine Horsma) and significant progress has been made in both of the original proposal objectives. Field testing for Unit 1 has occurred in over 12 schools (local and non-local sites with diverse student populations). Field testing for Unit 2 has occurred in over 15 schools (local and non-local sites) and will continue in 12-15 schools during the 96-97 school year. For both curricula, field-test sites and site teachers were selected for their interest in genetics education and in hands-on science education. Many of the site teachers had no previous experience with HGEP or the unit under development. Both of these first-year biology curriculum units, which contain genetics, biotechnology, societal, ethical and cultural issues related to HGP, are being implemented in many local and non-local schools (SF Bay Area, Southern California, Nebraska, Hawaii, and Texas) and in programs for teachers. These units will reach over 10,000 students in the SF Bay Area and continues to receive support from local corporate and private philanthropic organizations. Although HGEP unit development is nearing completion for both units, data is still being gathered and analyzed on unit effectiveness and student learning. The final field testing result from this analysis will

  1. A human breast cell model of pre-invasive to invasive transition

    SciTech Connect (OSTI)

    Bissell, Mina J; Rizki, Aylin; Weaver, Valerie M.; Lee, Sun-Young; Rozenberg, Gabriela I.; Chin, Koei; Myers, Connie A.; Bascom, Jamie L.; Mott, Joni D.; Semeiks, Jeremy R.; Grate, Leslie R.; Mian, I. Saira; Borowsky, Alexander D.; Jensen, Roy A.; Idowu, Michael O.; Chen, Fanqing; Chen, David J.; Petersen, Ole W.; Gray, Joe W.; Bissell, Mina J.

    2008-03-10

    A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from pre-invasive to invasive phenotype as it may occur 'spontaneously' in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted-basement membrane cultures. These cells remained non-invasive; however, unlike their non-malignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher grade tumors. To find functionally significant changes in transition from pre-invasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between pre-invasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP-9,-13,-15,-17 was up regulated in the invasive cells. Using siRNA based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which pre-invasive breast cells could acquire invasiveness in a metaplastic context.

  2. Human genome. 1993 Program report

    SciTech Connect (OSTI)

    Not Available

    1994-03-01

    The purpose of this report is to update the Human Genome 1991-92 Program Report and provide new information on the DOE genome program to researchers, program managers, other government agencies, and the interested public. This FY 1993 supplement includes abstracts of 60 new or renewed projects and listings of 112 continuing and 28 completed projects. These two reports, taken together, present the most complete published view of the DOE Human Genome Program through FY 1993. Research is progressing rapidly toward 15-year goals of mapping and sequencing the DNA of each of the 24 different human chromosomes.

  3. mir-30d Regulates multiple genes in the autophagy pathway and impairs autophagy process in human cancer cells

    SciTech Connect (OSTI)

    Yang, Xiaojun; Department of General Surgery, Gansu Provincial Hospital, Lanzhou, Gansu 710000 ; Zhong, Xiaomin; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011 ; Tanyi, Janos L.; Shen, Jianfeng; Xu, Congjian; Gao, Peng; Zheng, Tim M.; DeMichele, Angela; Zhang, Lin

    2013-02-15

    Highlights: ? Gene set enrichment analysis indicated mir-30d might regulate the autophagy pathway. ? mir-30d represses the expression of BECN1, BNIP3L, ATG12, ATG5 and ATG2. ? BECN1, BNIP3L, ATG12, ATG5 and ATG2 are direct targets of mir-30d. ? mir-30d inhibits autophagosome formation and LC3B-I conversion to LC3B-II. ? mir-30d regulates the autophagy process. -- Abstract: In human epithelial cancers, the microRNA (miRNA) mir-30d is amplified with high frequency and serves as a critical oncomir by regulating metastasis, apoptosis, proliferation, and differentiation. Autophagy, a degradation pathway for long-lived protein and organelles, regulates the survival and death of many cell types. Increasing evidence suggests that autophagy plays an important function in epithelial tumor initiation and progression. Using a combined bioinformatics approach, gene set enrichment analysis, and miRNA target prediction, we found that mir-30d might regulate multiple genes in the autophagy pathway including BECN1, BNIP3L, ATG12, ATG5, and ATG2. Our further functional experiments demonstrated that the expression of these core proteins in the autophagy pathway was directly suppressed by mir-30d in cancer cells. Finally, we showed that mir-30d regulated the autophagy process by inhibiting autophagosome formation and LC3B-I conversion to LC3B-II. Taken together, our results provide evidence that the oncomir mir-30d impairs the autophagy process by targeting multiple genes in the autophagy pathway. This result will contribute to understanding the molecular mechanism of mir-30d in tumorigenesis and developing novel cancer therapy strategy.

  4. Contractor Human Resource Management Programs

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    1996-09-30

    The purpose of this directive is to establish Department of Energy (DOE) responsibilities and requirements for the management and oversight of contractor Human Resource Management (HR) programs. Chg 1, 5-8-98; Chg 2, 11-22-09.

  5. Contractor Human Resource Management Programs

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    1996-09-30

    The purpose of this directive is to establish Department of Energy (DOE) responsibilities and requirements for the management and oversight of contractor Human Resource Management (HR) programs. Chg 1, 5-8-98; Chg 2, 11-22-09

  6. Protection of Human Research Subjects

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2009-12-09

    The order establishes Department of Energy (DOE) procedures and responsibilities for implementing the policy and requirements set forth in Title 10 Code of Federal Regulations (CFR) Part 745, Protection of Human Subjects, 45 CFR Part 46, and the Secretarial Policy Memorandum on Military or Intelligence-Related Human Subject Research, December 9, 2009. Supersedes DOE O 443.1A and DOE P 443.1A.

  7. Rab27a regulates epithelial sodium channel (ENaC) activity through synaptotagmin-like protein (SLP-5) and Munc13-4 effector mechanism

    SciTech Connect (OSTI)

    Saxena, Sunil K. . E-mail: ssaxena@stevens.edu; Horiuchi, Hisanori; Fukuda, Mitsunori

    2006-06-02

    Liddle's syndrome (excessive absorption of sodium ions) and PHA-1 (pseudohypoaldosteronism type 1) with decreased sodium absorption are caused by the mutations in the amiloride-sensitive epithelial sodium channel ENaC. Rab proteins are small GTPases involved in vesicle transport, docking, and fusion. Earlier, we reported that Rab27a inhibits ENaC-mediated currents through protein-protein interaction in HT-29 cells. We hereby report that Rab27a-dependent inhibition is associated with the GTP/GDP status as constitutively active or GTPase-deficient mutant Q78L inhibits amiloride-sensitive currents whereas GDP-locked inactive mutant T23N showed no effect. In order to further explore the molecular mechanism of this regulation, we performed competitive assays with two Rab27a-binding proteins: synaptotagmin-like protein (SLP-5) and Munc13-4 (a putative priming factor for exocytosis). Both proteins eliminate negative modulation of Rab27a on ENaC function. The SLP-5 reversal of Rab27a effect was restricted to C-terminal C2A/C2B domains assigned for putative phospholipids-binding function while the Rab27a-binding SHD motif imparted higher inhibition. The ENaC-mediated currents remain unaffected by Rab27a though SLP-5 appears to strongly bind it. The immunoprecipitation experiments suggest that in the presence of excessive Munc13-4 and SLP-5 proteins, Rab27a interaction with ENaC is diminished. Munc13-4 and SLP-5 limit the Rab27a availability to ENaC, thus minimizing its effect on channel function. These observations decisively prove that Rab27a inhibits ENaC function through a complex mechanism that involves GTP/GDP status, and protein-protein interactions involving Munc13-4 and SLP-5 effector proteins.

  8. Solar Energy Education. Humanities: activities and teacher's...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Humanities: activities and teacher's guide. Field test edition Citation Details In-Document Search Title: Solar Energy Education. Humanities: activities and teacher's guide. Field ...

  9. Habitat for Humanity | Open Energy Information

    Open Energy Info (EERE)

    Habitat for Humanity Jump to: navigation, search Name: Habitat for Humanity Place: Americus, GA Website: www.habitat.org References: NREL Technical Report: Zero Energy Home1...

  10. Human Reliability Program Orientation for Employees (Technical...

    Office of Scientific and Technical Information (OSTI)

    Human Reliability Program Orientation for Employees Citation Details In-Document Search ... PERSONNEL; RELIABILITY; US DOE HRP employee orientation, human reliability Word ...

  11. Rocky Mountain Humane Investing | Open Energy Information

    Open Energy Info (EERE)

    Rocky Mountain Humane Investing Jump to: navigation, search Name: Rocky Mountain Humane Investing Place: Allenspark, Colorado Zip: 80510 Product: Allenspark-based investment...

  12. Climate Human Capital | Open Energy Information

    Open Energy Info (EERE)

    Human Capital Jump to: navigation, search Name: Climate Human Capital Place: London, United Kingdom Zip: W1K 6NG Sector: Carbon, Renewable Energy, Services Product: Green executive...

  13. Human Capital Management | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    human capital requires comprehensive planning and analysis in order to develop, implement, and evaluate programs that support every facet of employee work life. DOE human capital ...

  14. Human Capital Management Accountability Program (HCMAP) | Department...

    Broader source: Energy.gov (indexed) [DOE]

    Human Capital Management Accountability Program (HCMAP) is an online program which serves ... and financial HR metrics that assist human resources professionals in identifying ...

  15. PIA - Human Resources - Personal Information Change Request ...

    Broader source: Energy.gov (indexed) [DOE]

    PIA - Human Resources - Personal Information Change Request - Idaho National Engineering Laboratory (278.62 KB) More Documents & Publications PIA - INL PeopleSoft - Human ...

  16. PRIVACY IMPACT ASSESSMENT: Human Resources Personal Information

    Broader source: Energy.gov (indexed) [DOE]

    Human Resources - Personal Information Change Request PIA Template Version 3 - May, 2009 ... Name of Information Human Resources - Personal Information Change Request System or IT ...

  17. PIA - Human Resources Management Information System (HRMIS) ...

    Broader source: Energy.gov (indexed) [DOE]

    Information System (HRMIS) PIA - Human Resources Management Information System (HRMIS) (490.32 KB) More Documents & Publications PIA - INL PeopleSoft - Human Resource System PIA - ...

  18. Human Capital Organization | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    Human Capital Officer provides leadership to the Department of Energy (DOE) on the impact and use of policies, proposals, programs, and partnerships related to all aspects of Human ...

  19. Tiny plastic lung mimics human pulmonary function

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Tiny plastic lung mimics human pulmonary function Tiny plastic lung mimics human pulmonary function Scientists are developing a miniature, tissue-engineered artificial lung that ...

  20. Human Resources Specialist - DETAIL (Recruitment) | Department...

    Energy Savers [EERE]

    Human Resources Specialist - DETAIL (Recruitment) Human Resources Specialist - DETAIL (Recruitment) Submitted by admin on Sat, 2016-08-20 00:15 Job Summary Organization Name ...

  1. Multiscale Simulations of Human Pathologies | Argonne Leadership...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Multiscale Simulations of Human Pathologies PI Name: George Karniadakis PI Email: ... of Sickle Hemoglobin Predicting Human Blood Viscosity in Silico Tightly Coupled ...

  2. DOE Human Resources Management Division - Hanford Site

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    About Hanford Cleanup Hanford History Hanford Site Wide Programs DOE Human Resources ... DOE Human Resources Management Division Email Email Page | Print Print Page | Text ...

  3. ATHENA surrogate human organ system approaches milestone

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Latest Issue:August 2016 all issues All Issues submit ATHENA surrogate human organ ... Editor Ute Haker Email ATHENA, the "Advanced Tissue-engineered Human Ectypal Network ...

  4. Human Resources Generalist | Princeton Plasma Physics Lab

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources Generalist Department: Human Resources Supervisor(s): Andrea Moten Staff: AM 3 Requisition Number: 1600683 The HR Generalist is responsible for performing a wide ...

  5. Project ATHENA creates surrogate human organ systems

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Project ATHENA creates surrogate human organ systems Alumni Link: Opportunities, News and ... All Issues submit Project ATHENA creates surrogate human organ systems The development ...

  6. The SACADA database for human reliability and human performance

    SciTech Connect (OSTI)

    Y. James Chang; Dennis Bley; Lawrence Criscione; Barry Kirwan; Ali Mosleh; Todd Madary; Rodney Nowell; Robert Richards; Emilie M. Roth; Scott Sieben; Antonios Zoulis

    2014-05-01

    Lack of appropriate and sufficient human performance data has been identified as a key factor affecting human reliability analysis (HRA) quality especially in the estimation of human error probability (HEP). The Scenario Authoring, Characterization, and Debriefing Application (SACADA) database was developed by the U.S. Nuclear Regulatory Commission (NRC) to address this data need. An agreement between NRC and the South Texas Project Nuclear Operating Company (STPNOC) was established to support the SACADA development with aims to make the SACADA tool suitable for implementation in the nuclear power plants' operator training program to collect operator performance information. The collected data would support the STPNOC's operator training program and be shared with the NRC for improving HRA quality. This paper discusses the SACADA data taxonomy, the theoretical foundation, the prospective data to be generated from the SACADA raw data to inform human reliability and human performance, and the considerations on the use of simulator data for HRA. Each SACADA data point consists of two information segments: context and performance results. Context is a characterization of the performance challenges to task success. The performance results are the results of performing the task. The data taxonomy uses a macrocognitive functions model for the framework. At a high level, information is classified according to the macrocognitive functions of detecting the plant abnormality, understanding the abnormality, deciding the response plan, executing the response plan, and team related aspects (i.e., communication, teamwork, and supervision). The data are expected to be useful for analyzing the relations between context, error modes and error causes in human performance.

  7. ATHENA, the Desktop Human "Body"

    SciTech Connect (OSTI)

    Iyer, Rashi; Harris, Jennifer

    2014-09-29

    Creating surrogate human organs, coupled with insights from highly sensitive mass spectrometry technologies, a new project is on the brink of revolutionizing the way we screen new drugs and toxic agents. ATHENA, the Advanced Tissue-engineered Human Ectypal Network Analyzer project team, is developing four human organ constructs - liver, heart, lung and kidney - that are based on a significantly miniaturized platform. Each organ component will be about the size of a smartphone screen, and the whole ATHENA "body" of interconnected organs would fit neatly on a desk. "By developing this 'homo minutus,' we are stepping beyond the need for animal or Petri dish testing: There are huge benefits in developing drug and toxicity analysis systems that can mimic the response of actual human organs," said Rashi Iyer, a senior scientist at Los Alamos National Laboratory, the lead laboratory on the five-year, $19 million multi-institutional effort. The project is supported by the Defense Threat Reduction Agency (DTRA). Some 40 percent of pharmaceuticals fail their clinical trials, Iyer noted, and there are thousands of chemicals whose effects on humans are simply unknown. Providing a realistic, cost-effective and rapid screening system such as ATHENA with high-throughput capabilities could provide major benefits to the medical field, screening more accurately and offering a greater chance of clinical trial success.

  8. ATHENA, the Desktop Human "Body"

    ScienceCinema (OSTI)

    Iyer, Rashi; Harris, Jennifer

    2015-01-05

    Creating surrogate human organs, coupled with insights from highly sensitive mass spectrometry technologies, a new project is on the brink of revolutionizing the way we screen new drugs and toxic agents. ATHENA, the Advanced Tissue-engineered Human Ectypal Network Analyzer project team, is developing four human organ constructs - liver, heart, lung and kidney - that are based on a significantly miniaturized platform. Each organ component will be about the size of a smartphone screen, and the whole ATHENA "body" of interconnected organs would fit neatly on a desk. "By developing this 'homo minutus,' we are stepping beyond the need for animal or Petri dish testing: There are huge benefits in developing drug and toxicity analysis systems that can mimic the response of actual human organs," said Rashi Iyer, a senior scientist at Los Alamos National Laboratory, the lead laboratory on the five-year, $19 million multi-institutional effort. The project is supported by the Defense Threat Reduction Agency (DTRA). Some 40 percent of pharmaceuticals fail their clinical trials, Iyer noted, and there are thousands of chemicals whose effects on humans are simply unknown. Providing a realistic, cost-effective and rapid screening system such as ATHENA with high-throughput capabilities could provide major benefits to the medical field, screening more accurately and offering a greater chance of clinical trial success.

  9. Human Resources | U.S. DOE Office of Science (SC)

    Office of Science (SC) Website

    Human Resources Human Resources and Administration (HRA) HRA Home About Human Resources Administration SC Correspondence Control Center (SC CCC) Contact Information Human Resources...

  10. Corporate Human Resources Information Services (CHIRS) PIA, Office...

    Broader source: Energy.gov (indexed) [DOE]

    Corporate Human Resources Information Services (CHIRS) PIA, Office of Human Capitol Management Corporate Human Resources Information Services (CHIRS) PIA, Office of Human Capitol ...

  11. About the Human Resource Management Team | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    Human Resource Management Team is responsible for human capital policy, human capital and organizational management, and human capital management initiatives. The team ensures an ...

  12. The effect of low dose ionizing radiation on homeostasis and functional integrity in an organotypic human skin model

    SciTech Connect (OSTI)

    von Neubeck, Claere; Geniza, Matthew; Kauer, Paula M.; Robinson, Joseph E.; Chrisler, William B.; Sowa, Marianne B.

    2015-05-01

    Outside the protection of earth’s atmosphere, astronauts are exposed to low doses of high linear energy transfer (LET) radiation. Future NASA plans for deep space missions or a permanent settlement on the moon are limited by the health risks associated with space radiation exposures. There is a paucity of direct epidemiological data for low dose exposures to space radiation-relevant high LET ions. Health risk models are used to estimate the risk for such exposures, though these models are based on high dose experiments. There is increasing evidence, however, that low and high dose exposures result in different signaling events at the molecular level, and may involve different response mechanisms. Further, despite their low abundance, high LET particles have been identified as the major contributor to health risk during manned space flight. The human skin is exposed in every external radiation scenario, making it an ideal epithelial tissue model in which to study radiation induced effects. Here, we exposed an in vitro three dimensional (3-D) human organotypic skin tissue model to low doses of high LET oxygen (O), silicon (Si) and iron (Fe) ions. We measured proliferation and differentiation profiles in the skin tissue and examined the integrity of the skin’s barrier function. We discuss the role of secondary particles in changing the proportion of cells receiving a radiation dose, emphasizing the possible impact on radiation-induced health issues in astronauts.

  13. WILD PIG ATTACKS ON HUMANS

    SciTech Connect (OSTI)

    Mayer, J.

    2013-04-12

    Attacks on humans by wild pigs (Sus scrofa) have been documented since ancient times. However, studies characterizing these incidents are lacking. In an effort to better understand this phenomenon, information was collected from 412 wild pig attacks on humans. Similar to studies of large predator attacks on humans, data came from a variety of sources. The various attacks compiled occurred in seven zoogeographic realms. Most attacks occurred within the species native range, and specifically in rural areas. The occurrence was highest during the winter months and daylight hours. Most happened under non-hunting circumstances and appeared to be unprovoked. Wounded animals were the chief cause of these attacks in hunting situations. The animals involved were typically solitary, male and large in size. The fate of the wild pigs involved in these attacks varied depending upon the circumstances, however, most escaped uninjured. Most human victims were adult males traveling on foot and alone. The most frequent outcome for these victims was physical contact/mauling. The severity of resulting injuries ranged from minor to fatal. Most of the mauled victims had injuries to only one part of their bodies, with legs/feet being the most frequent body part injured. Injuries were primarily in the form of lacerations and punctures. Fatalities were typically due to blood loss. In some cases, serious infections or toxemia resulted from the injuries. Other species (i.e., pets and livestock) were also accompanying some of the humans during these attacks. The fates of these animals varied from escaping uninjured to being killed. Frequency data on both non-hunting and hunting incidents of wild pig attacks on humans at the Savannah River Site, South Carolina, showed quantitatively that such incidents are rare.

  14. Low-Income Weatherization: The Human Dimension

    Office of Energy Efficiency and Renewable Energy (EERE)

    This presentation focuses on how the human dimension saves energy within low-income weatherization programs.

  15. Analysis of Human Genetic Linkage

    SciTech Connect (OSTI)

    Boehnke, M.

    1991-01-01

    Linkage analysis continues in its golden age. The convergence of several factors - advances in molecular biology, advances in statistical models and algorithms, and advances in computing technology - have made possible remarkable successes in the mapping of human genetic diseases and in the construction of human genetic maps. The goals of mapping all the most important simple Mendelian disorders and constructing fine-structure genetic maps for each of the human chromosomes soon will be reached, and linkage methods promise to help us understand the etiologies of many common and complex familial diseases. With the continuing rapid advance of the field, the appearance of the revised edition of Dr. Ott's book is particularly welcome. As with the first edition, the goal of the revised edition is to provide a concise, easy-to-read introduction to human linkage analysis. The revised edition includes chapters on basic genetics and cytogenetics, genes and genetic polymorphisms, aspects of statistical inference, methods of linkage analysis, the informativeness of family data, multipoint linkage analysis, penetrance, numerical and computerized methods, the variability of the recombination fraction, inconsistencies, and linkage analysis with disease loci. The results is not an encyclopedia providing everything one could ever want to know about linkage analysis but, rather, a guide to the important methods, topics, and problems of linkage analysis today. Overall, the book achieves an excellent compromise between presenting important conclusions and working out the details.

  16. Human factors in software development

    SciTech Connect (OSTI)

    Curtis, B.

    1986-01-01

    This book presents an overview of ergonomics/human factors in software development, recent research, and classic papers. Articles are drawn from the following areas of psychological research on programming: cognitive ergonomics, cognitive psychology, and psycholinguistics. Topics examined include: theoretical models of how programmers solve technical problems, the characteristics of programming languages, specification formats in behavioral research and psychological aspects of fault diagnosis.

  17. Human retroviruses and AIDS 1994

    SciTech Connect (OSTI)

    Myers, G.; Korber, B.; Wain-Hobson, S.; Jeang, Kuan-Teh; Henderson, L.E.; Pavlakis, G.N.

    1995-01-01

    This compendium, including accompanying floppy diskettes, is the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses. The scope of the compendium and database is best summarized by the five parts it comprises: (I) Nucleic Acid Alignments and Sequences; (II) Amino Acid Alignments; (III) Analysis; (IV) Related Sequences; (V) Database communications.

  18. A Literary Human Exinction Scenario

    SciTech Connect (OSTI)

    Tonn, Bruce Edward

    2009-11-01

    Mary Wollstonecraft Shelly's (MWS) novel, The Last Man, published in 1826, is an epic narrative about the destruction of the human race. This paper provides a synopsis of this book and assesses its relationships to contemporary future studies. The paper also delves into the history of apocalyptic writing and thinking, using this book an entry point to past literature.

  19. Expanding Human Cognition and Communication

    SciTech Connect (OSTI)

    Spohrer, Jim; Pierce, Brian M.; Murray, Cherry A.; Golledge, Reginald G.; Horn, Robert E.; Turkle, Sherry; Yonas, Gerold; Glicken Turnley, Jessica; Pollack, Jordan; Burger, Rudy; Robinett, Warren; Wilson, Larry Todd; Bainbridge, W. S.; Canton, J.; Kuekes, P.; Loomis, J.; Penz, P.

    2013-01-01

    To be able to chart the most profitable future directions for societal transformation and corresponding scientific research, five multidisciplinary themes focused on major goals have been identified to fulfill the overall motivating vision of convergence described in the previous pages. The first, “Expanding Human Cognition and Communication,” is devoted to technological breakthroughs that have the potential to enhance individuals’ mental and interaction abilities. Throughout the twentieth century, a number of purely psychological techniques were offered for strengthening human character and personality, but evaluation research has generally failed to confirm the alleged benefits of these methods (Druckman and Bjork 1992; 1994). Today, there is good reason to believe that a combination of methods, drawing upon varied branches of converging science and technology, would be more effective than attempts that rely upon mental training alone.

  20. Human factors in waste management

    SciTech Connect (OSTI)

    Moray, N.

    1994-10-01

    This article examines the role of human factors in radioactive waste management. Although few problems and ergonomics are special to radioactive waste management, some problems are unique especially with long term storage. The entire sociotechnical system must be looked at in order to see where improvement can take place because operator errors, as seen in Chernobyl and Bhopal, are ultimately the result of management errors.

  1. Contractor Human Resource Management Programs

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    1996-09-30

    The purpose of this directive is to establish Department of Energy (DOE) responsibilities and requirements for the management and oversight of contractor Human Resource Management (HR) programs. Chg 1, 5-8-98; Chg 2, 11-22-09; Chg 3, 2-23-10; Chg 4, 4-29-13. This order cancels DOE O 3220.1A, DOE O 3220.4A, DOE O 3220.6A, and DOE O 3309.1A.

  2. Contractor Human Resource Management Programs

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    1996-09-29

    This directive establishes DOE responsibilities and requirements for the management and oversight of contractor Human Resource Management (HR) programs. Chg 1, 5-8-98; Chg 2, 11-22-09; Chg 3, 2-23-10; Chg 4, 4-29-13. DOE O 350.1 Chg 5, dated 9-30-2014, cancels Chapters I-III of DOE O 350.1 Chg 4

  3. Integrating Human Performance and Technology

    SciTech Connect (OSTI)

    Ronald K. Farris; Heather Medema

    2012-05-01

    Human error is a significant factor in the cause and/or complication of events that occur in the commercial nuclear industry. In recent years, great gains have been made using Human Performance (HU) tools focused on targeting individual behaviors. However, the cost of improving HU is growing and resistance to add yet another HU tool certainly exists, particularly for those tools that increase the paperwork for operations. Improvements in HU that are the result of leveraging existing technology, such as hand-held mobile technologies, have the potential to reduce human error in controlling system configurations, safety tag-outs, and other verifications. Operator rounds, valve line-up verifications, containment closure verifications, safety & equipment protection, and system tagging can be supported by field-deployable wireless technologies. These devices can also support the availability of critical component data in the main control room and other locations. This research pilot project reviewing wireless hand-held technology is part of the Light Water Reactor Sustainability Program (LWRSP), a research and development (R&D) program sponsored by the U. S. Department of Energy (DOE). The project is being performed in close collaboration with industry R&D programs to provide the technical foundations for licensing, and managing the long-term, safe, and economical operation of current nuclear power plants. The LWRSP vision is to develop technologies and other solutions that can improve the reliability, sustain the safety, and extend the life of the current nuclear reactor fleet.

  4. Human Resource Directors (HRD) | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    Office (NE) 208-526-5711 groseae@id.doe.gov Marcus Lea Director, Office of Human Cap. Mgt. ... garcia@wapa.gov Rita Clinton Director, Human Resources Services (HQ) (202) 586-1038 ...

  5. MEMORANDUM FOR HUMAN RESOLIRCES DIRECTORS FROM:

    Broader source: Energy.gov (indexed) [DOE]

    April 27,2010 MEMORANDUM FOR HUMAN RESOLIRCES DIRECTORS FROM: s r x j ) bi Le OFFICE HE CHIEF HUMAN CAPITAL OFFICER SUBJECT: GUIDANCE MEMORANDUM 8: DOE FAIR LABOR STANDARDS ACT ...

  6. Mapping the Topology of the Human Genome

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Mapping the Topology of the Human Genome Mapping the Topology of the Human Genome Print Monday, 11 July 2016 00:00 Department of Energy facilities such as the Joint Genome ...

  7. 6.20 Mapping Human Brain Function

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    0 612011 6.20 Mapping Human Brain Function Many mysteries of the human brain have been unraveled by positron emission tomography (PET), an imaging tool used worldwide to diagnose ...

  8. Human Brain vs. Computer | GE Global Research

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Computer Processors Beat the Human Mind in the Future? Click to email this to a friend ... Can Computer Processors Beat the Human Mind in the Future? 2013.01.29 Chief Scientist Jim ...

  9. History of the DOE Human Genome Program

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    of the DOE Human Genome Program The following history is taken from the U.S. Department of Energy 1991-91 Human Genome Program Report (June 1992). This is an archived item. A brief ...

  10. Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.; Engelke, Udo F.; Boekhorst, Jos; Keegan, Kevin P.; Nielsen, Fiona G. G.; Betley, Jason; Weir, Jacqueline C.; Kingsbury, Zoya; et al

    2016-01-06

    Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessedmore » by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. In conclusion, our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer.« less

  11. GDB - Human Genome Database final report

    SciTech Connect (OSTI)

    Talbot, C. Conover, Jr.

    2002-01-08

    This is the DOE final report for the GDB, Human Genome Database, project at the Johns Hopkins University.

  12. Identification of Human Repetitive DNA Elements

    Energy Science and Technology Software Center (OSTI)

    1995-11-01

    PYTHIA identifies the subfamily membership of Alu sequences, occurrences of repetitive human DNA elements, and simple DNA sequences.

  13. Human factors: a necessary tool for industry

    SciTech Connect (OSTI)

    Starcher, K.O.

    1984-03-09

    The need for human factors (ergonomics) input in the layout of a ferroelectric ceramics laboratory is presented as an example of the overall need for human factors professionals in industry. However, even in the absence of one trained in human factors, knowledge of a few principles in ergonomics will provide many possibilities for improving performance in the industrial environment.

  14. Contractor Human Resource Management Programs

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    1996-09-30

    This directive establishes DOE responsibilities and requirements for the management and oversight of contractor Human Resource Management (HR) programs. Chg 1, 5-8-98; Chg 2, 11-22-09; Chg 3, 2-23-10; Chg 4, 4-29-13. DOE O 350.1 Chg 5, dated 9-30-2014, supersedes DOE O 350.1 Chg 4. The Order is revised to reflect the cancellation of Chapters 1-3 due to the incorporation of these chapters into DOE Order 350.3; reflect organizational changes; delete reference to the DOE Retrospective Rating Insurance Plan, which is no longer available; remove the CRD from Chapter VII.

  15. Simulation of human decision making

    DOE Patents [OSTI]

    Forsythe, J. Chris; Speed, Ann E.; Jordan, Sabina E.; Xavier, Patrick G.

    2008-05-06

    A method for computer emulation of human decision making defines a plurality of concepts related to a domain and a plurality of situations related to the domain, where each situation is a combination of at least two of the concepts. Each concept and situation is represented in the computer as an oscillator output, and each situation and concept oscillator output is distinguishable from all other oscillator outputs. Information is input to the computer representative of detected concepts, and the computer compares the detected concepts with the stored situations to determine if a situation has occurred.

  16. Purification, crystallization and preliminary X-ray diffraction of human S100A15

    SciTech Connect (OSTI)

    Boeshans, Karen M.; Wolf, Ronald; Voscopoulos, Christopher; Gillette, William; Esposito, Dominic; Mueser, Timothy C.; Yuspa, Stuart H.; Ahvazi, Bijan

    2006-05-01

    S100 proteins are differentially expressed during epithelial cell maturation, tumorigenesis and inflammation. The novel human S100A15 protein has been cloned, expressed, purified and crystallized in two crystal forms, a triclinic and a monoclinic form, which diffract to 1.7 and 2.0 Å, respectively. Human S100A15 is a novel member of the S100 family of EF-hand calcium-binding proteins and was recently identified in psoriasis, where it is significantly upregulated in lesional skin. The protein is implicated as an effector in calcium-mediated signal transduction pathways. Although its biological function is unclear, the association of the 11.2 kDa S100A15 with psoriasis suggests that it contributes to the pathogenesis of the disease and could provide a molecular target for therapy. To provide insight into the function of S100A15, the protein was crystallized to visualize its structure and to further the understanding of how the many similar calcium-binding mediator proteins in the cell distinguish their cognate target molecules. The S100A15 protein has been cloned, expressed and purified to homogeneity and produced two crystal forms. Crystals of form I are triclinic, with unit-cell parameters a = 33.5, b = 44.3, c = 44.8 Å, α = 71.2, β = 68.1, γ = 67.8° and an estimated two molecules in the asymmetric unit, and diffract to 1.7 Å resolution. Crystals of form II are monoclinic, with unit-cell parameters a = 82.1, b = 33.6, c = 52.2 Å, β = 128.2° and an estimated one molecule in the asymmetric unit, and diffract to 2.0 Å resolution. This structural analysis of the human S100A15 will further aid in the phylogenic comparison between the other members of the S100 protein family, especially the highly homologous paralog S100A7.

  17. Human Resources and Administration Homepage | U.S. DOE Office...

    Office of Science (SC) Website

    Home Human Resources and Administration (HRA) HRA Home About Human Resources Administration SC Correspondence Control Center (SC CCC) Contact Information Human Resources and...

  18. DOE Strategic Human Capital Plan (FY 2011 - 2015) | Department...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Strategic Human Capital Plan (FY 2011 - 2015) DOE Strategic Human Capital Plan (FY 2011 - 2015) The Strategic Human Capital Plan sets forth the framework for managing the ...

  19. PIA - Human Resources Management System | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    System PIA - Human Resources Management System (218.23 KB) More Documents & Publications PIA - INL PeopleSoft - Human Resource System PIA - Human Resources - Personal Information ...

  20. PIA - INL PeopleSoft - Human Resource System | Department of...

    Broader source: Energy.gov (indexed) [DOE]

    PeopleSoft - Human Resource System PIA - INL PeopleSoft - Human Resource System (333.96 KB) More Documents & Publications PIA - Human Resources - Personal Information Change ...

  1. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Irradiation Effects on Human Cortical Bone Fracture Behavior Print Wednesday, 28 July 2010 00:00 Human bone is strong ...

  2. Oldest hominid skeleton provides new evidence for human evolution

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    New evidence for human evolution Oldest hominid skeleton provides new evidence for human evolution The discovery reveals the biology of the first stage of human evolution better ...

  3. Molecular clocks control mutation rate in human cells

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    All Issues submit Molecular clocks control mutation rate in human cells Mutational processes may be responsible for a large proportion of human cancer, contribute to human ...

  4. ATHENA desktop human "body" reduces need for animal drug tests

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    ATHENA desktop human "body" ATHENA desktop human "body" reduces need for animal drug tests ATHENA project team is developing four human organ constructs that are based on a ...

  5. Crystal structure of human dynein light chain Dnlc2A: Structural insights into the interaction with IC74

    SciTech Connect (OSTI)

    Liu Junfeng; Wang Zhanxin; Wang Xinquan; Tang Qun; An Xiaomin; Gui Lulu; Liang Dongcai . E-mail: dcliang@sun5.ibp.ac.cn

    2006-10-27

    The human light chain of the motor protein dynein, Dnlc2A, is also a novel TGF-{beta}-signaling component, which is altered with high frequency in epithelial ovarian cancer. It is an important mediator of dynein and the development of cancer, owing to its ability to bind to the dynein intermediate light chain (DIC) IC74 and to regulate TGF-{beta}-dependent transcriptional events. Here we report the 2.1-A crystal structure of Dnlc2A using single anomalous diffraction. The proteins form a homodimer in solution and interact mainly through the helix {alpha}{sub 2}, strand {beta}{sub 3}, and the loop following this strand in each protein to generate a 10-stranded {beta}-sheet core. The surface of the {beta}-sheet core is mainly positively charged and predicted (by software PPI-Pred) to be the site that interacts with other partners. At the same time, the residues 79-82, 88, and 90 of each molecule formed two holes in the core. Residue 89 of each molecule, which is crucial for the DIC binding function of Dnlc2A, is within the holes. On the basis of these observations, we propose that the homodimer is the structural and functional unit maintained by hydrogen bonding interactions and hydrophobic packing, and that the patch of the surface of the {beta}-sheet core is the main area of interaction with other partners. Furthermore, the two holes would be the key sites to interact with IC74.

  6. Calcitriol inhibits Ether-a go-go potassium channel expression and cell proliferation in human breast cancer cells

    SciTech Connect (OSTI)

    Garcia-Becerra, Rocio; Diaz, Lorenza; Camacho, Javier; Barrera, David; Ordaz-Rosado, David; Morales, Angelica; Ortiz, Cindy Sharon; Avila, Euclides; Bargallo, Enrique; Arrecillas, Myrna; Halhali, Ali; Larrea, Fernando

    2010-02-01

    Antiproliferative actions of calcitriol have been shown to occur in many cell types; however, little is known regarding the molecular basis of this process in breast carcinoma. Ether-a-go-go (Eag1) potassium channels promote oncogenesis and are implicated in breast cancer cell proliferation. Since calcitriol displays antineoplastic effects while Eag1 promotes tumorigenesis, and both factors antagonically regulate cell cycle progression, we investigated a possible regulatory effect of calcitriol upon Eag1 as a mean to uncover new molecular events involved in the antiproliferative activity of this hormone in human breast tumor-derived cells. RT real-time PCR and immunocytochemistry showed that calcitriol suppressed Eag1 expression by a vitamin D receptor (VDR)-dependent mechanism. This effect was accompanied by inhibition of cell proliferation, which was potentiated by astemizole, a nonspecific Eag1 inhibitor. Immunohistochemistry and Western blot demonstrated that Eag1 and VDR abundance was higher in invasive-ductal carcinoma than in fibroadenoma, and immunoreactivity of both proteins was located in ductal epithelial cells. Our results provide evidence of a novel mechanism involved in the antiproliferative effects of calcitriol and highlight VDR as a cancer therapeutic target for breast cancer treatment and prevention.

  7. Human Reliability Analysis for Design: Using Reliability Methods for Human Factors Issues

    SciTech Connect (OSTI)

    Ronald Laurids Boring

    2010-11-01

    This paper reviews the application of human reliability analysis methods to human factors design issues. An application framework is sketched in which aspects of modeling typically found in human reliability analysis are used in a complementary fashion to the existing human factors phases of design and testing. The paper provides best achievable practices for design, testing, and modeling. Such best achievable practices may be used to evaluate and human system interface in the context of design safety certifications.

  8. Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin

    SciTech Connect (OSTI)

    Sood, Shilpa; Choudhary, Shambhunath; Wang, Hwa-Chain Robert

    2013-09-06

    Highlights: Triclocarban exposure induces breast epithelial cell carcinogenesis. Triclocarban induces the ErkNox pathway, ROS elevation, and DNA damage. Physiological doses of triclocarban induce cellular carcinogenesis. Non-cytotoxic curcumin blocks triclocarban-induced carcinogenesis and pathways. -- Abstract: More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the ErkNox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the ErkNox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as

  9. Linking Humans and Systems in Nuclear Power

    SciTech Connect (OSTI)

    Jacques Hugo

    2013-02-01

    Traditional engineering methods do not make provision for the integration of human considerations, while traditional human factors methods do not scale well to the complexity of large-scale nuclear power plant projects. Although the need for up-to-date human factors engineering processes and tools is recognised widely in industry, so far no formal guidance has been developed. This article proposes such a framework.

  10. Project ATHENA creates surrogate human organ systems

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Project ATHENA creates surrogate human organ systems Project ATHENA creates surrogate human organ systems The development of miniature surrogate human organs, coupled with highly sensitive mass spectrometry technologies, could one day revolutionize the way new drugs and toxic agents are studied. June 15, 2015 ATHENA prototype undergoes testing. ATHENA prototype undergoes testing. Contact Los Alamos National Laboratory Kevin Roark Communications Office (505) 665-9202 Email "By developing

  11. Apparatus and methods for a human extender

    DOE Patents [OSTI]

    Jansen, John F.

    2001-01-01

    A human extender controller for interface between a human operator and a physical object through a physical plant. The human extender controller uses an inner-feedback loop to increase the equivalent damping of the operating system to stabilize the system when it contacts with the environment and reduces the impact of the environment variation by utilizing a high feedback gain, determined by a root locus sketch. Because the stability of the human extender controller of the present invention is greatly enhanced over that of the prior art, the present invention is able to achieve a force reflection ratio 500 to 1 and capable of handling loads above the two (2) ton range.

  12. Transactions, Technology and Contractor Human Relations | Department...

    Office of Environmental Management (EM)

    of the Assistant General Counsel for Contractor Human Resources (GC-63) Litigation, Regulation and Enforcement Environment and Compliance Transactions, Technology and Contractor ...

  13. Transactions, Technology & Contractor Human Resources | Department...

    Broader source: Energy.gov (indexed) [DOE]

    Panel Technician | Credit: DOE Archives Solar Panel Technician | Credit: DOE Archives Offices of the Deputy General Counsel for Transactions, Technology, & Contractor Human...

  14. Human factors challenges for advanced process control

    SciTech Connect (OSTI)

    Stubler, W.F.; O`Hara, J..M.

    1996-08-01

    New human-system interface technologies provide opportunities for improving operator and plant performance. However, if these technologies are not properly implemented, they may introduce new challenges to performance and safety. This paper reports the results from a survey of human factors considerations that arise in the implementation of advanced human-system interface technologies in process control and other complex systems. General trends were identified for several areas based on a review of technical literature and a combination of interviews and site visits with process control organizations. Human factors considerations are discussed for two of these areas, automation and controls.

  15. Human Capital Management Accountability Program (HCMAP)

    Broader source: Energy.gov [DOE]

    Human Capital Management Accountability Program (HCMAP) is an online program which serves as the vehicle for identifying and measuring these three factors, effectiveness, efficiency, and timeliness...

  16. 2014 DOE Human Reliability Program (HRP) Workshop

    Office of Energy Efficiency and Renewable Energy (EERE)

    2014 DOE Human Reliability Program (HRP) Workshop - September 17-19, at the DOE National Training Center in Albuquerque, New Mexico.

  17. Multiscale Simulations of Human Pathologies | Argonne Leadership...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Inset shows the time evolution of thrombus formation. George Karniadakis, Brown University Multiscale Simulations of Human Pathologies PI Name: George Karniadakis PI Email: ...

  18. Multiscale Simulations of Human Pathologies | Argonne Leadership...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Karniadakis, Paris Perdikaris, and Yue Yu, Brown University; Leopold Grinberg, IBM T. J. Watson Research Center and Brown University Multiscale Simulations of Human Pathologies PI ...

  19. Immunogenic compositions comprising human immunodeficiency virus...

    Office of Scientific and Technical Information (OSTI)

    Patent: Immunogenic compositions comprising human immunodeficiency virus (HIV) mosaic Nef proteins Citation Details In-Document Search Title: Immunogenic compositions comprising...

  20. Atomic magnetometer for human magnetoencephalograpy.

    SciTech Connect (OSTI)

    Schwindt, Peter; Johnson, Cort N.

    2010-12-01

    We have developed a high sensitivity (<5 fTesla/{radical}Hz), fiber-optically coupled magnetometer to detect magnetic fields produced by the human brain. This is the first demonstration of a noncryogenic sensor that could replace cryogenic superconducting quantum interference device (SQUID) magnetometers in magnetoencephalography (MEG) and is an important advance in realizing cost-effective MEG. Within the sensor, a rubidium vapor is optically pumped with 795 laser light while field-induced optical rotations are measured with 780 nm laser light. Both beams share a single optical axis to maximize simplicity and compactness. In collaboration with neuroscientists at The Mind Research Network in Albuquerque, NM, the evoked responses resulting from median nerve and auditory stimulation were recorded with the atomic magnetometer and a commercial SQUID-based MEG system with signals comparing favorably. Multi-sensor operation has been demonstrated with two AMs placed on opposite sides of the head. Straightforward miniaturization would enable high-density sensor arrays for whole-head magnetoencephalography.

  1. Human retroviruses and AIDS 1997

    SciTech Connect (OSTI)

    Korber, B.; Foley, B.; Leitner, T.

    1997-12-01

    This compendium is the result of an effort to compile, organize, and rapidly publish as much relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses as possible. The scope of the compendium and database is best summarized by the four parts that it comprises: (1) Nucleic Acid Alignments, (2) Amino Acid Alignments, (3) Reviews and Analyses, and (4) Related Sequences. Information within all the parts is updated throughout the year on the Web site, http://hiv-web.lanl.gov. This year we are not including floppy diskettes as the entire compendium is available both at our Web site and at our ftp site. If you need floppy diskettes please contact either Bette Korber (btk@t10.lanl.gov) or Kersti Rock (karm@t10.lanl.gov) by email or fax ((505) 665-4453). While this publication could take the form of a review or sequence monograph, it is not so conceived. Instead, the literature from which the database is derived has simply been summarized and some elementary computational analyses have been performed upon the data. Interpretation and commentary have been avoided insofar as possible so that the reader can form his or her own judgments concerning the complex information. The exception to this are reviews submitted by experts in areas deemed of particular and basic importance to research involving AIDS viral sequence information. These are included in Part III, and are contributed by scientists with particular expertise in the area of interest. In addition to the general descriptions below of the parts of the compendium, the user should read the individual introductions for each part.

  2. Task Decomposition in Human Reliability Analysis

    SciTech Connect (OSTI)

    Boring, Ronald Laurids; Joe, Jeffrey Clark

    2014-06-01

    In the probabilistic safety assessments (PSAs) used in the nuclear industry, human failure events (HFEs) are determined as a subset of hardware failures, namely those hardware failures that could be triggered by human action or inaction. This approach is top-down, starting with hardware faults and deducing human contributions to those faults. Elsewhere, more traditionally human factors driven approaches would tend to look at opportunities for human errors first in a task analysis and then identify which of those errors is risk significant. The intersection of top-down and bottom-up approaches to defining HFEs has not been carefully studied. Ideally, both approaches should arrive at the same set of HFEs. This question remains central as human reliability analysis (HRA) methods are generalized to new domains like oil and gas. The HFEs used in nuclear PSAs tend to be top-down— defined as a subset of the PSA—whereas the HFEs used in petroleum quantitative risk assessments (QRAs) are more likely to be bottom-up—derived from a task analysis conducted by human factors experts. The marriage of these approaches is necessary in order to ensure that HRA methods developed for top-down HFEs are also sufficient for bottom-up applications.

  3. Human Reliability Considerations for Small Modular Reactors

    SciTech Connect (OSTI)

    OHara J. M.; Higgins, H.; DAgostino, A.; Erasmia, L.

    2012-01-27

    Small modular reactors (SMRs) are a promising approach to meeting future energy needs. Although the electrical output of an individual SMR is relatively small compared to that of typical commercial nuclear plants, they can be grouped to produce as much energy as a utility demands. Furthermore, SMRs can be used for other purposes, such as producing hydrogen and generating process heat. The design characteristics of many SMRs differ from those of current conventional plants and may require a distinct concept of operations. The U.S. Nuclear Regulatory Commission (NRC) conducted research to examine the human factors engineering and the operational aspects of SMRs. The research identified thirty potential human-performance issues that should be considered in the NRC's reviews of SMR designs and in future research activities. The purpose of this report is to illustrate how the issues can support SMR probabilistic risk analyses and their review by identifying potential human failure events for a subset of the issues. As part of addressing the human contribution to plant risk, human reliability analysis practitioners identify and quantify the human failure events that can negatively impact normal or emergency plant operations. The results illustrated here can be generalized to identify additional human failure events for the issues discussed and can be applied to those issues not discussed in this report.

  4. Chitosan-shelled oxygen-loaded nanodroplets abrogate hypoxia dysregulation of human keratinocyte gelatinases and inhibitors: New insights for chronic wound healing

    SciTech Connect (OSTI)

    Khadjavi, Amina; Magnetto, Chiara; Panariti, Alice; Argenziano, Monica; Gulino, Giulia Rossana; Rivolta, Ilaria; Cavalli, Roberta; Giribaldi, Giuliana; Guiot, Caterina; Prato, Mauro

    2015-08-01

    Background: : In chronic wounds, efficient epithelial tissue repair is hampered by hypoxia, and balances between the molecules involved in matrix turn-over such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are seriously impaired. Intriguingly, new oxygenating nanocarriers such as 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNs) might effectively target chronic wounds. Objective: : To investigate hypoxia and chitosan-shelled OLN effects on MMP/TIMP production by human keratinocytes. Methods: : HaCaT cells were treated for 24 h with 10% v/v OLNs both in normoxia or hypoxia. Cytotoxicity and cell viability were measured through biochemical assays; cellular uptake by confocal microscopy; and MMP and TIMP production by enzyme-linked immunosorbent assay or gelatin zymography. Results: : Normoxic HaCaT cells constitutively released MMP-2, MMP-9, TIMP-1 and TIMP-2. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. After cellular uptake by keratinocytes, nontoxic OLNs abrogated all hypoxia effects on MMP/TIMP secretion, restoring physiological balances. OLN abilities were specifically dependent on time-sustained oxygen diffusion from OLN core. Conclusion: : Chitosan-shelled OLNs effectively counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human keratinocytes. Therefore, topical administration of exogenous oxygen, properly encapsulated in nanodroplet formulations, might be a promising adjuvant approach to promote healing processes in hypoxic wounds. - Highlights: • Hypoxia impairs MMP9/TIMP1 and MMP2/TIMP2 balances in HaCaT human keratinocytes. • Chitosan-shelled oxygen-loaded nanodroplets (OLNs) are internalised by HaCaT cells. • OLNs are not toxic to HaCaT cells. • OLNs effectively counteract hypoxia effects on MMP/TIMP balances in HaCaT cells. • OLNs appear as promising and cost-effective therapeutic tools for hypoxic

  5. Human dopamine receptor and its uses

    DOE Patents [OSTI]

    Civelli, Olivier; Van Tol, Hubert Henri-Marie

    1999-01-01

    The present invention is directed toward the isolation, characterization and pharmacological use of the human D4 dopamine receptor. The nucleotide sequence of the gene corresponding to this receptor and alleleic variant thereof are provided by the invention. The invention also includes recombinant eukaryotic expression constructs capable of expressing the human D4 dopamine receptor in cultures of transformed eukaryotic cells. The invention provides cultures of transformed eukaryotic cells which synthesize the human D4 dopamine receptor, and methods for characterizing novel psychotropic compounds using such cultures.

  6. Mapping the Topology of the Human Genome

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Mapping the Topology of the Human Genome Mapping the Topology of the Human Genome Print Monday, 11 July 2016 00:00 Department of Energy facilities such as the Joint Genome Institute provide us with DNA sequences for entire genomes, most famously the human genome. However, a DNA sequence alone isn't sufficient to determine how a gene will function in a cell, or if indeed it will be functional at all. We also need to know the spatial 3D arrangement of the genome in the nucleus. A single strand of

  7. Enhancing Human and Planetary Health Through Innovation

    SciTech Connect (OSTI)

    Brown, Ben

    2014-10-17

    Ben Brown mesmerizes the audience on how to enhance human and planetary health through innovation at our '8 Big Ideas' Science at the Theater event on October 8th, 2014, in Oakland, California.

  8. HUMAN FACTORS GUIDANCE FOR CONTROL ROOM EVALUATION

    SciTech Connect (OSTI)

    OHARA,J.; BROWN,W.; STUBLER,W.; HIGGINS,J.; WACHTEL,J.; PERSENSKY,J.J.

    2000-07-30

    The Human-System Interface Design Review Guideline (NUREG-0700, Revision 1) was developed by the US Nuclear Regulatory Commission (NRC) to provide human factors guidance as a basis for the review of advanced human-system interface technologies. The guidance consists of three components: design review procedures, human factors engineering guidelines, and a software application to provide design review support called the ``Design Review Guideline.'' Since it was published in June 1996, Rev. 1 to NUREG-0700 has been used successfully by NRC staff, contractors and nuclear industry organizations, as well as by interested organizations outside the nuclear industry. The NRC has committed to the periodic update and improvement of the guidance to ensure that it remains a state-of-the-art design evaluation tool in the face of emerging and rapidly changing technology. This paper addresses the current research to update of NUREG-0700 based on the substantial work that has taken place since the publication of Revision 1.

  9. Implications of the Human Genome Project

    SciTech Connect (OSTI)

    Kitcher, P.

    1998-11-01

    The Human Genome Project (HGP), launched in 1991, aims to map and sequence the human genome by 2006. During the fifteen-year life of the project, it is projected that $3 billion in federal funds will be allocated to it. The ultimate aims of spending this money are to analyze the structure of human DNA, to identify all human genes, to recognize the functions of those genes, and to prepare for the biology and medicine of the twenty-first century. The following summary examines some of the implications of the program, concentrating on its scientific import and on the ethical and social problems that it raises. Its aim is to expose principles that might be used in applying the information which the HGP will generate. There is no attempt here to translate the principles into detailed proposals for legislation. Arguments and discussion can be found in the full report, but, like this summary, that report does not contain any legislative proposals.

  10. 2011-2015 Human Capital Management Plan

    Broader source: Energy.gov [DOE]

    The Office of Legacy Management (LM) needs skilled and engaged staff to accomplish our mission and carry out our responsibilities to the American people. This Human Capital Management Plan (HCMP or...

  11. 2016-2020 Strategic Human Capital Plan

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    the Chief Human Capital Officer 2016-2020 Strategic Human Capital Plan Cover Photo Description Beyond Double-Pane Windows While the invention of double-pane windows dates back to 1935, a true turning point in the technology came in the 1980s with a collaboration between the Department of Energy, private industry, and Lawrence Berkeley National Lab. Initial research and development by Berkeley Lab and a start-up company, Suntek Research Associates (now called Southwall Technologies), led to the

  12. Human Capital Accountability Program--Withdrawn

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2012-11-15

    Withdrawn 3-26-14. The purpose of maintaining and updating this directive is to (1) Ensure compliance with applicable laws, regulations, and other directives. (2) Reduce the risk of DOE losing any of its personnel authorities. (3) Incorporate functional accountability to ensure that Human Resource Directors' position descriptions and classifications are appropriate, selections result in quality leadership with skills needed, and performance plans and evaluations are consistent with Department and Administration human resources priorities and audit findings.

  13. A New Link Between Human and Bacterial Signaling Machinery

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    A New Link Between Human and Bacterial Signaling Machinery A New Link Between Human and Bacterial Signaling Machinery Print Tuesday, 19 August 2014 10:34 The human immune system...

  14. Functional and Structural Characterization of Human V3-Specific...

    Office of Scientific and Technical Information (OSTI)

    Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 ... Title: Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody ...

  15. Microsoft PowerPoint - Crouther.HumanCapitalInitiatives.042909

    Office of Environmental Management (EM)

    Human Capital Initiatives Presented to the Environmental Management Advisory Board (EMAB) By Desi Crouther, Acting Director Office of Human Capital Office of Environmental Management ...

  16. Molecular details of a starch utilization pathway in the human...

    Office of Scientific and Technical Information (OSTI)

    pathway in the human gut symbiont Eubacterium rectale Citation Details In-Document Search Title: Molecular details of a starch utilization pathway in the human gut symbiont ...

  17. Crystal structure of the human [sigma]1 receptor (Journal Article...

    Office of Scientific and Technical Information (OSTI)

    Crystal structure of the human sigma1 receptor Citation Details In-Document Search Title: Crystal structure of the human sigma1 receptor Authors: Schmidt, Hayden R. ; Zheng, ...

  18. Xylan utilization in human gut commensal bacteria is orchestrated...

    Office of Scientific and Technical Information (OSTI)

    Xylan utilization in human gut commensal bacteria is orchestrated by unique modular ... Title: Xylan utilization in human gut commensal bacteria is orchestrated by unique modular ...

  19. Characterizing Loop Dynamics and Ligand Recognition in Human...

    Office of Scientific and Technical Information (OSTI)

    Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza ... Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born ...

  20. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic...

  1. UNDP-Human Development Reports | Open Energy Information

    Open Energy Info (EERE)

    Human Development Reports Jump to: navigation, search Tool Summary LAUNCH TOOL Name: UNDP-Human Development Reports AgencyCompany Organization: United Nations Development...

  2. Human Capital: The Role of Ombudsmen in Dispute Resolution

    Broader source: Energy.gov (indexed) [DOE]

    United States General Accounting Office GAO April 2001 HUMAN CAPITAL The Role of Ombudsmen ... Accounting Office GS General Schedule HR human resource IBB International Broadcasting ...

  3. Office of the Chief Human Capital Officer | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    Office of the Chief Human Capital Officer Most Requested Benefits CHRIS (DOE Only) DOE & ... HR Contacts by Sub Agency Servicing Area HC Contacts by Functional Area Human Resource ...

  4. PIA - Savannah River Nuclear Solutions (SRNS) Human Resource...

    Broader source: Energy.gov (indexed) [DOE]

    (SRNS) Human Resource Management System (HRMS) PIA - Savannah River Nuclear Solutions (SRNS) Human Resource Management System (HRMS) (3.39 MB) More Documents & Publications PIA - ...

  5. 2014 Human Reliability Program Workshop Agenda | Department of...

    Broader source: Energy.gov (indexed) [DOE]

    September 17-19, 2014 2014 DOE Human Reliability Program Workshop And Webinar Agenda DOE ... 10 Code of Federal Regulations Part 712, Human Reliability Program INSPECTION REPORT: ...

  6. Manager's Desk Reference on Human Capital Management Flexibilities...

    Broader source: Energy.gov (indexed) [DOE]

    that can be used in day-to-day human capital management activities, especially ... Manager's Desk Reference on Human Capital Management Flexibilities (640.69 KB) Responsible ...

  7. Human Capital Policy Division (HC-11) | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    Provide a full range of staff support to the Chief Human Capital Officer including support required for internal and external responsibilities. Develop and revise the agency human ...

  8. DOE Strategic Human Capital Plan | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    The current Strategic Human Capital Plan (SHCP) sets forth the framework for managing the Department of Energy's (DOE) human capital system through 2020. This Plan, which replaces ...

  9. First Steps Toward Tribal Weatherization - Human Capacity Development...

    Broader source: Energy.gov (indexed) [DOE]

    Toward Tribal Weatherization - Human Capacity Development (DE-PA36-09GO99022) 2006 All ... Weatherization Training Program Phase 1: Development of human capacity to deliver ...

  10. Office of the Chief Human Capital Officer (HC-1) | Department...

    Broader source: Energy.gov (indexed) [DOE]

    HC-1 Mission and Function Statement The Office of the Chief Human Capital Officer (HC) ... agreementsrelationships related to all aspects of Human Capital Management (HCM). ...

  11. DOE Jobs Online (Hiring Manager), Office of Human Capitol Management...

    Broader source: Energy.gov (indexed) [DOE]

    Jobs Online (Hiring Manager), Office of Human Capitol Management Innovation and Solutions DOE Jobs Online (Hiring Manager), Office of Human Capitol Management Innovation and ...

  12. Office of Human Resource Services (HC-30) | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    This organization provides a full range of human capital management (HCM) operational ... Leadership Rita M. Clinton Director, Office of Human Resource Services Read Bio HC-30 ...

  13. Yurok Tribe - Tribal Utility Project and Human Capacity Building

    Broader source: Energy.gov (indexed) [DOE]

    Study (completed June 30, 2007) 2. Human Capacity Building in Energy Efficiency and ... Facility (QF) Possible Grant Funding Human Capacity Building Project Project Team ...

  14. Human Resources at Ames Laboratory | Critical Materials Institute

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Contact Information Contact information for Human Resources staff within The Ames Laboratory. Human Resources Office 105 TASF 515-294-2680 Diane Muncrief Manager Labor Relations - ...

  15. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic ...

  16. Neutrons provide new insights into human cell behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Neutrons provide new insights into human cell behavior Community Connections: Your link to ... All Issues submit Neutrons provide new insights into human cell behavior Physics and ...

  17. COLLOQUIUM: The Power of Neuroplasticity: Enhancing Human Potential...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    COLLOQUIUM: The Power of Neuroplasticity: Enhancing Human Potential Dr. Paula Tallal ... designed based on research findings from human and animal research and translated into ...

  18. Antibody library project could unlock mysteries of human gene...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Mysteries of human gene function Antibody library project could unlock mysteries of human gene function By looking at antibodies, researchers can identify where, in a cell, genes ...

  19. Molecular clocks control mutation rate in human cells

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Molecular clocks control mutation rate in human cells Molecular clocks control mutation rate in human cells These clock-like mutational processes could ultimately be responsible ...

  20. Hand-Held Analyzer Quickly Detects Buried Human Remains - Energy...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Hand-Held Analyzer Quickly Detects Buried Human Remains Oak Ridge National Laboratory ... and auditory cues to quickly alert investigators to the presence of buried human remains. ...

  1. Scientists call for antibody 'bar code' system to follow Human...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Scientists call for antibody 'bar code' system to follow Human Genome Project Researchers ... on the scale of the now-completed Human Genome Project. (Image: Public Domain, ...

  2. Modeling and Simulation of Human Behavior in Buildings

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Laboratory Modeling and Simulation of Human Behavior in Buildings 2015 Building ... to IEA EBC Annex 66 4 Complexity of Human Behavior * Inherent uncertainty * ...

  3. River Corridor Baseline Risk Assessment (RCBRA) Human Health...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    12, 2011 River Corridor Baseline Risk Assessment (RCBRA) Human Health Risk Assessment (Volume 2) * RCBRA Human Health Risk Assessment is final - Response provided to HAB ...

  4. Structure of Human Argonaute2: A Programmable Ribonuclease |...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Argonaute2: A Programmable Ribonuclease Wednesday, July 31, 2013 Ribonucleases ... Institute were able to solve the three-dimensional structure of human Argonaute2 (Fig 1A). ...

  5. "OUT OF AFRICA: GENETICS AND HUMAN MIGRATIONS", Prof. Gyan Bhanot...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    "OUT OF AFRICA: GENETICS AND HUMAN MIGRATIONS", Prof. Gyan Bhanot, Department of Molecular Biology, Biochemistry and Physics, Rutgers University OUT OF AFRICA: GENETICS AND HUMAN ...

  6. Neutrons provide new insights into human cell behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Neutrons provide new insights into human cell behavior Alumni Link: Opportunities, News ... All Issues submit Neutrons provide new insights into human cell behavior Physics and ...

  7. Human Factors Engineering Analysis Tool - Energy Innovation Portal

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Factors Engineering Analysis Tool Software tool that enables easy and quick selection of applicable regulatory guidelines as starting point for human factors engineering ...

  8. Scientists call for antibody 'bar code' system to follow Human...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Scientists call for antibody 'bar code' system to follow Human Genome Project Alumni Link: ... Scientists call for antibody 'bar code' system to follow Human Genome Project Researchers ...

  9. Human Resources | U.S. DOE Office of Science (SC)

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources Integrated Support Center (ISC) ISC Home About Services Freedom of ... Services Human Resources Print Text Size: A A A FeedbackShare Page Related Links Forms ...

  10. The Oak Ridge Institute for Science and Education Human Subjects...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Subjects Research Program PrivacySecurity Statement Contact | Forms PurposeMission ... The Oak Ridge Institute for Science and Education (ORISE) Human Subjects Research Program ...

  11. Structure of the human M2 muscarinic acetylcholine receptor bound...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist Citation Details In-Document Search Title: Structure of the human M2 muscarinic acetylcholine ...

  12. Stories of Discovery & Innovation: From Human Genome to Materials...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    From Human Genome to Materials "Genome" Energy Frontier Research Centers (EFRCs) EFRCs ... Stories of Discovery & Innovation: From Human Genome to Materials "Genome" Print Text ...

  13. Fossil analysis pushes back human split from other primates by...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Fossil analysis pushes back human split from other primates Fossil analysis pushes back human split from other primates by two million years C. abyssinicus revealed answers about ...

  14. Human Subjects Protection Program Homepage | U.S. DOE Office...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    HSPP Home Human Subjects Protection Program (HSPP) HSPP Home About Institutional Review ... Contact BER Home Contact Information Human Subjects Protection Program U.S. ...

  15. Human immunodeficiency virus type 1 clade M mosaic gag polypeptides...

    Office of Scientific and Technical Information (OSTI)

    Patent: Human immunodeficiency virus type 1 clade M mosaic gag polypeptides Citation Details In-Document Search Title: Human immunodeficiency virus type 1 clade M mosaic gag ...

  16. Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility

    SciTech Connect (OSTI)

    Lu, Renquan; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 ; Sun, Xinghui; Department of Medicine, Harvard Medical School, MA 02115 ; Xiao, Ran; Zhou, Lei; Gao, Xiang; Guo, Lin; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer We generated stable transduced HE4 overexpression and knockdown cells. Black-Right-Pointing-Pointer HE4 was associated with EOC cell adhesion and motility. Black-Right-Pointing-Pointer HE4 might have some effects on activation of EGFR-MAPK signaling pathway. Black-Right-Pointing-Pointer HE4 play an important role in EOC tumorigenicity. -- Abstract: Human epididymis protein 4 (HE4) is a novel and specific biomarker for epithelial ovarian cancer (EOC). We previously demonstrated that serum HE4 levels were significantly elevated in the majority of EOC patients but not in subjects with benign disease or healthy controls. However, the precise mechanism of HE4 protein function is unknown. In this study, we generated HE4-overexpressing SKOV3 cells and found that stably transduced cells promoted cell adhesion and migration. Knockdown of HE4 expression was achieved by stable transfection of SKOV3 cells with a construct encoding a short hairpin DNA directed against the HE4 gene. Correspondingly, the proliferation and spreading ability of HE4-expressed cells were inhibited by HE4 suppression. Mechanistically, impaired EGFR and Erk1/2 phosphorylation were observed in cells with HE4 knockdown. The phosphorylation was restored when the knockdown cells were cultured in conditioned medium containing HE4. Moreover, in vivo tumorigenicity showed that HE4 suppression markedly inhibited the growth of tumors. This suggests that expression of HE4 is associated with cancer cell adhesion, migration and tumor growth, which can be related to its effects on the EGFR-MAPK signaling pathway. Our results provide evidence of the cellular and molecular mechanisms that may underlie the motility-promoting role of HE4 in EOC progression. The role of HE4 as a target for gene-based therapy might be considered in future studies.

  17. Mapping and Sequencing the Human Genome

    DOE R&D Accomplishments [OSTI]

    1988-01-01

    Numerous meetings have been held and a debate has developed in the biological community over the merits of mapping and sequencing the human genome. In response a committee to examine the desirability and feasibility of mapping and sequencing the human genome was formed to suggest options for implementing the project. The committee asked many questions. Should the analysis of the human genome be left entirely to the traditionally uncoordinated, but highly successful, support systems that fund the vast majority of biomedical research. Or should a more focused and coordinated additional support system be developed that is limited to encouraging and facilitating the mapping and eventual sequencing of the human genome. If so, how can this be done without distorting the broader goals of biological research that are crucial for any understanding of the data generated in such a human genome project. As the committee became better informed on the many relevant issues, the opinions of its members coalesced, producing a shared consensus of what should be done. This report reflects that consensus.

  18. A technique for human error analysis (ATHEANA)

    SciTech Connect (OSTI)

    Cooper, S.E.; Ramey-Smith, A.M.; Wreathall, J.; Parry, G.W.

    1996-05-01

    Probabilistic risk assessment (PRA) has become an important tool in the nuclear power industry, both for the Nuclear Regulatory Commission (NRC) and the operating utilities. Human reliability analysis (HRA) is a critical element of PRA; however, limitations in the analysis of human actions in PRAs have long been recognized as a constraint when using PRA. A multidisciplinary HRA framework has been developed with the objective of providing a structured approach for analyzing operating experience and understanding nuclear plant safety, human error, and the underlying factors that affect them. The concepts of the framework have matured into a rudimentary working HRA method. A trial application of the method has demonstrated that it is possible to identify potentially significant human failure events from actual operating experience which are not generally included in current PRAs, as well as to identify associated performance shaping factors and plant conditions that have an observable impact on the frequency of core damage. A general process was developed, albeit in preliminary form, that addresses the iterative steps of defining human failure events and estimating their probabilities using search schemes. Additionally, a knowledge- base was developed which describes the links between performance shaping factors and resulting unsafe actions.

  19. Ontology-enriched Visualization of Human Anatomy

    SciTech Connect (OSTI)

    Pouchard, LC

    2005-12-20

    The project focuses on the problem of presenting a human anatomical 3D model associated with other types of human systemic information ranging from physiological to anatomical information while navigating the 3D model. We propose a solution that integrates a visual 3D interface and navigation features with the display of structured information contained in an ontology of anatomy where the structures of the human body are formally and semantically linked. The displayed and annotated anatomy serves as a visual entry point into a patient's anatomy, medical indicators and other information. The ontology of medical information provides labeling to the highlighted anatomical parts in the 3D display. Because of the logical organization and links between anatomical objects found in the ontology and associated 3D model, the analysis of a structure by a physician is greatly enhanced. Navigation within the 3D visualization and between this visualization and objects representing anatomical concepts within the model is also featured.

  20. Advancing Usability Evaluation through Human Reliability Analysis

    SciTech Connect (OSTI)

    Ronald L. Boring; David I. Gertman

    2005-07-01

    This paper introduces a novel augmentation to the current heuristic usability evaluation methodology. The SPAR-H human reliability analysis method was developed for categorizing human performance in nuclear power plants. Despite the specialized use of SPAR-H for safety critical scenarios, the method also holds promise for use in commercial off-the-shelf software usability evaluations. The SPAR-H method shares task analysis underpinnings with human-computer interaction, and it can be easily adapted to incorporate usability heuristics as performance shaping factors. By assigning probabilistic modifiers to heuristics, it is possible to arrive at the usability error probability (UEP). This UEP is not a literal probability of error but nonetheless provides a quantitative basis to heuristic evaluation. When combined with a consequence matrix for usability errors, this method affords ready prioritization of usability issues.

  1. Human factors in nuclear technology - a history

    SciTech Connect (OSTI)

    Jones, D.B. )

    1992-01-01

    Human factors, human factors engineering (HFE), or ergonomics did not receive much formal attention in nuclear technology prior to the Three Mile Island Unit 2 (TMI-2) incident. Three principal reasons exist for this lack of concern. First, emerging technologies show little concern with how people will use a new system. Making the new technology work is considered more important than the people who will use it. Second, the culture of the users of nuclear power did not recognize a need for human factors. Traditional utilities had well established and effective engineering designs for control of electric power generation, while medicine considered the use of nuclear isotopes another useful tool, not requiring special ergonomics. Finally, the nuclear industry owed much to Admiral Rickover. He was definitely opposed.

  2. Human-mouse comparative genomics: successes and failures to reveal functional regions of the human genome

    SciTech Connect (OSTI)

    Pennacchio, Len A.; Baroukh, Nadine; Rubin, Edward M.

    2003-05-15

    Deciphering the genetic code embedded within the human genome remains a significant challenge despite the human genome consortium's recent success at defining its linear sequence (Lander et al. 2001; Venter et al. 2001). While useful strategies exist to identify a large percentage of protein encoding regions, efforts to accurately define functional sequences in the remaining {approx}97 percent of the genome lag. Our primary interest has been to utilize the evolutionary relationship and the universal nature of genomic sequence information in vertebrates to reveal functional elements in the human genome. This has been achieved through the combined use of vertebrate comparative genomics to pinpoint highly conserved sequences as candidates for biological activity and transgenic mouse studies to address the functionality of defined human DNA fragments. Accordingly, we describe strategies and insights into functional sequences in the human genome through the use of comparative genomics coupled wit h functional studies in the mouse.

  3. Annotated bibliography of human factors applications literature

    SciTech Connect (OSTI)

    McCafferty, D.B.

    1984-09-30

    This bibliography was prepared as part of the Human Factors Technology Project, FY 1984, sponsored by the Office of Nuclear Safety, US Department of Energy. The project was conducted by Lawrence Livermore National Laboratory, with Essex Corporation as a subcontractor. The material presented here is a revision and expansion of the bibliographic material developed in FY 1982 as part of a previous Human Factors Technology Project. The previous bibliography was published September 30, 1982, as Attachment 1 to the FY 1982 Project Status Report.

  4. Three Human Cell Types Respond to Multi-Walled Carbon Nanotubes and Titanium Dioxide Nanobelts with Cell-Specific Transcriptomic and Proteomic Expression Patterns.

    SciTech Connect (OSTI)

    Tilton, Susan C.; Karin, Norman J.; Tolic, Ana; Xie, Yumei; Lai, Xianyin; Hamilton, Raymond F.; Waters, Katrina M.; Holian, Andrij; Witzmann, Frank A.; Orr, Galya

    2014-08-01

    The growing use of engineered nanoparticles (NPs) in commercial and medical applications raises the urgent need for tools that can predict NP toxicity. Global transcriptome and proteome analyses were conducted on three human cell types, exposed to two high aspect ratio NP types, to identify patterns of expression that might indicate high versus low NP toxicity. Three cell types representing the most common routes of human exposure to NPs, including macrophage-like (THP-1), small airway epithelial and intestinal (Caco-2/HT29-MTX) cells, were exposed to TiO2 nanobelts (TiO2-NB; high toxicity) and multi-walled carbon nanotubes (MWCNT; low toxicity) at low (10 g/mL) and high (100 g/mL) concentrations for 1 and 24 h. Unique patterns of gene and protein expressions were identified for each cell type, with no differentially expressed (p < 0.05, 1.5-fold change) genes or proteins overlapping across all three cell types. While unique to each cell type, the early response was primarily independent of NP type, showing similar expression patterns in response to both TiO2-NB and MWCNT. The early response might, therefore, indicate a general response to insult. In contrast, the 24 h response was unique to each NP type. The most significantly (p < 0.05) enriched biological processes in THP-1 cells indicated TiO2-NB regulation of pathways associated with inflammation, apoptosis, cell cycle arrest, DNA replication stress and genomic instability, while MWCNT-regulated pathways indicated increased cell proliferation, DNA repair and anti-apoptosis. These two distinct sets of biological pathways might, therefore, underlie cellular responses to high and low NP toxicity, respectively.

  5. Impact of the [delta]F508 Mutation in First Nucleotide-binding Domain of Human Cystic Fibrosis Transmembrane Conductance Regulator on Domain Folding and Structure

    SciTech Connect (OSTI)

    Lewis, Hal A.; Zhao, Xun; Wang, Chi; Sauder, J. Michael; Rooney, Isabelle; Noland, Brian W.; Lorimer, Don; Kearins, Margaret C.; Conners, Kris; Condon, Brad; Maloney, Peter C.; Guggino, William B.; Hunt, John F.; Emtage, Spencer (SG); (Columbia); (JHU)

    2010-07-19

    Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), commonly the deletion of residue Phe-508 (DeltaF508) in the first nucleotide-binding domain (NBD1), which results in a severe reduction in the population of functional channels at the epithelial cell surface. Previous studies employing incomplete NBD1 domains have attributed this to aberrant folding of DeltaF508 NBD1. We report structural and biophysical studies on complete human NBD1 domains, which fail to demonstrate significant changes of in vitro stability or folding kinetics in the presence or absence of the DeltaF508 mutation. Crystal structures show minimal changes in protein conformation but substantial changes in local surface topography at the site of the mutation, which is located in the region of NBD1 believed to interact with the first membrane spanning domain of CFTR. These results raise the possibility that the primary effect of DeltaF508 is a disruption of proper interdomain interactions at this site in CFTR rather than interference with the folding of NBD1. Interestingly, increases in the stability of NBD1 constructs are observed upon introduction of second-site mutations that suppress the trafficking defect caused by the DeltaF508 mutation, suggesting that these suppressors might function indirectly by improving the folding efficiency of NBD1 in the context of the full-length protein. The human NBD1 structures also solidify the understanding of CFTR regulation by showing that its two protein segments that can be phosphorylated both adopt multiple conformations that modulate access to the ATPase active site and functional interdomain interfaces.

  6. Protection of Human Subjects in Classified Research

    Broader source: Directives, Delegations, and Requirements [Office of Management (MA)]

    2016-01-21

    This notice supplements DOE O 443.1B and 10 CFR Part 745 by addressing the Department of Energy (DOE)-specific requirements for the protection of human subjects involved in research that is classified, in whole or in part.

  7. Report on the Human Genome Initiative

    SciTech Connect (OSTI)

    Tinoco, I.; Cahill, G.; Cantor, C.; Caskey, T.; Dulbecco, R.; Engelhardt, D. L.; Hood, L.; Lerman, L. S.; Mendelsohn, M. L.; Sinsheimer, R. L.; Smith, T.; Soll, D.; Stormo, G.; White, R. L.

    1987-04-01

    The report urges DOE and the Nation to commit to a large. multi-year. multidisciplinary. technological undertaking to order and sequence the human genome. This effort will first require significant innovation in general capability to manipulate DNA. major new analytical methods for ordering and sequencing. theoretical developments in computer science and mathematical biology, and great expansions in our ability to store and manipulate the information and to interface it with other large and diverse genetic databases. The actual ordering and sequencing involves the coordinated processing of some 3 billion bases from a reference human genome. Science is poised on the rudimentary edge of being able to read and understand human genes. A concerted. broadly based. scientific effort to provide new methods of sufficient power and scale should transform this activity from an inefficient one-gene-at-a-time. single laboratory effort into a coordinated. worldwide. comprehensive reading of "the book of man". The effort will be extraordinary in scope and magnitude. but so will be the benefit to biological understanding. new technology and the diagnosis and treatment of human disease.

  8. Human Health Science Building Geothermal Heat Pumps

    Broader source: Energy.gov [DOE]

    Project objectives: Construct a ground sourced heat pump, heating, ventilation, and air conditioning system for the new Oakland University Human Health Sciences Building utilizing variable refrigerant flow (VRF) heat pumps. A pair of dedicated outdoor air supply units will utilize a thermally regenerated desiccant dehumidification section. A large solar thermal system along with a natural gas backup boiler will provide the thermal regeneration energy.

  9. Top-down and bottom-up definitions of human failure events in human reliability analysis

    SciTech Connect (OSTI)

    Boring, Ronald Laurids

    2014-10-01

    In the probabilistic risk assessments (PRAs) used in the nuclear industry, human failure events (HFEs) are determined as a subset of hardware failures, namely those hardware failures that could be triggered by human action or inaction. This approach is top-down, starting with hardware faults and deducing human contributions to those faults. Elsewhere, more traditionally human factors driven approaches would tend to look at opportunities for human errors first in a task analysis and then identify which of those errors is risk significant. The intersection of top-down and bottom-up approaches to defining HFEs has not been carefully studied. Ideally, both approaches should arrive at the same set of HFEs. This question is crucial, however, as human reliability analysis (HRA) methods are generalized to new domains like oil and gas. The HFEs used in nuclear PRAs tend to be top-down—defined as a subset of the PRA—whereas the HFEs used in petroleum quantitative risk assessments (QRAs) often tend to be bottom-up—derived from a task analysis conducted by human factors experts. The marriage of these approaches is necessary in order to ensure that HRA methods developed for top-down HFEs are also sufficient for bottom-up applications.

  10. Project ATHENA Creates Surrogate Human Organ Systems

    SciTech Connect (OSTI)

    MacQueen, Luke; Knospel, Fanny; Sherrod, Stacy; Iyer, Rashi

    2015-06-15

    The development of miniature surrogate human organs, coupled with highly sensitive mass spectrometry technologies, could one day revolutionize the way new drugs and toxic agents are studied. “By developing this ‘homo minutus,’ we are stepping beyond the need for animal or Petri dish testing: There are huge benefits in developing drug and toxicity analysis systems that can mimic the response of actual human organs,” said Rashi Iyer, a senior scientist at Los Alamos National Laboratory. ATHENA, the Advanced Tissue-engineered Human Ectypal Network Analyzer project team, is nearing the full integration of four human organ constructs — liver, heart, lung and kidney — each organ component is about the size of a smartphone screen, and the whole ATHENA “body” of interconnected organs will fit neatly on a desk. A new video available on the Los Alamos National Laboratory YouTube channel updates the ATHENA project as it begins to integrate the various organ systems into a single system (link to video here). Some 40 percent of pharmaceuticals fail their clinical trials and there are thousands of chemicals whose effects on humans are simply unknown. Providing a realistic, cost-effective and rapid screening system such as ATHENA with high-throughput capabilities could provide major benefits to the medical field, screening more accurately and offering a greater chance of clinical trial success. ATHENA is funded by the Defense Threat Reduction Agency (DTRA) and is a collaboration of Los Alamos National Laboratory, Harvard University, Vanderbilt University, Charité Universitätsmedizin, Berlin, Germany, CFD Research Corporation, and the University of California San Francisco.

  11. Do myoepithelial cells hold the key for breast tumorprogression?

    SciTech Connect (OSTI)

    Polyak, Kornelia; Hu, Min

    2005-11-18

    Mammary myoepithelial cells have been the foster child of breast cancer biology and have been largely ignored since they were considered to be less important for tumorigenesis than luminal epithelial cells from which most of breast carcinomas are thought to arise. In recent years as our knowledge in stem cell biology and the cellular microenvironment has been increasing myoepithelial cells are slowly starting to gain more attention. Emerging data raise the hypothesis if myoepithelial cells play a key role in breast tumor progression by regulating the in situ to invasive carcinoma transition and if myoepithelial cells are part of the mammary stem cell niche. Paracrine interactions between myoepithelial and luminal epithelial cells are known to be important for cell cycle arrest, establishing epithelial cell polarity, and inhibiting migration and invasion. Based on these functions normal mammary myoepithelial cells have been called ''natural tumor suppressors''. However, during tumor progression myoepithelial cells seem to loose these properties and eventually they themselves diminish as tumors become invasive. Better understanding of myoepithelial cell function and their role in tumor progression may lead to their exploitation for cancer therapeutic and preventative measures.

  12. HSI Prototypes for Human Systems Simulation Laboratory

    SciTech Connect (OSTI)

    Jokstad, Håkon; McDonald, Rob

    2015-09-01

    This report describes in detail the design and features of three Human System Interface (HSI) prototypes developed by the Institutt for Energiteknikk (IFE) in support of the U.S. Department of Energy’s Light Water Reactor Sustainability Program under Contract 128420 through Idaho National Laboratory (INL). The prototypes are implemented for the Generic Pressurized Water Reactor simulator and installed in the Human Systems Simulation Laboratory at INL. The three prototypes are: 1) Power Ramp display 2) RCS Heat-up and Cool-down display 3) Estimated time to limit display The power ramp display and the RCS heat-up/cool-down display are designed to provide good visual indications to the operators on how well they are performing their task compared to their target ramp/heat-up/cool-down rate. The estimated time to limit display is designed to help operators restore levels or pressures before automatic or required manual actions are activated.

  13. Bridging Resilience Engineering and Human Reliability Analysis

    SciTech Connect (OSTI)

    Ronald L. Boring

    2010-06-01

    There has been strong interest in the new and emerging field called resilience engineering. This field has been quick to align itself with many existing safety disciplines, but it has also distanced itself from the field of human reliability analysis. To date, the discussion has been somewhat one-sided, with much discussion about the new insights afforded by resilience engineering. This paper presents an attempt to address resilience engineering from the perspective of human reliability analysis (HRA). It is argued that HRA shares much in common with resilience engineering and that, in fact, it can help strengthen nascent ideas in resilience engineering. This paper seeks to clarify and ultimately refute the arguments that have served to divide HRA and resilience engineering.

  14. Justice and the Human Genome Project

    SciTech Connect (OSTI)

    Murphy, T.F.; Lappe, M.

    1992-01-01

    Most of the essays gathered in this volume were first presented at a conference, Justice and the Human Genome, in Chicago in early November, 1991. The goal of the, conference was to consider questions of justice as they are and will be raised by the Human Genome Project. To achieve its goal of identifying and elucidating the challenges of justice inherent in genomic research and its social applications the conference drew together in one forum members from academia, medicine, and industry with interests divergent as rate-setting for insurance, the care of newborns, and the history of ethics. The essays in this volume address a number of theoretical and practical concerns relative to the meaning of genomic research.

  15. Justice and the Human Genome Project

    SciTech Connect (OSTI)

    Murphy, T.F.; Lappe, M.

    1992-12-31

    Most of the essays gathered in this volume were first presented at a conference, Justice and the Human Genome, in Chicago in early November, 1991. The goal of the, conference was to consider questions of justice as they are and will be raised by the Human Genome Project. To achieve its goal of identifying and elucidating the challenges of justice inherent in genomic research and its social applications the conference drew together in one forum members from academia, medicine, and industry with interests divergent as rate-setting for insurance, the care of newborns, and the history of ethics. The essays in this volume address a number of theoretical and practical concerns relative to the meaning of genomic research.

  16. Justice and the human genome project

    SciTech Connect (OSTI)

    Murphy, T.F.; Lappe, M.A.

    1995-04-01

    This book is a collection of nine essays originally presented at a conference entitled {open_quotes}Justice and the Human Genome{close_quotes} held in Chicago in late 1991. The goal of the articles in this collection is to explore questions of justice raised by developments in genomic research and by applications of genetic knowledge and technology. The Human Genome Project (HGP) is used as a starting point for exploring these questions, but, as Marc Lappe recognizes, the database generated by HGP research will have implications far beyond the medical applications frequently used to justify this research effort. Thus, the book`s contributors consider questions of justice in relation to screening and testing for various predispositions, conditions, and diseases and gene therapy but also examine testing for other characteristics, forensic uses of genetic information, issues associated with DNA banks, and (hypothetical) genetic enhancement possibilities.

  17. Human Reliability Analysis for Small Modular Reactors

    SciTech Connect (OSTI)

    Ronald L. Boring; David I. Gertman

    2012-06-01

    Because no human reliability analysis (HRA) method was specifically developed for small modular reactors (SMRs), the application of any current HRA method to SMRs represents tradeoffs. A first- generation HRA method like THERP provides clearly defined activity types, but these activity types do not map to the human-system interface or concept of operations confronting SMR operators. A second- generation HRA method like ATHEANA is flexible enough to be used for SMR applications, but there is currently insufficient guidance for the analyst, requiring considerably more first-of-a-kind analyses and extensive SMR expertise in order to complete a quality HRA. Although no current HRA method is optimized to SMRs, it is possible to use existing HRA methods to identify errors, incorporate them as human failure events in the probabilistic risk assessment (PRA), and quantify them. In this paper, we provided preliminary guidance to assist the human reliability analyst and reviewer in understanding how to apply current HRA methods to the domain of SMRs. While it is possible to perform a satisfactory HRA using existing HRA methods, ultimately it is desirable to formally incorporate SMR considerations into the methods. This may require the development of new HRA methods. More practicably, existing methods need to be adapted to incorporate SMRs. Such adaptations may take the form of guidance on the complex mapping between conventional light water reactors and small modular reactors. While many behaviors and activities are shared between current plants and SMRs, the methods must adapt if they are to perform a valid and accurate analysis of plant personnel performance in SMRs.

  18. Individual Differences in Human Reliability Analysis

    SciTech Connect (OSTI)

    Jeffrey C. Joe; Ronald L. Boring

    2014-06-01

    While human reliability analysis (HRA) methods include uncertainty in quantification, the nominal model of human error in HRA typically assumes that operator performance does not vary significantly when they are given the same initiating event, indicators, procedures, and training, and that any differences in operator performance are simply aleatory (i.e., random). While this assumption generally holds true when performing routine actions, variability in operator response has been observed in multiple studies, especially in complex situations that go beyond training and procedures. As such, complexity can lead to differences in operator performance (e.g., operator understanding and decision-making). Furthermore, psychological research has shown that there are a number of known antecedents (i.e., attributable causes) that consistently contribute to observable and systematically measurable (i.e., not random) differences in behavior. This paper reviews examples of individual differences taken from operational experience and the psychological literature. The impact of these differences in human behavior and their implications for HRA are then discussed. We propose that individual differences should not be treated as aleatory, but rather as epistemic. Ultimately, by understanding the sources of individual differences, it is possible to remove some epistemic uncertainty from analyses.

  19. Monoamine oxidase: Radiotracer chemistry and human studies

    SciTech Connect (OSTI)

    Fowler, Joanna S.; Logan, Jean; Shumay, Elena; Alia-Klein, Nelly; Wang, Gene-Jack; Volkow, Nora D.

    2015-03-01

    Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinsons disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.

  20. Monoamine oxidase: Radiotracer chemistry and human studies

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Fowler, Joanna S.; Logan, Jean; Shumay, Elena; Alia-Klein, Nelly; Wang, Gene-Jack; Volkow, Nora D.

    2015-03-01

    Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson’s disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variablesmore » which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.« less

  1. Monoamine oxidase: Radiotracer chemistry and human studies

    SciTech Connect (OSTI)

    Fowler, Joanna S.; Logan, Jean; Shumay, Elena; Alia-Klein, Nelly; Wang, Gene-Jack; Volkow, Nora D.

    2015-03-01

    Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson’s disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.

  2. Current trends in mapping human genes

    SciTech Connect (OSTI)

    Mckusick, V.A. )

    1991-01-01

    The human is estimated to have at least 50,000 expressed genes (gene loci). Some information is available concerning about 5,000 of these gene loci and about 1,900 have been mapped, i.e., assigned to specific chromosomes (and in most instances particular chromosome regions). Progress has been achieved by a combination of physical mapping (e.g., study of somatic cell hybrids and chromosomal in situ hybridization) and genetic mapping (e.g., genetic linkage studies). New methods for both physical and genetic mapping are expanding the armamentarium. The usefulness of the mapping information is already evident; the spin-off from the Human Genome Project (HGP) begins immediately. the complete nucleotide sequence is the ultimate map of the human genome. Sequencing, although already under way for limited segments of the genome, will await further progress in gene mapping, and in particular creation of contig maps for each chromosome. Meanwhile the technology of sequencing and sequence information handling will be developed.

  3. Human-system Interfaces for Automatic Systems

    SciTech Connect (OSTI)

    OHara, J.M.; Higgins,J.; Fleger, S.; Barnes V.

    2010-11-07

    Automation is ubiquitous in modern complex systems, and commercial nuclear- power plants are no exception. Automation is applied to a wide range of functions including monitoring and detection, situation assessment, response planning, and response implementation. Automation has become a 'team player' supporting personnel in nearly all aspects of system operation. In light of its increasing use and importance in new- and future-plants, guidance is needed to conduct safety reviews of the operator's interface with automation. The objective of this research was to develop such guidance. We first characterized the important HFE aspects of automation, including six dimensions: levels, functions, processes, modes, flexibility, and reliability. Next, we reviewed literature on the effects of all of these aspects of automation on human performance, and on the design of human-system interfaces (HSIs). Then, we used this technical basis established from the literature to identify general principles for human-automation interaction and to develop review guidelines. The guidelines consist of the following seven topics: automation displays, interaction and control, automation modes, automation levels, adaptive automation, error tolerance and failure management, and HSI integration. In addition, our study identified several topics for additional research.

  4. Preliminary Framework for Human-Automation Collaboration

    SciTech Connect (OSTI)

    Oxstrand, Johanna Helene; Le Blanc, Katya Lee; Spielman, Zachary Alexander

    2015-09-01

    The Department of Energy’s Advanced Reactor Technologies Program sponsors research, development and deployment activities through its Next Generation Nuclear Plant, Advanced Reactor Concepts, and Advanced Small Modular Reactor (aSMR) Programs to promote safety, technical, economical, and environmental advancements of innovative Generation IV nuclear energy technologies. The Human Automation Collaboration (HAC) Research Project is located under the aSMR Program, which identifies developing advanced instrumentation and controls and human-machine interfaces as one of four key research areas. It is expected that the new nuclear power plant designs will employ technology significantly more advanced than the analog systems in the existing reactor fleet as well as utilizing automation to a greater extent. Moving towards more advanced technology and more automation does not necessary imply more efficient and safer operation of the plant. Instead, a number of concerns about how these technologies will affect human performance and the overall safety of the plant need to be addressed. More specifically, it is important to investigate how the operator and the automation work as a team to ensure effective and safe plant operation, also known as the human-automation collaboration (HAC). The focus of the HAC research is to understand how various characteristics of automation (such as its reliability, processes, and modes) effect an operator’s use and awareness of plant conditions. In other words, the research team investigates how to best design the collaboration between the operators and the automated systems in a manner that has the greatest positive impact on overall plant performance and reliability. This report addresses the Department of Energy milestone M4AT-15IN2302054, Complete Preliminary Framework for Human-Automation Collaboration, by discussing the two phased development of a preliminary HAC framework. The framework developed in the first phase was used as the

  5. Human System Simulation in Support of Human Performance Technical Basis at NPPs

    SciTech Connect (OSTI)

    David Gertman; Katya Le Blanc; alan mecham; william phoenix; Magdy Tawfik; Jeffrey Joe

    2010-06-01

    This paper focuses on strategies and progress toward establishing the Idaho National Laboratorys (INLs) Human Systems Simulator Laboratory at the Center for Advanced Energy Studies (CAES), a consortium of Idaho State Universities. The INL is one of the National Laboratories of the US Department of Energy. One of the first planned applications for the Human Systems Simulator Laboratory is implementation of a dynamic nuclear power plant simulation (NPP) where studies of operator workload, situation awareness, performance and preference will be carried out in simulated control rooms including nuclear power plant control rooms. Simulation offers a means by which to review operational concepts, improve design practices and provide a technical basis for licensing decisions. In preparation for the next generation power plant and current government and industry efforts in support of light water reactor sustainability, human operators will be attached to a suite of physiological measurement instruments and, in combination with traditional Human Factors Measurement techniques, carry out control room tasks in simulated advanced digital and hybrid analog/digital control rooms. The current focus of the Human Systems Simulator Laboratory is building core competence in quantitative and qualitative measurements of situation awareness and workload. Of particular interest is whether introduction of digital systems including automated procedures has the potential to reduce workload and enhance safety while improving situation awareness or whether workload is merely shifted and situation awareness is modified in yet to be determined ways. Data analysis is carried out by engineers and scientists and includes measures of the physical and neurological correlates of human performance. The current approach supports a user-centered design philosophy (see ISO 13407 Human Centered Design Process for Interactive Systems, 1999) wherein the context for task performance along with the

  6. UC 9-8-309 - Human Remains | Open Energy Information

    Open Energy Info (EERE)

    9 - Human Remains Jump to: navigation, search OpenEI Reference LibraryAdd to library Legal Document- StatuteStatute: UC 9-8-309 - Human RemainsLegal Abstract Governs discovery of...

  7. RCW - 68.50 Human Remains | Open Energy Information

    Open Energy Info (EERE)

    68.50 Human Remains Jump to: navigation, search OpenEI Reference LibraryAdd to library Legal Document- RegulationRegulation: RCW - 68.50 Human RemainsLegal Published NA Year...

  8. PIA - Human Resources System/Payroll System | Department of Energy

    Broader source: Energy.gov (indexed) [DOE]

    SystemPayroll System PIA - Human Resources SystemPayroll System (291.51 KB) More Documents & Publications PIA - INL PeopleSoft - Human Resource System PIA - INL SECURITY ...

  9. Office of Executive Resources Office of the Chief Human Capital...

    Broader source: Energy.gov (indexed) [DOE]

    Office of Executive Resources Office of the Chief Human Capital Officer U.S. Department of ... The request must be submitted to the Office of the Chief Human Capital Officer, Office of ...

  10. Office of Executive Resources Office of the Chief Human Capital...

    Broader source: Energy.gov (indexed) [DOE]

    Office of Executive Resources Office of the Chief Human Capital Officer U.S. Department of ... Chief Human Capital Officer (CHCO) and Office of Executive Resources (OER). (1) Develop ...

  11. The Crystal Structure of Human, Nicotine Metabolizing Cytochrome...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    The Crystal Structure of Human, Nicotine Metabolizing Cytochrome P450 2A6 J.K. Yano1, ... The human cytochrome P450 2A6 is principally involved in the break down of nicotine in the ...

  12. Short-term Human Vision Protection from Intense Light Sources...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Short-term Human Vision Protection from Intense Light Sources The primary objective of this invention is to minimize the sensitivity of the human eye to intense visible light by ...

  13. Consortium to design human trials of mosaic HIV vaccine

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human trials of mosaic HIV vaccine Consortium to design human trials of mosaic HIV vaccine The vaccine represents a novel strategy for fighting the virus that causes AIDS by ...

  14. BigNeuron: Unlocking the Secrets of the Human Brain

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    BigNeuron: Unlocking the Secrets of the Human Brain BigNeuron: Unlocking the Secrets of the Human Brain Berkeley Researchers and Supercomputers to Help Create a Standard 3D Neuron ...

  15. COLLOQUIUM: Human Impacts on the Earth's Geologic Carbon Cycle...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    January 15, 2014, 4:00pm to 5:30pm Colloquia MBG Auditorium COLLOQUIUM: Human Impacts on ... Human Impacts on the Earth's Geologic Carbon Cycle Colloquium Committee: The Princeton ...

  16. Changes in Delegations of Authority from the Office of Human...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    from the Office of Human Capital Management by Jim McDonald Rescinds specific delegation orders that are rescinded as a result of the restructuring of the human capital function ...

  17. Human Resources at Colorado School of Mines | Critical Materials...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Employment at Colorado School of Mines Office of Human Resources: 1500 Illinois St., Suite ... Assistant Director (303)-273-3056 Link to Office of Human Resources Link to Job Openings

  18. What Is the Relationship of Electricity and the Human Body? ...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Is the Relationship of Electricity and the Human Body? Click to email this to a friend ... What Is the Relationship of Electricity and the Human Body? 2012.05.30 Chief Scientist Jim ...

  19. ATHENA desktop human "body" could reduce need for animal drug...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    ATHENA could reduce need for animal drug tests ATHENA desktop human "body" could reduce need for animal drug tests ATHENA project team is developing four human organ constructs that ...

  20. Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

    SciTech Connect (OSTI)

    Salaita, Khalid; Nair, Pradeep M; Petit, Rebecca S; Neve, Richard M; Das, Debopriya; Gray, Joe W; Groves, Jay T

    2009-09-09

    Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

  1. Network Analysis of Epidermal Growth Factor Signaling using Integrated Genomic, Proteomic and Phosphorylation Data

    SciTech Connect (OSTI)

    Waters, Katrina M.; Liu, Tao; Quesenberry, Ryan D.; Willse, Alan R.; Bandyopadhyay, Somnath; Kathmann, Loel E.; Weber, Thomas J.; Smith, Richard D.; Wiley, H. S.; Thrall, Brian D.

    2012-03-29

    To understand how integration of multiple data types can help decipher cellular responses at the systems level, we analyzed the mitogenic response of human mammary epithelial cells to epidermal growth factor (EGF) using whole genome microarrays, mass spectrometry-based proteomics and large-scale western blots with over 1000 antibodies. A time course analysis revealed significant differences in the expression of 3172 genes and 596 proteins, including protein phosphorylation changes measured by western blot. Integration of these disparate data types showed that each contributed qualitatively different components to the observed cell response to EGF and that varying degrees of concordance in gene expression and protein abundance measurements could be linked to specific biological processes. Networks inferred from individual data types were relatively limited, whereas networks derived from the integrated data recapitulated the known major cellular responses to EGF and exhibited more highly connected signaling nodes than networks derived from any individual dataset. While cell cycle regulatory pathways were altered as anticipated, we found the most robust response to mitogenic concentrations of EGF was induction of matrix metalloprotease cascades, highlighting the importance of the EGFR system as a regulator of the extracellular environment. These results demonstrate the value of integrating multiple levels of biological information to more accurately reconstruct networks of cellular response.

  2. OMB 1910-5122, Human Reliability Program - Description of Collections |

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Department of Energy OMB 1910-5122, Human Reliability Program - Description of Collections OMB 1910-5122, Human Reliability Program - Description of Collections Human Reliability Program Certification (DOE F 470.3). Under the Department of Energy Human Reliability Program (HRP), individuals who are applicants for or incumbents in designated positions must be evaluated to ensure that they meet the requirements for certification in the program. This form documents that each part of the

  3. Chesapeake Habitat for Humanity: Affordable Housing Case Study

    SciTech Connect (OSTI)

    2006-08-28

    This case study describes a partnership with Chesapeake Habitat for Humanity to renovate five Baltimore historic rowhouses.

  4. Human Behavior, Standards and Tools to Improve Design & Operation |

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Department of Energy Human Behavior, Standards and Tools to Improve Design & Operation Human Behavior, Standards and Tools to Improve Design & Operation Three steps of the technical approach to the human energy behavior loop: (1) Investigate the operations of building energy and services systems through behavior-related data collection, (2) Understand the human behavior through data analytics, data mining, and modeling, and (3) Improve the building performance by applying behavioral

  5. Global environmental change: Modifying human contributions through education

    SciTech Connect (OSTI)

    Carter, L.M.

    1997-12-31

    The 1995 Intergovernmental Panel on Climate Change (IPCC) Science report concludes that evidence now available {open_quotes}points toward a discernible human influence on global climate{close_quotes}. Reductions in emissions will require changes in human behavior. Knowledge, often through education, is an important moderator of human environmental behavior. This study assessed whether gains in global environmental change knowledge would lead to changes in human behaviors that could be deemed environmentally responsible.

  6. DOE Jobs Online (Hiring Manager), Office of Human Capitol Management

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Innovation and Solutions | Department of Energy Jobs Online (Hiring Manager), Office of Human Capitol Management Innovation and Solutions DOE Jobs Online (Hiring Manager), Office of Human Capitol Management Innovation and Solutions DOE Jobs Online (Hiring Manager), Office of Human Capitol Management Innovation and Solutions DOE Jobs Online (Hiring Manager), Office of Human Capitol Management Innovation and Solutions (1.46 MB) More Documents & Publications PIA - GovTrip (DOE data) LM

  7. Human Portable Radiation Detection System Communications Package Evaluation

    SciTech Connect (OSTI)

    Morgen, Gerald P.; Peterson, William W.

    2009-06-11

    Testing and valuation of the Human Portable Radiation Detection System Communications Package for the US Coast Guard.

  8. Case Study: Southeast Volusia Habitat for Humanity | Department of Energy

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Southeast Volusia Habitat for Humanity Case Study: Southeast Volusia Habitat for Humanity Case Study: Southeast Volusia Habitat for Humanity In August 2013, Southeast Volusia County Habitat for Humanity (Volusia Habitat) completed its first U.S. Department of Energy (DOE) Zero Energy Ready Home in Edgewater, on the Atlantic coast of central Florida. This 1,250- ft2, 3-bedroom, 2-bath home achieved a Home Energy Rating System (HERS) score of 49. That is 70 points better than typical existing

  9. PIA - Savannah River Nuclear Solutions (SRNS) Human Resource Management

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    System (HRMS) | Department of Energy (SRNS) Human Resource Management System (HRMS) PIA - Savannah River Nuclear Solutions (SRNS) Human Resource Management System (HRMS) PIA - Savannah River Nuclear Solutions (SRNS) Human Resource Management System (HRMS) PIA - Savannah River Nuclear Solutions (SRNS) Human Resource Management System (HRMS) (3.39 MB) More Documents & Publications PIA - Savannah River Nuclear Solution (SRNS) Procurement Cycle System (PCS) PIA - Savannah River Site

  10. Human borna disease virus infection impacts host proteome and histone lysine acetylation in human oligodendroglia cells

    SciTech Connect (OSTI)

    Liu, Xia; Zhao, Libo; Yang, Yongtao; Bode, Liv; Huang, Hua; Liu, Chengyu; Huang, Rongzhong; Zhang, Liang; and others

    2014-09-15

    Background: Borna disease virus (BDV) replicates in the nucleus and establishes persistent infections in mammalian hosts. A human BDV strain was used to address the first time, how BDV infection impacts the proteome and histone lysine acetylation (Kac) of human oligodendroglial (OL) cells, thus allowing a better understanding of infection-driven pathophysiology in vitro. Methods: Proteome and histone lysine acetylation were profiled through stable isotope labeling for cell culture (SILAC)-based quantitative proteomics. The quantifiable proteome was annotated using bioinformatics. Histone acetylation changes were validated by biochemistry assays. Results: Post BDV infection, 4383 quantifiable differential proteins were identified and functionally annotated to metabolism pathways, immune response, DNA replication, DNA repair, and transcriptional regulation. Sixteen of the thirty identified Kac sites in core histones presented altered acetylation levels post infection. Conclusions: BDV infection using a human strain impacted the whole proteome and histone lysine acetylation in OL cells. - Highlights: • A human strain of BDV (BDV Hu-H1) was used to infect human oligodendroglial cells (OL cells). • This study is the first to reveal the host proteomic and histone Kac profiles in BDV-infected OL cells. • BDV infection affected the expression of many transcription factors and several HATs and HDACs.

  11. Human factors issues in qualitative and quantitative safety analyses

    SciTech Connect (OSTI)

    Hahn, H.A.

    1993-10-01

    Humans are a critical and integral part of any operational system, be it a nuclear reactor, a facility for assembly or disassembling hazardous components, or a transportation network. In our concern over the safety of these systems, we often focus our attention on the hardware engineering components of such systems. However, experience has repeatedly demonstrated that it is often the human component that is the primary determinant of overall system safety. Both the nuclear reactor accidents at Chernobyl and Three Mile Island and shipping disasters such as the Exxon Valdez and the Herald of Free Enterprise accidents are attributable to human error. Concern over human contributions to system safety prompts us to include reviews of human factors issues in our safety analyses. In the conduct of Probabilistic Risk Assessments (PRAs), human factors issues are addressed using a quantitative method called Human Reliability Analysis (HRA). HRAs typically begin with the identification of potential sources of human error in accident sequences of interest. Human error analysis often employs plant and/or procedures walk-downs in which the analyst considers the ``goodness`` of procedures, training, and human-machine interfaces concerning their potential contribution to human error. Interviews with expert task performers may also be conducted. In the application of HRA, once candidate sources of human error have been identified, error probabilities are developed.

  12. Assay for mutagenesis in heterozygous diploid human lymphoblasts

    DOE Patents [OSTI]

    Skopek, Thomas R.; Liber, Howard L.; Penman, Bruce W.; Thilly, William G.; Hoppe, IV, Henry

    1981-01-01

    An assay is disclosed for determining mutagenic damage caused by the administration of a known or suspected mutagen to diploid human lymphoblastoid cell lines. The gene locus employed for this assay is the gene for thymidine kinase, uridine kinase, or cytidine deaminase. Since human lymphoblastoid cells contain two genes for these enzymes, heterozygotes of human lymphoblastoid cells are used in this assay.

  13. Trichloroethylene toxicity in a human hepatoma cell line

    SciTech Connect (OSTI)

    Thevenin, E.; McMillian, J.

    1994-12-31

    The experiments conducted in this study were designed to determine the usefullness of hepatocyte cultures and a human hepatoma cell line as model systems for assessing human susceptibility to hepatocellular carcinoma due to exposure to trichloroethylene. The results from these studies will then be analyzed to determine if human cell lines can be used to conduct future experiments of this nature.

  14. PIA - Human Resources - Personal Information Change Request - Idaho

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    National Engineering Laboratory | Department of Energy - Personal Information Change Request - Idaho National Engineering Laboratory PIA - Human Resources - Personal Information Change Request - Idaho National Engineering Laboratory PIA - Human Resources - Personal Information Change Request - Idaho National Engineering Laboratory PIA - Human Resources - Personal Information Change Request - Idaho National Engineering Laboratory (278.62 KB) More Documents & Publications PIA - INL

  15. MODELING HUMAN RELIABILITY ANALYSIS USING MIDAS

    SciTech Connect (OSTI)

    Ronald L. Boring; Donald D. Dudenhoeffer; Bruce P. Hallbert; Brian F. Gore

    2006-05-01

    This paper summarizes an emerging collaboration between Idaho National Laboratory and NASA Ames Research Center regarding the utilization of high-fidelity MIDAS simulations for modeling control room crew performance at nuclear power plants. The key envisioned uses for MIDAS-based control room simulations are: (i) the estimation of human error with novel control room equipment and configurations, (ii) the investigative determination of risk significance in recreating past event scenarios involving control room operating crews, and (iii) the certification of novel staffing levels in control rooms. It is proposed that MIDAS serves as a key component for the effective modeling of risk in next generation control rooms.

  16. Human somatic, germinal and heritable mutagenicity

    SciTech Connect (OSTI)

    Mendelsohn, M.L.

    1987-05-01

    This report deals with the general process of variant formation rather than with the consequences of a specific variant being present. It focusses on mutational mechanisms, mutagens, and the method for detecting de novo mutants and estimating mutation rate. It is to human genetics much like disease causation and prevention medicine are to medicine as a whole. The word ''mutagenicity'' is used in the title and throughout the text to connote the causation of all classes of genetic damage. Mutagenicity and the corresponding words mutation, mutagen and mutagenesis can have multiple meaning, sometimes relating to gene mutation, sometimes to heritable mutation, and somtimes to all types of genetic damage. 38 refs., 1 tab.

  17. SU-E-J-107: Supervised Learning Model of Aligned Collagen for Human Breast Carcinoma Prognosis

    SciTech Connect (OSTI)

    Bredfeldt, J; Liu, Y; Conklin, M; Keely, P; Eliceiri, K; Mackie, T

    2014-06-01

    Purpose: Our goal is to develop and apply a set of optical and computational tools to enable large-scale investigations of the interaction between collagen and tumor cells. Methods: We have built a novel imaging system for automating the capture of whole-slide second harmonic generation (SHG) images of collagen in registry with bright field (BF) images of hematoxylin and eosin stained tissue. To analyze our images, we have integrated a suite of supervised learning tools that semi-automatically model and score collagen interactions with tumor cells via a variety of metrics, a method we call Electronic Tumor Associated Collagen Signatures (eTACS). This group of tools first segments regions of epithelial cells and collagen fibers from BF and SHG images respectively. We then associate fibers with groups of epithelial cells and finally compute features based on the angle of interaction and density of the collagen surrounding the epithelial cell clusters. These features are then processed with a support vector machine to separate cancer patients into high and low risk groups. Results: We validated our model by showing that eTACS produces classifications that have statistically significant correlation with manual classifications. In addition, our system generated classification scores that accurately predicted breast cancer patient survival in a cohort of 196 patients. Feature rank analysis revealed that TACS positive fibers are more well aligned with each other, generally lower density, and terminate within or near groups of epithelial cells. Conclusion: We are working to apply our model to predict survival in larger cohorts of breast cancer patients with a diversity of breast cancer types, predict response to treatments such as COX2 inhibitors, and to study collagen architecture changes in other cancer types. In the future, our system may be used to provide metastatic potential information to cancer patients to augment existing clinical assays.

  18. Understanding the origins of human cancer

    SciTech Connect (OSTI)

    Alexandrov, L. B.

    2015-12-04

    All cancers originate from a single cell that starts to behave abnormally, to divide uncontrollably, and, eventually, to invade adjacent tissues (1). The aberrant behavior of this single cell is due to somatic mutations—changes in the genomic DNA produced by the activity of different mutational processes (1). These various mutational processes include exposure to exogenous or endogenous mutagens, abnormal DNA editing, the incomplete fidelity of DNA polymerases, and failure of DNA repair mechanisms (2). Early studies that sequenced TP53, the most commonly mutated gene in human cancer, provided evidence that mutational processes leave distinct imprints of somatic mutations on the genome of a cancer cell (3). For example, C:G>A:T transversions predominate in smoking-associated lung cancer, whereas C:G>T:A transitions occurring mainly at dipyrimidines and CC:GG>TT:AA double-nucleotide substitutions are common in ultraviolet light–associated skin cancers. Moreover, these patterns of mutations matched the ones induced experimentally by tobacco mutagens and ultraviolet light, respectively, the major, known, exogenous carcinogenic influences in these cancer types, and demonstrated that examining patterns of mutations in cancer genomes can yield information about the mutational processes that cause human cancer (4).

  19. Structure of Human Ferritin L Chain

    SciTech Connect (OSTI)

    Wang,Z.; Li, C.; Ellenburg, M.; Soistman, E.; Ruble, J.; Wright, B.; Ho, J.; Carter, D.

    2006-01-01

    Ferritin is the major iron-storage protein present in all cells. It generally contains 24 subunits, with different ratios of heavy chain (H) to light chain (L), in the shape of a hollow sphere hosting up to 4500 ferric Fe atoms inside. H-rich ferritins catalyze the oxidation of iron(II), while L-rich ferritins promote the nucleation and storage of iron(III). Several X-ray structures have been determined, including those of L-chain ferritins from horse spleen (HoSF), recombinant L-chain ferritins from horse (HoLF), mouse (MoLF) and bullfrog (BfLF) as well as recombinant human H-chain ferritin (HuHF). Here, structures have been determined of two crystal forms of recombinant human L-chain ferritin (HuLF) obtained from native and perdeuterated proteins. The structures show a cluster of acidic residues at the ferrihydrite nucleation site and at the iron channel along the threefold axis. An ordered Cd{sup 2+} structure is observed within the iron channel, offering further insight into the route and mechanism of iron transport into the capsid. The loop between helices D and E, which is disordered in many other L-chain structures, is clearly visible in these two structures. The crystals generated from perdeuterated HuLF will be used for neutron diffraction studies.

  20. Nucleic acids encoding human trithorax protein

    DOE Patents [OSTI]

    Evans, Glen A.; Djabali, Malek; Selleri, Licia; Parry, Pauline

    2001-01-01

    In accordance with the present invention, there is provided an isolated peptide having the characteristics of human trithorax protein (as well as DNA encoding same, antisense DNA derived therefrom and antagonists therefor). The invention peptide is characterized by having a DNA binding domain comprising multiple zinc fingers and at least 40% amino acid identity with respect to the DNA binding domain of Drosophila trithorax protein and at least 70% conserved sequence with respect to the DNA binding domain of Drosophila trithorax protein, and wherein said peptide is encoded by a gene located at chromosome 11 of the human genome at q23. Also provided are methods for the treatment of subject(s) suffering from immunodeficiency, developmental abnormality, inherited disease, or cancer by administering to said subject a therapeutically effective amount of one of the above-described agents (i.e., peptide, antagonist therefor, DNA encoding said peptide or antisense DNA derived therefrom). Also provided is a method for the diagnosis, in a subject, of immunodeficiency, developmental abnormality, inherited disease, or cancer associated with disruption of chromosome 11 at q23.

  1. Understanding the origins of human cancer

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Alexandrov, L. B.

    2015-12-04

    All cancers originate from a single cell that starts to behave abnormally, to divide uncontrollably, and, eventually, to invade adjacent tissues (1). The aberrant behavior of this single cell is due to somatic mutations—changes in the genomic DNA produced by the activity of different mutational processes (1). These various mutational processes include exposure to exogenous or endogenous mutagens, abnormal DNA editing, the incomplete fidelity of DNA polymerases, and failure of DNA repair mechanisms (2). Early studies that sequenced TP53, the most commonly mutated gene in human cancer, provided evidence that mutational processes leave distinct imprints of somatic mutations on themore » genome of a cancer cell (3). For example, C:G>A:T transversions predominate in smoking-associated lung cancer, whereas C:G>T:A transitions occurring mainly at dipyrimidines and CC:GG>TT:AA double-nucleotide substitutions are common in ultraviolet light–associated skin cancers. Moreover, these patterns of mutations matched the ones induced experimentally by tobacco mutagens and ultraviolet light, respectively, the major, known, exogenous carcinogenic influences in these cancer types, and demonstrated that examining patterns of mutations in cancer genomes can yield information about the mutational processes that cause human cancer (4).« less

  2. Science-Based Simulation Model of Human Performance for Human Reliability Analysis

    SciTech Connect (OSTI)

    Dana L. Kelly; Ronald L. Boring; Ali Mosleh; Carol Smidts

    2011-10-01

    Human reliability analysis (HRA), a component of an integrated probabilistic risk assessment (PRA), is the means by which the human contribution to risk is assessed, both qualitatively and quantitatively. However, among the literally dozens of HRA methods that have been developed, most cannot fully model and quantify the types of errors that occurred at Three Mile Island. Furthermore, all of the methods lack a solid empirical basis, relying heavily on expert judgment or empirical results derived in non-reactor domains. Finally, all of the methods are essentially static, and are thus unable to capture the dynamics of an accident in progress. The objective of this work is to begin exploring a dynamic simulation approach to HRA, one whose models have a basis in psychological theories of human performance, and whose quantitative estimates have an empirical basis. This paper highlights a plan to formalize collaboration among the Idaho National Laboratory (INL), the University of Maryland, and The Ohio State University (OSU) to continue development of a simulation model initially formulated at the University of Maryland. Initial work will focus on enhancing the underlying human performance models with the most recent psychological research, and on planning follow-on studies to establish an empirical basis for the model, based on simulator experiments to be carried out at the INL and at the OSU.

  3. HUMAN RELIABILITY ANALYSIS FOR COMPUTERIZED PROCEDURES

    SciTech Connect (OSTI)

    Ronald L. Boring; David I. Gertman; Katya Le Blanc

    2011-09-01

    This paper provides a characterization of human reliability analysis (HRA) issues for computerized procedures in nuclear power plant control rooms. It is beyond the scope of this paper to propose a new HRA approach or to recommend specific methods or refinements to those methods. Rather, this paper provides a review of HRA as applied to traditional paper-based procedures, followed by a discussion of what specific factors should additionally be considered in HRAs for computerized procedures. Performance shaping factors and failure modes unique to computerized procedures are highlighted. Since there is no definitive guide to HRA for paper-based procedures, this paper also serves to clarify the existing guidance on paper-based procedures before delving into the unique aspects of computerized procedures.

  4. Mapping genes to human chromosome 19

    SciTech Connect (OSTI)

    Connolly, Sarah

    1996-05-01

    For this project, 22 Expressed Sequence Tags (ESTs) were fine mapped to regions of human chromosome 19. An EST is a short DNA sequence that occurs once in the genome and corresponds to a single expressed gene. {sup 32}P-radiolabeled probes were made by polymerase chain reaction for each EST and hybridized to filters containing a chromosome 19-specific cosmid library. The location of the ESTs on the chromosome was determined by the location of the ordered cosmid to which the EST hybridized. Of the 22 ESTs that were sublocalized, 6 correspond to known genes, and 16 correspond to anonymous genes. These localized ESTs may serve as potential candidates for disease genes, as well as markers for future physical mapping.

  5. Insights from Human/Mouse genome comparisons

    SciTech Connect (OSTI)

    Pennacchio, Len A.

    2003-03-30

    Large-scale public genomic sequencing efforts have provided a wealth of vertebrate sequence data poised to provide insights into mammalian biology. These include deep genomic sequence coverage of human, mouse, rat, zebrafish, and two pufferfish (Fugu rubripes and Tetraodon nigroviridis) (Aparicio et al. 2002; Lander et al. 2001; Venter et al. 2001; Waterston et al. 2002). In addition, a high-priority has been placed on determining the genomic sequence of chimpanzee, dog, cow, frog, and chicken (Boguski 2002). While only recently available, whole genome sequence data have provided the unique opportunity to globally compare complete genome contents. Furthermore, the shared evolutionary ancestry of vertebrate species has allowed the development of comparative genomic approaches to identify ancient conserved sequences with functionality. Accordingly, this review focuses on the initial comparison of available mammalian genomes and describes various insights derived from such analysis.

  6. Modeling aspects of human memory for scientific study.

    SciTech Connect (OSTI)

    Caudell, Thomas P.; Watson, Patrick; McDaniel, Mark A.; Eichenbaum, Howard B.; Cohen, Neal J.; Vineyard, Craig Michael; Taylor, Shawn Ellis; Bernard, Michael Lewis; Morrow, James Dan; Verzi, Stephen J.

    2009-10-01

    Working with leading experts in the field of cognitive neuroscience and computational intelligence, SNL has developed a computational architecture that represents neurocognitive mechanisms associated with how humans remember experiences in their past. The architecture represents how knowledge is organized and updated through information from individual experiences (episodes) via the cortical-hippocampal declarative memory system. We compared the simulated behavioral characteristics with those of humans measured under well established experimental standards, controlling for unmodeled aspects of human processing, such as perception. We used this knowledge to create robust simulations of & human memory behaviors that should help move the scientific community closer to understanding how humans remember information. These behaviors were experimentally validated against actual human subjects, which was published. An important outcome of the validation process will be the joining of specific experimental testing procedures from the field of neuroscience with computational representations from the field of cognitive modeling and simulation.

  7. Some aspects of statistical modeling of human-error probability

    SciTech Connect (OSTI)

    Prairie, R. R.

    1982-01-01

    Human reliability analyses (HRA) are often performed as part of risk assessment and reliability projects. Recent events in nuclear power have shown the potential importance of the human element. There are several on-going efforts in the US and elsewhere with the purpose of modeling human error such that the human contribution can be incorporated into an overall risk assessment associated with one or more aspects of nuclear power. An effort that is described here uses the HRA (event tree) to quantify and model the human contribution to risk. As an example, risk analyses are being prepared on several nuclear power plants as part of the Interim Reliability Assessment Program (IREP). In this process the risk analyst selects the elements of his fault tree that could be contributed to by human error. He then solicits the HF analyst to do a HRA on this element.

  8. Beyond The Human Genome: What's Next? (LBNL Summer Lecture Series)

    ScienceCinema (OSTI)

    Rokhsar, Daniel

    2014-05-06

    UC Berkeley's Daniel Rokhsar and his colleagues were instrumental in contributing the sequences for three of the human body's chromosomes in the effort to decipher the blueprint of life- the completion of the DNA sequencing of the human genome. Now he is turning to the structure and function of genes in other organisms, some of them no less important to the planet's future than the human map. Hear the latest in this lecture from Lawrence Berkeley National Laboratory.

  9. Office of the Chief Human Capital Officer | Department of Energy

    Broader source: All U.S. Department of Energy (DOE) Office Webpages

    Human Capital Officer Search Search form Search Office of the Chief Human Capital Officer Office of the Chief Human Capital Officer Services Services Home Benefits Benefits Home DOE Workers' Compensation Program Insurance Military/Reservist Retirement Telework Thrift Savings Plan (TSP) Wellness Programs Executive Resources Learning and Workforce Development New Employee Orientation Policy and Guidance Policy and Guidance Home Compensation Employment/Staffing Employment/Staffing Home Recruitment

  10. Contacts for the Assistant General Counsel for Contractor Human Resources |

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Department of Energy Contractor Human Resources Contacts for the Assistant General Counsel for Contractor Human Resources Jean S. Stucky, Assistant General Counsel for Contractor Human Resources 202-586-7532 jean.stucky@hq.doe.gov Eva M. Auman, Attorney-Adviser 202-287-5630 Grant Programs Legacy/Closure Sites Hanford Moab National Energy Testing Laboratory National Renewable Energy Laboratory Pacific Northwest National Laboratory Waste Isolation Pilot Project (Carlsbad Field Office) Thomas

  11. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Irradiation Effects on Human Cortical Bone Fracture Behavior Print Wednesday, 28 July 2010 00:00 Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or

  12. Integrated Human Futures Modeling in Egypt

    SciTech Connect (OSTI)

    Passell, Howard D.; Aamir, Munaf Syed; Bernard, Michael Lewis; Beyeler, Walter E.; Fellner, Karen Marie; Hayden, Nancy Kay; Jeffers, Robert Fredric; Keller, Elizabeth James Kistin; Malczynski, Leonard A.; Mitchell, Michael David; Silver, Emily; Tidwell, Vincent C.; Villa, Daniel; Vugrin, Eric D.; Engelke, Peter; Burrow, Mat; Keith, Bruce

    2016-01-01

    The Integrated Human Futures Project provides a set of analytical and quantitative modeling and simulation tools that help explore the links among human social, economic, and ecological conditions, human resilience, conflict, and peace, and allows users to simulate tradeoffs and consequences associated with different future development and mitigation scenarios. In the current study, we integrate five distinct modeling platforms to simulate the potential risk of social unrest in Egypt resulting from the Grand Ethiopian Renaissance Dam (GERD) on the Blue Nile in Ethiopia. The five platforms simulate hydrology, agriculture, economy, human ecology, and human psychology/behavior, and show how impacts derived from development initiatives in one sector (e.g., hydrology) might ripple through to affect other sectors and how development and security concerns may be triggered across the region. This approach evaluates potential consequences, intended and unintended, associated with strategic policy actions that span the development-security nexus at the national, regional, and international levels. Model results are not intended to provide explicit predictions, but rather to provide system-level insight for policy makers into the dynamics among these interacting sectors, and to demonstrate an approach to evaluating short- and long-term policy trade-offs across different policy domains and stakeholders. The GERD project is critical to government-planned development efforts in Ethiopia but is expected to reduce downstream freshwater availability in the Nile Basin, fueling fears of negative social and economic impacts that could threaten stability and security in Egypt. We tested these hypotheses and came to the following preliminary conclusions. First, the GERD will have an important short-term impact on water availability, food production, and hydropower production in Egypt, depending on the short- term reservoir fill rate. Second, the GERD will have a very small impact on

  13. Human Papillomavirus (HPV) Infection in Squamous Cell Carcinomas...

    Office of Scientific and Technical Information (OSTI)

    Human Papillomavirus (HPV) Infection in Squamous Cell Carcinomas Arising From the ... Resource Relation: Journal Name: International Journal of Radiation Oncology, Biology and ...

  14. Genome Wide Evaluation of Normal Human Tissue in Response to...

    Office of Scientific and Technical Information (OSTI)

    Wide Evaluation of Normal Human Tissue in Response to Controlled, In vivo Low-Dose Low LET Ionizing Radiation Exposure: Pathways and Mechanisms Final Report, September 2013 Rocke,...

  15. Sandia Energy - Results from the Human Resilience Index and Modeling...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Results from the Human Resilience Index and Modeling project were reported recently in the National Intelligence Council's Global Trends 2030 Report Home Infrastructure Security...

  16. Building America Case Study: Columbia County Habitat for Humanity...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Columbia County Habitat for Humanity Passive Townhomes Hudson, New York PROJECT INFORMATION Project Name: Columbia Passive Townhomes II Location: Hudson, NY Partners: Columbia ...

  17. Creating a Tiny Human Body on a Chip

    ScienceCinema (OSTI)

    Hunsberger, Maren; Soscia, Dave; Moya, Monica

    2016-03-16

    LLNL science communicator Maren Hunsberger takes us "Inside the Lab" to learn about the iChip (In-vitro Chip-based Human Investigational Platform) project at Lawrence Livermore National Laboratory. "One application of the iChip system would be to develop new pharmaceutical drugs," explains Dave Soscia, LLNL postdoc. "When you test in a mouse for example, it's not as close to the human system as you can get. If we can take human cells and put them on devices and actually mimic the structure and function of the organ systems in the human, we can actually replace animal testing and even make a better system for testing pharmaceutical drugs."

  18. Handbook of human-reliability analysis with emphasis on nuclear...

    Office of Scientific and Technical Information (OSTI)

    emphasis on nuclear power plant applications. Final report Citation Details In-Document Search Title: Handbook of human-reliability analysis with emphasis on nuclear power plant ...

  19. Acid soluble platelet aggregating material isolated from human umbilical cord

    DOE Patents [OSTI]

    Schneider, Morris D.

    1983-01-01

    Acid soluble, pepsin sensitive platelet aggregating material isolated from human umbilical cord tissue by extraction with dilute aqueous acid, method of isolation and use to control bleeding.

  20. Columbia County Habitat for Humanity Passive Townhomes (Technical...

    Office of Scientific and Technical Information (OSTI)

    (specifically with respect to exterior wall, space-conditioning, and ventilation strategies) within the labor and budget context inherent in a Habitat for Humanity project. ...

  1. Metabolome of human gut microbiome is predictive of host dysbiosis

    SciTech Connect (OSTI)

    Larsen, Peter E.; Dai, Yang

    2015-09-14

    Background: Humans live in constant and vital symbiosis with a closely linked bacterial ecosystem called the microbiome, which influences many aspects of human health. When this microbial ecosystem becomes disrupted, the health of the human host can suffer; a condition called dysbiosis. The community compositions of human microbiomes also vary dramatically from individual to individual, and over time, making it difficult to uncover the underlying mechanisms linking the microbiome to human health. We propose that a microbiome’s interaction with its human host is not necessarily dependent upon the presence or absence of particular bacterial species, but instead is dependent on its community metabolome; an emergent property of the microbiome. Results: Using data from a previously published, longitudinal study of microbiome populations of the human gut, we extrapolated information about microbiome community enzyme profiles and metabolome models. Using machine learning techniques, we demonstrated that the aggregate predicted community enzyme function profiles and modeled metabolomes of a microbiome are more predictive of dysbiosis than either observed microbiome community composition or predicted enzyme function profiles. Conclusions: Specific enzyme functions and metabolites predictive of dysbiosis provide insights into the molecular mechanisms of microbiome–host interactions. The ability to use machine learning to predict dysbiosis from microbiome community interaction data provides a potentially powerful tool for understanding the links between the human microbiome and human health, pointing to potential microbiome-based diagnostics and therapeutic interventions.

  2. Massively Parallel Models of the Human Circulatory System (Conference...

    Office of Scientific and Technical Information (OSTI)

    Massively Parallel Models of the Human Circulatory System Citation Details In-Document ... Sponsoring Org: USDOE Country of Publication: United States Language: English Subject: 59 ...

  3. DOE human genome program contractor-grantee workshop VI

    SciTech Connect (OSTI)

    1997-10-01

    Research is presented from the workshop on the Human Genome Project. Topics include sequencing, genetic mapping, informatics, ethical and legal issues, and infrastructure.

  4. OSTIblog Articles in the Human Genome Project Topic | OSTI, US...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Related Topics: Charles DeLisi, DNA, DOE Research & Development (R&D) Accomplishments, genomics, Human Genome Project, Santa Fe Workshop, sequencing Read more... DOE Research ...

  5. Metabolome of human gut microbiome is predictive of host dysbiosis

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Larsen, Peter E.; Dai, Yang

    2015-09-14

    Background: Humans live in constant and vital symbiosis with a closely linked bacterial ecosystem called the microbiome, which influences many aspects of human health. When this microbial ecosystem becomes disrupted, the health of the human host can suffer; a condition called dysbiosis. The community compositions of human microbiomes also vary dramatically from individual to individual, and over time, making it difficult to uncover the underlying mechanisms linking the microbiome to human health. We propose that a microbiome’s interaction with its human host is not necessarily dependent upon the presence or absence of particular bacterial species, but instead is dependent onmore » its community metabolome; an emergent property of the microbiome. Results: Using data from a previously published, longitudinal study of microbiome populations of the human gut, we extrapolated information about microbiome community enzyme profiles and metabolome models. Using machine learning techniques, we demonstrated that the aggregate predicted community enzyme function profiles and modeled metabolomes of a microbiome are more predictive of dysbiosis than either observed microbiome community composition or predicted enzyme function profiles. Conclusions: Specific enzyme functions and metabolites predictive of dysbiosis provide insights into the molecular mechanisms of microbiome–host interactions. The ability to use machine learning to predict dysbiosis from microbiome community interaction data provides a potentially powerful tool for understanding the links between the human microbiome and human health, pointing to potential microbiome-based diagnostics and therapeutic interventions.« less

  6. Identifying Requirements for Effective Human-Automation Teamwork

    SciTech Connect (OSTI)

    Jeffrey C. Joe; John O'Hara; Heather D. Medema; Johanna H. Oxstrand

    2014-06-01

    Previous studies have shown that poorly designed human-automation collaboration, such as poorly designed communication protocols, often leads to problems for the human operators, such as: lack of vigilance, complacency, and loss of skills. These problems often lead to suboptimal system performance. To address this situation, a considerable amount of research has been conducted to improve human-automation collaboration and to make automation function better as a “team player.” Much of this research is based on an understanding of what it means to be a good team player from the perspective of a human team. However, the research is often based on a simplified view of human teams and teamwork. In this study, we sought to better understand the capabilities and limitations of automation from the standpoint of human teams. We first examined human teams to identify the principles for effective teamwork. We next reviewed the research on integrating automation agents and human agents into mixed agent teams to identify the limitations of automation agents to conform to teamwork principles. This research resulted in insights that can lead to more effective human-automation collaboration by enabling a more realistic set of requirements to be developed based on the strengths and limitations of all agents.

  7. Structure and mechanism of human DNA polymerase [eta] (Journal...

    Office of Scientific and Technical Information (OSTI)

    DNA polymerase eta Citation Details In-Document ... Here we report high-resolution crystal structures of human ... OSTI Identifier: 1002510 Resource Type: Journal Article ...

  8. Director, Human Resources Shared Service Center (Management and Performance)

    Broader source: Energy.gov [DOE]

    The Office of the Chief Human Capital Officer (OCHCO) is a progressive and contemporary organization that partners with the DOE leadership to maximize the talent, diversity, commitment and...

  9. Building America Case Study: Habitat for Humanity, The Woods...

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    Type: Single-family, affordable Partners: Tacoma Public Utilities, mytpu.org Habitat for Humanity of Tacoma Pierce County, WA, tpc-habitat.org Building America Partnership for ...

  10. Fluorescent tracking of nickel ions in human cultured cells ...

    Office of Scientific and Technical Information (OSTI)

    Fluorescent tracking of nickel ions in human cultured cells Citation Details In-Document ... B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International ...

  11. Groundwater Resources Assessment under the Pressures of Humanity...

    Open Energy Info (EERE)

    Resources Assessment under the Pressures of Humanity and Climate Change (GRAPHIC) Jump to: navigation, search Tool Summary LAUNCH TOOL Name: Groundwater Resources Assessment under...

  12. Handbook of human-reliability analysis with emphasis on nuclear...

    Office of Scientific and Technical Information (OSTI)

    nuclear power plant applications. Final report Citation Details In-Document Search Title: Handbook of human-reliability analysis with emphasis on nuclear power plant applications. ...

  13. Before House Subcommittee on Africa, Global Health, Global Human...

    Broader source: Energy.gov (indexed) [DOE]

    Testimony of Jonathan Elkind, Acting Assistant Secretary, Office of International Affairs Before House Subcommittee on Africa, Global Health, Global Human Rights, and International ...

  14. First Steps Towards Tribal Weatherization: Human Capacity Development

    Broader source: Energy.gov (indexed) [DOE]

    Towards Tribal Weatherization: Human Capacity Development October 2011 October 2011 Cook Inlet Tribal Council's Weatherization Apprenticeship October 2011 March 2010 - March 2012 ...

  15. First Steps Towards Tribal Weatherization: Human Capacity Development

    Broader source: Energy.gov (indexed) [DOE]

    Steps Towards tribal weatherization: human capacity development October 2010 - Cook Inlet Tribal Council Weatherization Apprenticeship March 2010 February 2012 Cook Inlet Tribal ...

  16. Human Resources at Oak Ridge National Laboratory | Critical Materials...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Oak Ridge National Laboratory Contact Information The main contact for human resources for CMI at Oak Ridge National Laboratory: David Lett Phone: 865-576-5675 Email: ...

  17. POLICY BULLETIN: POL-5- Declassification Instruction "25X1-human"

    Broader source: Energy.gov [DOE]

    Provides instructions on the appropriate action to take when classification guide topics or source documents cite "25X1-human" declassification instructions.

  18. Human Resources at Lawrence Livermore National Laboratory | Critical...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Lawrence Livermore National Laboratory Careers at Lawrence Livermore National Laboratory Main contacts in Human Resources for recruitment and hiring: Jennifer Brizel Recruitment & ...

  19. Human Resources at Critical Materials Institute | Critical Materials...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources at Critical Materials Institute Each partner within the Critical Materials Institute manages its own hiring. Use these links to find key contacts for CMI partners ...

  20. Human Resources at Idaho National Laboratory | Critical Materials...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Idaho National Laboratory Link to Office of Human Resources INL Staffing (208) 526-5888 Link to infographic on reasons to work at INL

  1. Fifty Years of THERP and Human Reliability Analysis

    SciTech Connect (OSTI)

    Ronald L. Boring

    2012-06-01

    In 1962 at a Human Factors Society symposium, Alan Swain presented a paper introducing a Technique for Human Error Rate Prediction (THERP). This was followed in 1963 by a Sandia Laboratories monograph outlining basic human error quantification using THERP and, in 1964, by a special journal edition of Human Factors on quantification of human performance. Throughout the 1960s, Swain and his colleagues focused on collecting human performance data for the Sandia Human Error Rate Bank (SHERB), primarily in connection with supporting the reliability of nuclear weapons assembly in the US. In 1969, Swain met with Jens Rasmussen of Risø National Laboratory and discussed the applicability of THERP to nuclear power applications. By 1975, in WASH-1400, Swain had articulated the use of THERP for nuclear power applications, and the approach was finalized in the watershed publication of the NUREG/CR-1278 in 1983. THERP is now 50 years old, and remains the most well known and most widely used HRA method. In this paper, the author discusses the history of THERP, based on published reports and personal communication and interviews with Swain. The author also outlines the significance of THERP. The foundations of human reliability analysis are found in THERP: human failure events, task analysis, performance shaping factors, human error probabilities, dependence, event trees, recovery, and pre- and post-initiating events were all introduced in THERP. While THERP is not without its detractors, and it is showing signs of its age in the face of newer technological applications, the longevity of THERP is a testament of its tremendous significance. THERP started the field of human reliability analysis. This paper concludes with a discussion of THERP in the context of newer methods, which can be seen as extensions of or departures from Swain’s pioneering work.

  2. Human Factors Aspects of Operating Small Reactors

    SciTech Connect (OSTI)

    OHara, J.M.; Higgins, J.; Deem, R.; Xing, J.; DAgostino, A.

    2010-11-07

    The nuclear-power community has reached the stage of proposing advanced reactor designs to support power generation for decades to come. They are considering small modular reactors (SMRs) as one approach to meet these energy needs. While the power output of individual reactor modules is relatively small, they can be grouped to produce reactor sites with different outputs. Also, they can be designed to generate hydrogen, or to process heat. Many characteristics of SMRs are quite different from those of current plants, and so may require a concept of operations (ConOps) that also is different. The U.S. Nuclear Regulatory Commission (NRC) has begun examining the human factors engineering- (HFE) and ConOps- aspects of SMRs; if needed, they will formulate guidance to support SMR licensing reviews. We developed a ConOps model, consisting of the following dimensions: Plant mission; roles and responsibilities of all agents; staffing, qualifications, and training; management of normal operations; management of off-normal conditions and emergencies; and, management of maintenance and modifications. We are reviewing information on SMR design to obtain data about each of these dimensions, and have identified several preliminary issues. In addition, we are obtaining operations-related information from other types of multi-module systems, such as refineries, to identify lessons learned from their experience. Here, we describe the project's methodology and our preliminary findings.

  3. Before House Subcommittee on Africa, Global Health, Global Human Rights,

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    and International Organizations, Committee on Foreign Affairs | Department of Energy House Subcommittee on Africa, Global Health, Global Human Rights, and International Organizations, Committee on Foreign Affairs Before House Subcommittee on Africa, Global Health, Global Human Rights, and International Organizations, Committee on Foreign Affairs Testimony of Jonathan Elkind, Acting Assistant Secretary, Office of International Affairs Before House Subcommittee on Africa, Global Health, Global

  4. Summary of human responses to ventilation

    SciTech Connect (OSTI)

    Seppanen, Olli A.; Fisk, William J.

    2004-06-01

    The effects of ventilation on indoor air quality and health is a complex issue. It is known that ventilation is necessary to remove indoor generated pollutants from indoor air or dilute their concentration to acceptable levels. But, as the limit values of all pollutants are not known, the exact determination of required ventilation rates based on pollutant concentrations and associated risks is seldom possible. The selection of ventilation rates has to be based also on epidemiological research (e.g. Seppanen et al., 1999), laboratory and field experiments (e.g. CEN 1996, Wargocki et al., 2002a) and experience (e.g. ECA 2003). Ventilation may also have harmful effects on indoor air quality and climate if not properly designed, installed, maintained and operated as summarized by Seppdnen (2003). Ventilation may bring indoors harmful substances that deteriorate the indoor environment. Ventilation also affects air and moisture flow through the building envelope and may lead to moisture problems that deteriorate the structures of the building. Ventilation changes the pressure differences over the structures of building and may cause or prevent the infiltration of pollutants from structures or adjacent spaces. Ventilation is also in many cases used to control the thermal environment or humidity in buildings. Ventilation can be implemented with various methods which may also affect health (e.g. Seppdnen and Fisk, 2002, Wargocki et al., 2002a). In non residential buildings and hot climates, ventilation is often integrated with air-conditioning which makes the operation of ventilation system more complex. As ventilation is used for many purposes its health effects are also various and complex. This paper summarizes the current knowledge on positive and negative effects of ventilation on health and other human responses. The focus of the paper is on office-type working environment and residential buildings. In the industrial premises the problems of air quality are usually

  5. Alternative splicing variants of human Fbx4 disturb cyclin D1 proteolysis in human cancer

    SciTech Connect (OSTI)

    Chu, Xiufeng; Zhang, Ting; Wang, Jie; Li, Meng; Zhang, Xiaolei; Tu, Jing; Sun, Shiqin; Chen, Xiangmei; Lu, Fengmin

    2014-04-25

    Highlights: The expression of Fbx4 was significantly lower in HCC tissues. Novel splicing variants of Fbx4 were identified. These novel variants are much more abundant in human cancer tissues and cells. The novel Fbx4 isoforms could promote cell proliferation and migration in vitro. These isoforms showed less capability for cyclin D1 binding and degradation. - Abstract: Fbx4 is a specific substrate recognition component of SCF ubiquitin ligases that catalyzes the ubiquitination and subsequent degradation of cyclin D1 and Trx1. Two isoforms of human Fbx4 protein, the full length Fbx4? and the C-terminal truncated Fbx4? have been identified, but their functions remain elusive. In this study, we demonstrated that the mRNA level of Fbx4 was significantly lower in hepatocellular carcinoma tissues than that in the corresponding non-tumor tissues. More importantly, we identified three novel splicing variants of Fbx4: Fbx4? (missing 168245nt of exon1), Fbx4? (missing exon6) and a N-terminal reading frame shift variant (missing exon2). Using cloning sequencing and RT-PCR, we demonstrated these novel splice variants are much more abundant in human cancer tissues and cell lines than that in normal tissues. When expressed in Sk-Hep1 and NIH3T3 cell lines, Fbx4?, Fbx4? and Fbx4? could promote cell proliferation and migration in vitro. Concordantly, these isoforms could disrupt cyclin D1 degradation and therefore increase cyclin D1 expression. Moreover, unlike the full-length isoform Fbx4? that mainly exists in cytoplasm, Fbx4?, Fbx4?, and Fbx4? locate in both cytoplasm and nucleus. Since cyclin D1 degradation takes place in cytoplasm, the nuclear distribution of these Fbx4 isoforms may not be involved in the down-regulation of cytoplasmic cyclin D1. These results define the impact of alternative splicing on Fbx4 function, and suggest that the attenuated cyclin D1 degradation by these novel Fbx4 isoforms provides a new insight for aberrant cyclin D1 expression in

  6. Finishing The Euchromatic Sequence Of The Human Genome

    SciTech Connect (OSTI)

    Rubin, Edward M.; Lucas, Susan; Richardson, Paul; Rokhsar, Daniel; Pennacchio, Len

    2004-09-07

    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process.The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers {approx}99% of the euchromatic genome and is accurate to an error rate of {approx}1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number,birth and death. Notably, the human genome seems to encode only20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.

  7. The Development of A Human Systems Simulation Laboratory: Strategic Direction

    SciTech Connect (OSTI)

    Jacques Hugo; Katya le Blanc; David Gertman

    2012-07-01

    The Human System Simulation Laboratory (HSSL) at the Idaho National Laboratory is one of few facilities of its kind that allows human factors researchers to evaluate various aspects of human performance and human system interaction for proposed reactor designs and upgrades. A basic system architecture, physical configuration and simulation capability were established to enable human factors researchers to support multiple, simultaneous simulations and also different power plant technologies. Although still evolving in terms of its technical and functional architecture, the HSSL is already proving its worth in supporting current and future nuclear industry needs for light water reactor sustainability and small modular reactors. The evolution of the HSSL is focused on continual physical and functional refinement to make it a fully equipped, reconfigurable facility where advanced research, testing and validation studies can be conducted on a wider range of reactor technologies. This requires the implementation of additional plant models to produce empirical research data on human performance with emerging human-system interaction technologies. Additional beneficiaries of this information include system designers and HRA practitioners. To ensure that results of control room crew studies will be generalizable to the existing and evolving fleet of US reactors, future expansion of the HSSL may also include other SMR plant models, plant-specific simulators and a generic plant model aligned to the current generation of pressurized water reactors (PWRs) and future advanced reactor designs. Collaboration with industry partners is also proving to be a vital component of the facility as this helps to establish a formal basis for current and future human performance experiments to support nuclear industry objectives. A long-range Program Plan has been developed for the HSSL to ensure that the facility will support not only the Department of Energys Light Water Reactor

  8. Structure and Receptor Specificity of an Avian Flu Antigen

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    combined effects could allow the Viet04 virus to escape entrapment by mucins in the lungs and increase binding to susceptible human epithelial cells. These mutations therefore...

  9. Search for: All records | SciTech Connect

    Office of Scientific and Technical Information (OSTI)

    ... human bronchial epithelial cells and in lungs of CD-1 mice Jin, Hua ; Shen, Shuijie ; ... administration of dauricine caused GSH depletion and apoptosis in lungs of mice. ...

  10. Search for: All records | SciTech Connect

    Office of Scientific and Technical Information (OSTI)

    ... Response of Human Lung Epithelial Cells to Engineered Nanoparticles. Bachand, George ; ... For example, pants and shirts are routinely manufactured with silver nanoparticles to ...

  11. 99M-technetium labeled macroaggregated human serum albumin pharmaceutical

    DOE Patents [OSTI]

    Winchell, Harry S.; Barak, Morton; Van Fleet, III, Parmer

    1977-05-17

    A reagent comprising macroaggregated human serum albumin having dispersed therein particles of stannous tin and a method for instantly making a labeled pharmaceutical therefrom, are disclosed. The labeled pharmaceutical is utilized in organ imaging.

  12. Habitat for Humanity of Metro Denver Zero Energy Demonstration Home

    SciTech Connect (OSTI)

    Not Available

    2008-04-01

    This brochure describes the 2005 demonstration home designed by NREL and the Habitat for Humanity of Metro Denver. The completed home produced 24% more energy than it consumed over 12 months.

  13. Metabolome of human gut microbiome is predictive of host dysbiosis

    Office of Scientific and Technical Information (OSTI)

    ... Nature. 2014;509(7500):357-60. 48. Lax S, Smith DP, Hampton-Marcell J, Owens SM, Handley KM, Scott NM, et al. Longitudinal analysis of microbial interaction between humans and the ...

  14. Human choice and climate change. Volume 1: The societal framework

    SciTech Connect (OSTI)

    Rayner, S.; Malone, E.L.

    1997-12-31

    Foreward: Preface; Introduction; Science and decisionmaking; Population and climate change; Human needs and wants; Cultural discourses; Institutional frameworks for political action; and Sponsoring organizations, International Advisory Board, and project participants.

  15. The sequence and analysis of duplication rich human chromosome 16

    SciTech Connect (OSTI)

    Martin, Joel; Han, Cliff; Gordon, Laurie A.; Terry, Astrid; Prabhakar, Shyam; She, Xinwei; Xie, Gary; Hellsten, Uffe; Man Chan, Yee; Altherr, Michael; Couronne, Olivier; Aerts, Andrea; Bajorek, Eva; Black, Stacey; Blumer, Heather; Branscomb, Elbert; Brown, Nancy C.; Bruno, William J.; Buckingham, Judith M.; Callen, David F.; Campbell, Connie S.; Campbell, Mary L.; Campbell, Evelyn W.; Caoile, Chenier; Challacombe, Jean F.; Chasteen, Leslie A.; Chertkov, Olga; Chi, Han C.; Christensen, Mari; Clark, Lynn M.; Cohn, Judith D.; Denys, Mirian; Detter, John C.; Dickson, Mark; Dimitrijevic-Bussod, Mira; Escobar, Julio; Fawcett, Joseph J.; Flowers, Dave; Fotopulos, Dea; Glavina, Tijana; Gomez, Maria; Gonzales, Eidelyn; Goodstein, David; Goodwin, Lynne A.; Grady, Deborah L.; Grigoriev, Igor; Groza, Matthew; Hammon, Nancy; Hawkins, Trevor; Haydu, Lauren; Hildebrand, Carl E.; Huang, Wayne; Israni, Sanjay; Jett, Jamie; Jewett, Phillip E.; Kadner, Kristen; Kimball, Heather; Kobayashi, Arthur; Krawczyk, Marie-Claude; Leyba, Tina; Longmire, Jonathan L.; Lopez, Frederick; Lou, Yunian; Lowry, Steve; Ludeman, Thom; Mark, Graham A.; Mcmurray, Kimberly L.; Meincke, Linda J.; Morgan, Jenna; Moyzis, Robert K.; Mundt, Mark O.; Munk, A. Christine; Nandkeshwar, Richard D.; Pitluck, Sam; Pollard, Martin; Predki, Paul; Parson-Quintana, Beverly; Ramirez, Lucia; Rash, Sam; Retterer, James; Ricke, Darryl O.; Robinson, Donna L.; Rodriguez, Alex; Salamov, Asaf; Saunders, Elizabeth H.; Scott, Duncan; Shough, Timothy; Stallings, Raymond L.; Stalvey, Malinda; Sutherland, Robert D.; Tapia, Roxanne; Tesmer, Judith G.; Thayer, Nina; Thompson, Linda S.; Tice, Hope; Torney, David C.; Tran-Gyamfi, Mary; Tsai, Ming; Ulanovsky, Levy E.; Ustaszewska, Anna; Vo, Nu; White, P. Scott; Williams, Albert L.; Wills, Patricia L.; Wu, Jung-Rung; Wu, Kevin; Yang, Joan; DeJong, Pieter; Bruce, David; Doggett, Norman; Deaven, Larry; Schmutz, Jeremy; Grimwood, Jane; Richardson, Paul; et al.

    2004-08-01

    We report here the 78,884,754 base pairs of finished human chromosome 16 sequence, representing over 99.9 percent of its euchromatin. Manual annotation revealed 880 protein coding genes confirmed by 1,637 aligned transcripts, 19 tRNA genes, 341 pseudogenes and 3 RNA pseudogenes. These genes include metallothionein, cadherin and iroquois gene families, as well as the disease genes for polycystic kidney disease and acute myelomonocytic leukemia. Several large-scale structural polymorphisms spanning hundreds of kilobasepairs were identified and result in gene content differences across humans. One of the unique features of chromosome 16 is its high level of segmental duplication, ranked among the highest of the human autosomes. While the segmental duplications are enriched in the relatively gene poor pericentromere of the p-arm, some are involved in recent gene duplication and conversion events which are likely to have had an impact on the evolution of primates and human disease susceptibility.

  16. A human reliability analysis of a nuclear explosives dismantlement

    SciTech Connect (OSTI)

    Bott, T.F.

    1995-07-01

    This paper describes the methodology used in a human reliability analysis (HRA) conducted during a quantitative hazard assessment of a nuclear weapon disassembly process performed at the Pantex plant. The probability of human errors during the disassembly process is an extremely important aspect of estimating accident-sequence frequency for nuclear weapons processing. The methods include the systematic identification of potential human-initiated or enabled accident sequences using an accident-sequence fault tree, the extensive use of walkthroughs and videotaping of the disassembly process, and hands-on testing of postulated human errors. THERP modeling of rule-based behavior and operational data analysis of errors in skill-based behavior are described. A simple method for evaluating the approximate likelihood of nonmalevolent violations of procedures was developed and used to examine the process. The HRA occurred concurrently with process design, so considerable interaction between the analysts and designers occurred and resulted in design changes that are discussed in the paper.

  17. Apparatus and methods for a human de-amplifier system

    DOE Patents [OSTI]

    Kress, Reid L.; Jansen, John F.

    2000-01-01

    A human de-amplifier system for interfacing a human operator and a physical object through a physical plant, wherein the physical object has dimensions in the range of 1 micrometer to 1 mm. The human de-amplifier system uses an inner-feedback loop to increases the equivalent damping of the operating system to stabilize the system when it contacts with the environment and reduces the impact of the environment variation by utilizing a high feedback gain, determined by a root locus sketch. Because the stability of the human de-amplifier system of the present invention is greatly enhanced over that of the prior art, the de-amplifier system is able to manipulate the physical object has dimensions in the range of 1 micrometer to 1 mm with high stability and accuracy. The system also has a monitoring device to monitor the motion of the physical object under manipulation.

  18. Quantification of the effects of dependence on human error probabiliti...

    Office of Scientific and Technical Information (OSTI)

    In estimating the probabilities of human error in the performance of a series of tasks in a nuclear power plant, the situation-specific characteristics of the series must be ...

  19. Immunogenic compositions comprising human immunodeficiency virus (HIV) mosaic Nef proteins

    DOE Patents [OSTI]

    Korber, Bette T.; Perkins, Simon; Bhattacharya, Tanmoy; Fischer, William M.; Theiler, James; Letvin, Norman; Haynes, Barton F.; Hahn, Beatrice H.; Yusim, Karina; Kuiken, Carla

    2012-02-21

    The present invention relates to mosaic clade M HIV-1 Nef polypeptides and to compositions comprising same. The polypeptides of the invention are suitable for use in inducing an immune response to HIV-1 in a human.

  20. ORS 97 - Rights and Duties Relating to Cemeteries, Human Bodies...

    Open Energy Info (EERE)

    97 - Rights and Duties Relating to Cemeteries, Human Bodies and Anatomical Gifts Jump to: navigation, search OpenEI Reference LibraryAdd to library Legal Document- StatuteStatute:...

  1. NMHPD Application for Permit to Excavate Human Burials | Open...

    Open Energy Info (EERE)

    NMHPD Application for Permit to Excavate Human Burials Jump to: navigation, search OpenEI Reference LibraryAdd to library Legal Document- OtherOther: NMHPD Application for Permit...

  2. Confederated Tribes of Warm Springs - Human Capacity Building

    Broader source: Energy.gov (indexed) [DOE]

    Grant DE-PS36-06G096038 Human Capacity Building for Renewable Energy Development. Warm Spring Power and Water Enterprise Mark K. Johnson Jr. Prepared by: Warm Springs Power & Water ...

  3. Chief Human Capital Officer Memo on Improving DOE Recruitment...

    Broader source: Energy.gov (indexed) [DOE]

    Improving DOE Recruitment and Hiring Processes (540.02 KB) Responsible Contacts Kenneth Venuto Director, Office of Human Capital Management E-mail kenneth.venuto@hq.doe.gov More ...

  4. Human Capital: The Role of Ombudsmen in Dispute Resolution |...

    Broader source: Energy.gov (indexed) [DOE]

    Human Capital: The Role of Ombudsmen in Dispute Resolution (339.67 KB) More Documents & Publications The Role of Ombudsmen in Dispute Resolution TT Coordinator Ltr dated May 13 ...

  5. Predicting Human Blood Viscosity in Silico | Argonne Leadership...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Predicting Human Blood Viscosity in Silico Authors: Fedosov., D. A., Pan, W., Caswell, B., Gompper, G., Karniadakis, G.E. The viscosity of blood has long been used as an indicator ...

  6. The Sequence and Analysis of Duplication Rich Human Chromosome 16

    DOE R&D Accomplishments [OSTI]

    Martin, Joel; Han, Cliff; Gordon, Laurie A.; Terry, Astrid; Prabhakar, Shyam; She, Xinwei; Xie, Gary; Hellsten, Uffe; Man Chan, Yee; Altherr, Michael; Couronne, Olivier; Aerts, Andrea; Bajorek, Eva; Black, Stacey; Blumer, Heather; Branscomb, Elbert; Brown, Nancy C.; Bruno, William J.; Buckingham, Judith M.; Callen, David F.; Campbell, Connie S.; Campbell, Mary L.; Campbell, Evelyn W.; Caoile, Chenier; Challacombe, Jean F.; Chasteen, Leslie A.; Chertkov, Olga; Chi, Han C.; Christensen, Mari; Clark, Lynn M.; Cohn, Judith D.; Denys, Mirian; Detter, John C.; Dickson, Mark; Dimitrijevic-Bussod, Mira; Escobar, Julio; Fawcett, Joseph J.; Flowers, Dave; Fotopulos, Dea; Glavina, Tijana; Gomez, Maria; Gonzales, Eidelyn; Goodstein, David; Goodwin, Lynne A.; Grady, Deborah L.; Grigoriev, Igor; Groza, Matthew; Hammon, Nancy; Hawkins, Trevor; Haydu, Lauren; Hildebrand, Carl E.; Huang, Wayne; Israni, Sanjay; Jett, Jamie; Jewett, Phillip E.; Kadner, Kristen; Kimball, Heather; Kobayashi, Arthur; Krawczyk, Marie-Claude; Leyba, Tina; Longmire, Jonathan L.; Lopez, Frederick; Lou, Yunian; Lowry, Steve; Ludeman, Thom; Mark, Graham A.; Mcmurray, Kimberly L.; Meincke, Linda J.; Morgan, Jenna; Moyzis, Robert K.; Mundt, Mark O.; Munk, A. Christine; Nandkeshwar, Richard D.; Pitluck, Sam; Pollard, Martin; Predki, Paul; Parson-Quintana, Beverly; Ramirez, Lucia; Rash, Sam; Retterer, James; Ricke, Darryl O.; Robinson, Donna L.; Rodriguez, Alex; Salamov, Asaf; Saunders, Elizabeth H.; Scott, Duncan; Shough, Timothy; Stallings, Raymond L.; Stalvey, Malinda; Sutherland, Robert D.; Tapia, Roxanne; Tesmer, Judith G.; Thayer, Nina; Thompson, Linda S.; Tice, Hope; Torney, David C.; Tran-Gyamfi, Mary; Tsai, Ming; Ulanovsky, Levy E.; Ustaszewska, Anna; Vo, Nu; White, P. Scott; Williams, Albert L.; Wills, Patricia L.; Wu, Jung-Rung; Wu, Kevin; Yang, Joan; DeJong, Pieter; Bruce, David; Doggett, Norman; Deaven, Larry; Schmutz, Jeremy; Grimwood, Jane; Richardson, Paul; et al.

    2004-01-01

    We report here the 78,884,754 base pairs of finished human chromosome 16 sequence, representing over 99.9 percent of its euchromatin. Manual annotation revealed 880 protein coding genes confirmed by 1,637 aligned transcripts, 19 tRNA genes, 341 pseudogenes and 3 RNA pseudogenes. These genes include metallothionein, cadherin and iroquois gene families, as well as the disease genes for polycystic kidney disease and acute myelomonocytic leukemia. Several large-scale structural polymorphisms spanning hundreds of kilobasepairs were identified and result in gene content differences across humans. One of the unique features of chromosome 16 is its high level of segmental duplication, ranked among the highest of the human autosomes. While the segmental duplications are enriched in the relatively gene poor pericentromere of the p-arm, some are involved in recent gene duplication and conversion events which are likely to have had an impact on the evolution of primates and human disease susceptibility.

  7. Defining Human Failure Events for Petroleum Risk Analysis

    SciTech Connect (OSTI)

    Ronald L. Boring; Knut Øien

    2014-06-01

    In this paper, an identification and description of barriers and human failure events (HFEs) for human reliability analysis (HRA) is performed. The barriers, called target systems, are identified from risk significant accident scenarios represented as defined situations of hazard and accident (DSHAs). This report serves as the foundation for further work to develop petroleum HFEs compatible with the SPAR-H method and intended for reuse in future HRAs.

  8. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or tomography, is a popular method of investigating micrometer deformation and fracture behavior in

  9. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or tomography, is a popular method of investigating micrometer deformation and fracture behavior in

  10. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or tomography, is a popular method of investigating micrometer deformation and fracture behavior in

  11. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or tomography, is a popular method of investigating micrometer deformation and fracture behavior in

  12. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or tomography, is a popular method of investigating micrometer deformation and fracture behavior in

  13. Irradiation Effects on Human Cortical Bone Fracture Behavior

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Irradiation Effects on Human Cortical Bone Fracture Behavior Print Human bone is strong but still fallible. To better predict fracturing in bone, researchers need a mechanistic framework to understand the changes taking place on different size scales within bone, as well as the role of sustained irradiation damage. Combining in situ mechanical testing with synchrotron x-ray diffraction imaging and/or tomography, is a popular method of investigating micrometer deformation and fracture behavior in

  14. Solar Energy Education. Humanities: activities and teacher's guide. Field

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    test edition (Technical Report) | SciTech Connect Humanities: activities and teacher's guide. Field test edition Citation Details In-Document Search Title: Solar Energy Education. Humanities: activities and teacher's guide. Field test edition × You are accessing a document from the Department of Energy's (DOE) SciTech Connect. This site is a product of DOE's Office of Scientific and Technical Information (OSTI) and is provided as a public service. Visit OSTI to utilize additional

  15. UPDATING THE NRC GUIDANCE FOR HUMAN FACTORS ENGINEERING REVIEWS.

    SciTech Connect (OSTI)

    O HARA,J.M.; BROWN,W.S.; HIGGINS,J.C.; PERSENSKY,J.J.; LEWIS,P.M.; BONGARRA,J.

    2002-09-15

    The U.S. Nuclear Regulatory Commission (NRC) reviews the human factors engineering (HFE) aspects of nuclear plants. NUREG-0800 (Standard Review Plan), Chapter 18, ''Human Factors Engineering,'' is the principal NRC staff guidance document. Two main documents provide the review criteria to support the evaluations. The HFE Program Review Model (NUREG-0711) addresses the design process from planning to verification and validation to design implementation. The Human-System Interface Design Review Guidelines (NUREG-0700) provides the guidelines for the review of the HFE aspects of human-system interface technology, such as alarms, information systems, controls, and control room design. Since these documents were published in 1994 and 1996 respectively, they have been used by NRC staff, contractors, nuclear industry organizations, as well as by numerous organizations outside the nuclear industry. Using feedback from users and NRC research conducted in recent years, both documents have been revised and updated. This was done to ensure that they remain state-of-the-art evaluation tools for changing nuclear industry issues and emerging technologies. This paper describes the methodology used to revise and update the documents and summarizes the changes made to each and their current contents. Index Terms for this report are: Control system human factors, Ergonomics, Human factors, Nuclear power generation safety.

  16. Human factors engineering report for the cold vacuum drying facility

    SciTech Connect (OSTI)

    IMKER, F.W.

    1999-06-30

    The purpose of this report is to present the results and findings of the final Human Factors Engineering (HFE) technical analysis and evaluation of the Cold Vacuum Drying Facility (CVDF). Ergonomics issues are also addressed in this report, as appropriate. This report follows up and completes the preliminary work accomplished and reported by the Preliminary HFE Analysis report (SNF-2825, Spent Nuclear Fuel Project Cold Vacuum Drying Facility Human Factors Engineering Analysis: Results and Findings). This analysis avoids redundancy of effort except for ensuring that previously recommended HFE design changes have not affected other parts of the system. Changes in one part of the system may affect other parts of the system where those changes were not applied. The final HFE analysis and evaluation of the CVDF human-machine interactions (HMI) was expanded to include: the physical work environment, human-computer interface (HCI) including workstation and software, operator tasks, tools, maintainability, communications, staffing, training, and the overall ability of humans to accomplish their responsibilities, as appropriate. Key focal areas for this report are the process bay operations, process water conditioning (PWC) skid, tank room, and Central Control Room operations. These key areas contain the system safety-class components and are the foundation for the human factors design basis of the CVDF.

  17. "Human-on-a-Chip" Technology Could Replace Animal Testing | Department...

    Broader source: Energy.gov (indexed) [DOE]

    Maren Hunsberger takes us "Inside the Lab" to learn about the "human-on-a-chip" project. | ... viruses, or drugs on human beings without resorting to animal or even human test subjects? ...

  18. MEMO RANUM FOR HUMAN RESOURCES DIRECTORS FROM: S~J\O~TOR OFFICE b:\HUMAN CAPITAL MANAGEMENT

    Office of Energy Efficiency and Renewable Energy (EERE) Indexed Site

    0 MEMO RANUM FOR HUMAN RESOURCES DIRECTORS FROM: S~J\O~TOR OFFICE b:\HUMAN CAPITAL MANAGEMENT SUBJECT: GUIDANCE MEMORANDUM #13 REEMPLOYMENT PRIORITY LIST SELECTIONS This memorandum provides guidance for using the Department of Energy's (DOE) Reemployment Priority List (RPL). The DOE RPL is designed to provide priority consideration to employees who have lost their jobs through reduction in force. or who have fully recovered from a compensable injury after more than 1 year. Employees may only

  19. Crossreactivity of a human autoimmune TCR is dominated by a single...

    Office of Scientific and Technical Information (OSTI)

    Crossreactivity of a human autoimmune TCR is dominated by a single TCR loop Citation Details In-Document Search Title: Crossreactivity of a human autoimmune TCR is dominated ...

  20. MEMO RANUM FOR HUMAN RESOURCES DIRECTORS FROM: S~J\\O~TOR OFFICE...

    Broader source: Energy.gov (indexed) [DOE]

    0 MEMO RANUM FOR HUMAN RESOURCES DIRECTORS FROM: SJOTOR OFFICE b:HUMAN CAPITAL MANAGEMENT SUBJECT: GUIDANCE MEMORANDUM 13 REEMPLOYMENT PRIORITY LIST SELECTIONS This memorandum ...

  1. Microsoft Word - DOE Human Capital Strategic Plan 2011-2015.docx

    Broader source: Energy.gov (indexed) [DOE]

    DOE HUMAN CAPITAL STRATEGIC PLAN FY 2011 - FY 2015 DOE HUMAN CAPITAL STRATEGIC PLAN FY 2011 - FY 2015 TABLE OF CONTENTS EXECUTIVE SUMMARY ......

  2. Human Subjects Research Database (HSRD) | U.S. DOE Office of...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Subjects Research Database (HSRD) Human Subjects Protection Program (HSPP) HSPP Home About Institutional Review Boards (IRBs) Education and Resources CITI Courses DOE ...

  3. For Prospective Human Subjects | U.S. DOE Office of Science ...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Prospective Human Subjects Human Subjects Protection Program (HSPP) HSPP Home About For Researchers For IRB Managers Administrators For IRB Members For Institutional Officials ...

  4. Human Resources Advisory Office | U.S. DOE Office of Science...

    Broader source: All U.S. Department of Energy (DOE) Office Webpages (Extended Search)

    Human Resources Advisory Office Management OM Home About Program Direction and Analysis Human Resources Advisory Office Administration Contact Information Management U.S. ...

  5. Simulation and Non-Simulation Based Human Reliability Analysis Approaches

    SciTech Connect (OSTI)

    Boring, Ronald Laurids; Shirley, Rachel Elizabeth; Joe, Jeffrey Clark; Mandelli, Diego

    2014-12-01

    Part of the U.S. Department of Energy’s Light Water Reactor Sustainability (LWRS) Program, the Risk-Informed Safety Margin Characterization (RISMC) Pathway develops approaches to estimating and managing safety margins. RISMC simulations pair deterministic plant physics models with probabilistic risk models. As human interactions are an essential element of plant risk, it is necessary to integrate human actions into the RISMC risk model. In this report, we review simulation-based and non-simulation-based human reliability assessment (HRA) methods. Chapter 2 surveys non-simulation-based HRA methods. Conventional HRA methods target static Probabilistic Risk Assessments for Level 1 events. These methods would require significant modification for use in dynamic simulation of Level 2 and Level 3 events. Chapter 3 is a review of human performance models. A variety of methods and models simulate dynamic human performance; however, most of these human performance models were developed outside the risk domain and have not been used for HRA. The exception is the ADS-IDAC model, which can be thought of as a virtual operator program. This model is resource-intensive but provides a detailed model of every operator action in a given scenario, along with models of numerous factors that can influence operator performance. Finally, Chapter 4 reviews the treatment of timing of operator actions in HRA methods. This chapter is an example of one of the critical gaps between existing HRA methods and the needs of dynamic HRA. This report summarizes the foundational information needed to develop a feasible approach to modeling human interactions in the RISMC simulations.

  6. Assessing human rights impacts in corporate development projects

    SciTech Connect (OSTI)

    Salcito, Kendyl; University of Basel, P.O. Box, CH-4003 Basel; NomoGaia, 1900 Wazee Street, Suite 303, Denver, CO 80202; NewFields, LLC, Denver, CO 80202 ; Utzinger, Jrg; University of Basel, P.O. Box, CH-4003 Basel ; Weiss, Mitchell G.; Mnch, Anna K.; Singer, Burton H.; Krieger, Gary R.; Wielga, Mark; NewFields, LLC, Denver, CO 80202

    2013-09-15

    Human rights impact assessment (HRIA) is a process for systematically identifying, predicting and responding to the potential impact on human rights of a business operation, capital project, government policy or trade agreement. Traditionally, it has been conducted as a desktop exercise to predict the effects of trade agreements and government policies on individuals and communities. In line with a growing call for multinational corporations to ensure they do not violate human rights in their activities, HRIA is increasingly incorporated into the standard suite of corporate development project impact assessments. In this context, the policy world's non-structured, desk-based approaches to HRIA are insufficient. Although a number of corporations have commissioned and conducted HRIA, no broadly accepted and validated assessment tool is currently available. The lack of standardisation has complicated efforts to evaluate the effectiveness of HRIA as a risk mitigation tool, and has caused confusion in the corporate world regarding company duties. Hence, clarification is needed. The objectives of this paper are (i) to describe an HRIA methodology, (ii) to provide a rationale for its components and design, and (iii) to illustrate implementation of HRIA using the methodology in two selected corporate development projectsa uranium mine in Malawi and a tree farm in Tanzania. We found that as a prognostic tool, HRIA could examine potential positive and negative human rights impacts and provide effective recommendations for mitigation. However, longer-term monitoring revealed that recommendations were unevenly implemented, dependent on market conditions and personnel movements. This instability in the approach to human rights suggests a need for on-going monitoring and surveillance. -- Highlights: We developed a novel methodology for corporate human rights impact assessment. We piloted the methodology on two corporate projectsa mine and a plantation. Human rights

  7. Shotgun metaproteomics of the human distal gut microbiota

    SciTech Connect (OSTI)

    VerBerkmoes, N.C.; Russell, A.L.; Shah, M.; Godzik, A.; Rosenquist, M.; Halfvarsson, J.; Lefsrud, M.G.; Apajalahti, J.; Tysk, C.; Hettich, R.L.; Jansson, Janet K.

    2008-10-15

    The human gut contains a dense, complex and diverse microbial community, comprising the gut microbiome. Metagenomics has recently revealed the composition of genes in the gut microbiome, but provides no direct information about which genes are expressed or functioning. Therefore, our goal was to develop a novel approach to directly identify microbial proteins in fecal samples to gain information about the genes expressed and about key microbial functions in the human gut. We used a non-targeted, shotgun mass spectrometry-based whole community proteomics, or metaproteomics, approach for the first deep proteome measurements of thousands of proteins in human fecal samples, thus demonstrating this approach on the most complex sample type to date. The resulting metaproteomes had a skewed distribution relative to the metagenome, with more proteins for translation, energy production and carbohydrate metabolism when compared to what was earlier predicted from metagenomics. Human proteins, including antimicrobial peptides, were also identified, providing a non-targeted glimpse of the host response to the microbiota. Several unknown proteins represented previously undescribed microbial pathways or host immune responses, revealing a novel complex interplay between the human host and its associated microbes.

  8. Predicting Tissue-Specific Enhancers in the Human Genome

    SciTech Connect (OSTI)

    Pennacchio, Len A.; Loots, Gabriela G.; Nobrega, Marcelo A.; Ovcharenko, Ivan

    2006-07-01

    Determining how transcriptional regulatory signals areencoded in vertebrate genomes is essential for understanding the originsof multi-cellular complexity; yet the genetic code of vertebrate generegulation remains poorly understood. In an attempt to elucidate thiscode, we synergistically combined genome-wide gene expression profiling,vertebrate genome comparisons, and transcription factor binding siteanalysis to define sequence signatures characteristic of candidatetissue-specific enhancers in the human genome. We applied this strategyto microarray-based gene expression profiles from 79 human tissues andidentified 7,187 candidate enhancers that defined their flanking geneexpression, the majority of which were located outside of knownpromoters. We cross-validated this method for its ability to de novopredict tissue-specific gene expression and confirmed its reliability in57 of the 79 available human tissues, with an average precision inenhancer recognition ranging from 32 percent to 63 percent, and asensitivity of 47 percent. We used the sequence signatures identified bythis approach to assign tissue-specific predictions to ~;328,000human-mouse conserved noncoding elements in the human genome. Byoverlapping these genome-wide predictions with a large in vivo dataset ofenhancers validated in transgenic mice, we confirmed our results with a28 percent sensitivity and 50 percent precision. These results indicatethe power of combining complementary genomic datasets as an initialcomputational foray into the global view of tissue-specific generegulation in vertebrates.

  9. Interim report of the Advisory Committee on human radiation experiments

    SciTech Connect (OSTI)

    Not Available

    1994-10-21

    The Advisory Committee on Human Radiation Experiments was created by President Clinton to advise the Human Radiation Interagency Working Group on the ethical and scientific criteria applicable to human radiation experiments carried out or sponsored by the U.S. Government. The Committee seeks to answer several fundamental question: What ethics criteria should be used to evaluate human radiation experiments? What was the Federal Government`s role in human radiation experiments? What are the criteria for determining appropriate Federal responses where wrongs or harms have occurred? What lessons learned from studying past and present research standards and practices should be applied to the future? The Committee has been gathering vast amounts of information and working to render it orderly and accessible. In the next six months, the Committee will continue with the tasks of data gathering and organizing. The focus of the work, however, will be developing criteria for judging historical and contemporary experiments, policies, and procedures, as well as criteria for remedies that may be appropriate where harms or wrongs have ocurred. Based on findings, the Committee will make specific recommendations regarding policies for the future.

  10. Allometric scaling for predicting human clearance of bisphenol A

    SciTech Connect (OSTI)

    Collet, Séverine H. Picard-Hagen, Nicole Lacroix, Marlène Z. Puel, Sylvie Viguié, Catherine Bousquet-Melou, Alain Toutain, Pierre-Louis Gayrard, Véronique

    2015-05-01

    The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02 kg (mice) to 495 kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79 L/min (equivalent to 25.6 mL/kg.min) with a 95% prediction interval of 0.36 to 8.83 L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man. - Highlights: • Allometric scaling was used to predict BPA pharmacokinetic parameters in humans. • In all species, BPA plasma clearance approached hepatic blood flow. • Human BPA clearance was estimated to be 1.79 L/min.

  11. Athletic equipment microbiota are shaped by interactions with human skin

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Wood, Mariah; Gibbons, Sean M.; Lax, Simon; Eshoo-Anton, Tifani W.; Owens, Sarah M.; Kennedy, Suzanne; Gilbert, Jack A.; Hampton-Marcell, Jarrad T.

    2015-06-19

    Background: Americans spend the vast majority of their lives in built environments. Even traditionally outdoor pursuits, such as exercising, are often now performed indoors. Bacteria that colonize these indoor ecosystems are primarily derived from the human microbiome. The modes of human interaction with indoor surfaces and the physical conditions associated with each surface type determine the steady-state ecology of the microbial community. Results: Bacterial assemblages associated with different surfaces in three athletic facilities, including floors, mats, benches, free weights, and elliptical handles, were sampled every other hour (8 am to 6 pm) for 2 days. Surface and equipment type hadmore » a stronger influence on bacterial community composition than the facility in which they were housed. Surfaces that were primarily in contact with human skin exhibited highly dynamic bacterial community composition and non-random co-occurrence patterns, suggesting that different host microbiomes—shaped by selective forces—were being deposited on these surfaces through time. Bacterial assemblages found on the floors and mats changed less over time, and species co-occurrence patterns appeared random, suggesting more neutral community assembly. Conclusions: These longitudinal patterns highlight the dramatic turnover of microbial communities on surfaces in regular contact with human skin. By uncovering these longitudinal patterns, this study promotes a better understanding of microbe-human interactions within the built environment.« less

  12. IDHEAS – A NEW APPROACH FOR HUMAN RELIABILITY ANALYSIS

    SciTech Connect (OSTI)

    G. W. Parry; J.A Forester; V.N. Dang; S. M. L. Hendrickson; M. Presley; E. Lois; J. Xing

    2013-09-01

    This paper describes a method, IDHEAS (Integrated Decision-Tree Human Event Analysis System) that has been developed jointly by the US NRC and EPRI as an improved approach to Human Reliability Analysis (HRA) that is based on an understanding of the cognitive mechanisms and performance influencing factors (PIFs) that affect operator responses. The paper describes the various elements of the method, namely the performance of a detailed cognitive task analysis that is documented in a crew response tree (CRT), and the development of the associated time-line to identify the critical tasks, i.e. those whose failure results in a human failure event (HFE), and an approach to quantification that is based on explanations of why the HFE might occur.

  13. Recombinant human bone morphogenetic protein induces bone formation

    SciTech Connect (OSTI)

    Wang, E.A.; Rosen, V.; D'Alessandro, J.S.; Bauduy, M.; Cordes, P.; Harada, T.; Israel, D.I.; Hewick, R.M.; Kerns, K.M.; LaPan, P.; Luxenberg, D.P.; McQuaid, D.; Moutsatsos, I.K.; Nove, J.; Wozney, J.M. )

    1990-03-01

    The authors have purified and characterized active recombinant human bone morphogenetic protein (BMP) 2A. Implantation of the recombinant protein in rats showed that a single BMP can induce bone formation in vivo. A dose-response and time-course study using the rat ectopic bone formation assay revealed that implantation of 0.5-115 {mu}g of partially purified recombinant human BMP-2A resulted in cartilage by day 7 and bone formation by day 14. The time at which bone formation occurred was dependent on the amount of BMP-2A implanted; at high doses bone formation could be observed at 5 days. The cartilage- and bone-inductive activity of the recombinant BMP-2A is histologically indistinguishable from that of bone extracts. Thus, recombinant BMP-2A has therapeutic potential to promote de novo bone formation in humans.

  14. The Human Genome Initiative of the Department of Energy

    DOE R&D Accomplishments [OSTI]

    1988-01-01

    The structural characterization of genes and elucidation of their encoded functions have become a cornerstone of modern health research, biology and biotechnology. A genome program is an organized effort to locate and identify the functions of all the genes of an organism. Beginning with the DOE-sponsored, 1986 human genome workshop at Santa Fe, the value of broadly organized efforts supporting total genome characterization became a subject of intensive study. There is now national recognition that benefits will rapidly accrue from an effective scientific infrastructure for total genome research. In the US genome research is now receiving dedicated funds. Several other nations are implementing genome programs. Supportive infrastructure is being improved through both national and international cooperation. The Human Genome Initiative of the Department of Energy (DOE) is a focused program of Resource and Technology Development, with objectives of speeding and bringing economies to the national human genome effort. This report relates the origins and progress of the Initiative.

  15. (Meeting on human dimensions of global environmental change)

    SciTech Connect (OSTI)

    Rayner, S.

    1990-12-18

    Traveler attended the meeting of the Standing Committee on the Human Dimensions of Global Environmental Change of the International Social Science Council (ISSC) and the Scientific Symposium organized by the Standing Committee. The purpose of the meeting and symposium was to discuss the Draft Framework and the Workplan of the Standing Committee prior to its presentation to the 1990 Congress of the ISSC on November 28--30, 1990. The meetings indicate that ORNL Global Environmental Studies Center is on the international leading edge of human dimensions research, except in the area of human dimensions data systems. This weakness could be rectified by close collaboration with the efforts of the Consortium for International Earth Science Information Network (CIESIN) in Michigan.

  16. Toxicological and epidemiological aspects of global warming on human health

    SciTech Connect (OSTI)

    Ando, M.; Yamamoto, S.; Wakamatsu, K.; Kawahara, I.; Asanuma, S.

    1996-12-31

    Since human activities are responsible for anthropogenic greenhouse gases emissions, climate models project an increase in the global surface temperature of 0.9 C to 4.0 C by 2100. For human health, it is projected that global warming may have a critical effect on the increased periods of severe heat stress in summer throughout the world. Global warming may have a critical issue on the increased periods of severe heat stress that have a potential impact on peroxidative damage in humans and animals. Lipid peroxidative damage is markedly related to GSH peroxidase activities, therefore the study was carried out to analyze the relationship between biochemical adaptability and the lipid peroxidative damage especially intracellular structure, such as mitochondria and endoplasmic reticulum depending on the exposure time of heat stress.

  17. Understanding mutagenesis through delineation of mutational signatures in human cancer

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Petljak, Mia; Alexandrov, Ludmil B.

    2016-05-04

    Each individual cell within a human body acquires a certain number of somatic mutations during a course of its lifetime. These mutations originate from a wide spectra of both endogenous and exogenous mutational processes that leave distinct patterns of mutations, termed mutational signatures, embedded within the genomes of all cells. In recent years, the vast amount of data produced by sequencing of cancer genomes was coupled with novel mathematical models and computational tools to generate the first comprehensive map of mutational signatures in human cancer. Up to date, >30 distinct mutational signatures have been identified, and etiologies have been proposedmore » for many of them. This paper provides a brief historical background on examination of mutational patterns in human cancer, summarizes the knowledge accumulated since introducing the concept of mutational signatures and discusses their future potential applications and perspectives within the field.« less

  18. Apolipoprotein E promotes lipid accumulation and differentiation in human adipocytes

    SciTech Connect (OSTI)

    Lasrich, Dorothee; Bartelt, Alexander; Grewal, Thomas; Heeren, Joerg

    2015-09-10

    Several studies in mice indicate a role for apolipoprotein E (APOE) in lipid accumulation and adipogenic differentiation in adipose tissue. However, little is yet known if APOE functions in a similar manner in human adipocytes. This prompted us to compare lipid loading and expression of adipocyte differentiation markers in APOE-deficient and control adipocytes using the differentiated human mesenchymal stem cell line hMSC-Tert as well as primary human and mouse adipocytes as model systems. Differentiated hMSC-Tert were stably transduced with or without siRNA targeting APOE while murine adipocytes were isolated from wild type and Apoe knockout mice. Human APOE knockdown hMSC-Tert adipocytes accumulated markedly less triglycerides compared to control cells. This correlated with strongly decreased gene expression levels of adipocyte markers such as adiponectin (ADIPOQ) and fatty acid binding protein 4 (FABP4) as well as the key transcription factor driving adipocyte differentiation, peroxisome proliferator activator receptor gamma (PPARG), in particular the PPARG2 isoform. Similarly, differentiation of murine Apoe-deficient adipocytes was characterized by reduced gene expression of Adipoq, Fabp4 and Pparg. Interestingly, incubation of APOE-deficient hMSC-Tert adipocytes with conditioned media from APOE3-overexpressing adipocytes or APOE-containing Very Low Density Lipoprotein (VLDL) partially restored triglyceride accumulation, but were unable to induce adipocyte differentiation, as judged by expression of adipocyte markers. Taken together, depletion of endogenous APOE in human adipocytes severely impairs lipid accumulation, which is associated with an inability to initiate differentiation. - Highlights: • Immortalized human mesenchymal stem cells were used to study adipocyte development. • Knockdown of endogenous APOE lead to impaired lipid accumulation and adipogenesis. • APOE supplementation partially restored lipid accumulation but not differentiation.

  19. Human Factors Considerations in New Nuclear Power Plants: Detailed Analysis.

    SciTech Connect (OSTI)

    OHara,J.; Higgins, J.; Brown, W.; Fink, R.

    2008-02-14

    This Nuclear Regulatory Commission (NRC) sponsored study has identified human-performance issues in new and advanced nuclear power plants. To identify the issues, current industry developments and trends were evaluated in the areas of reactor technology, instrumentation and control technology, human-system integration technology, and human factors engineering (HFE) methods and tools. The issues were organized into seven high-level HFE topic areas: Role of Personnel and Automation, Staffing and Training, Normal Operations Management, Disturbance and Emergency Management, Maintenance and Change Management, Plant Design and Construction, and HFE Methods and Tools. The issues where then prioritized into four categories using a 'Phenomena Identification and Ranking Table' methodology based on evaluations provided by 14 independent subject matter experts. The subject matter experts were knowledgeable in a variety of disciplines. Vendors, utilities, research organizations and regulators all participated. Twenty issues were categorized into the top priority category. This Brookhaven National Laboratory (BNL) technical report provides the detailed methodology, issue analysis, and results. A summary of the results of this study can be found in NUREG/CR-6947. The research performed for this project has identified a large number of human-performance issues for new control stations and new nuclear power plant designs. The information gathered in this project can serve as input to the development of a long-term strategy and plan for addressing human performance in these areas through regulatory research. Addressing human-performance issues will provide the technical basis from which regulatory review guidance can be developed to meet these challenges. The availability of this review guidance will help set clear expectations for how the NRC staff will evaluate new designs, reduce regulatory uncertainty, and provide a well-defined path to new nuclear power plant licensing.

  20. In silico prediction of xenobiotic metabolism in humans

    SciTech Connect (OSTI)

    Mu, Fangping

    2009-01-01

    Xenobiotic metabolism in humans is catalyzed by a few enzymes with broad substrate specificities, which provide the overall broad chemical specificity for nearly all xenobiotics that humans encounter. Xenobiotic metabolism are classified into functional group biotransformations. Based on bona fide reactions and negative examples for each reaction class, support vector machine (SVM) classifiers are built. The input to SVM is a set of atomic and molecular features to define the electrostatic, steric, energetic, geometrical and topological environment of the atoms in the reaction center under the molecule. Results show that the overall sensitivity and specificity of classifiers is around 87%.

  1. Accommodating complexity and human behaviors in decision analysis.

    SciTech Connect (OSTI)

    Backus, George A.; Siirola, John Daniel; Schoenwald, David Alan; Strip, David R.; Hirsch, Gary B.; Bastian, Mark S.; Braithwaite, Karl R.; Homer, Jack

    2007-11-01

    This is the final report for a LDRD effort to address human behavior in decision support systems. One sister LDRD effort reports the extension of this work to include actual human choices and additional simulation analyses. Another provides the background for this effort and the programmatic directions for future work. This specific effort considered the feasibility of five aspects of model development required for analysis viability. To avoid the use of classified information, healthcare decisions and the system embedding them became the illustrative example for assessment.

  2. Human choice and climate change. Four volume set

    SciTech Connect (OSTI)

    Rayner, S.; Malone, E.L.

    1997-12-31

    The four-volume set assesses social science research relevant to global climate change from a wide-ranging interdisciplinary perspective. Taking human choice within social institutions as the starting point, noted researchers examine climate change issues in the context of societal issues such as population and consumption; cultural, institutional, and economic arrangements for human well-being; and the social processes by which decisions are made from local to global levels. This four-volume assessment is intended to complement the work of the intergovernmental Panel on Climate Change.

  3. THE VALIDITY OF HUMAN AND COMPUTERIZED WRITING ASSESSMENT

    SciTech Connect (OSTI)

    Ronald L. Boring

    2005-09-01

    This paper summarizes an experiment designed to assess the validity of essay grading between holistic and analytic human graders and a computerized grader based on latent semantic analysis. The validity of the grade was gauged by the extent to which the students knowledge of the topic correlated with the graders expert knowledge. To assess knowledge, Pathfinder networks were generated by the student essay writers, the holistic and analytic graders, and the computerized grader. It was found that the computer generated grades more closely matched the definition of valid grading than did human generated grades.

  4. Depleted uranium human health risk assessment, Jefferson Proving Ground, Indiana

    SciTech Connect (OSTI)

    Ebinger, M.H.; Hansen, W.R.

    1994-04-29

    The risk to human health from fragments of depleted uranium (DU) at Jefferson Proving Ground (JPG) was estimated using two types of ecosystem pathway models. A steady-state, model of the JPG area was developed to examine the effects of DU in soils, water, and vegetation on deer that were hunted and consumed by humans. The RESRAD code was also used to estimate the effects of farming the impact area and consuming the products derived from the farm. The steady-state model showed that minimal doses to humans are expected from consumption of deer that inhabit the impact area. Median values for doses to humans range from about 1 mrem ({plus_minus}2.4) to 0.04 mrem ({plus_minus}0.13) and translate to less than 1 {times} 10{sup {minus}6} detriments (excess cancers) in the population. Monte Carlo simulation of the steady-state model was used to derive the probability distributions from which the median values were drawn. Sensitivity analyses of the steady-state model showed that the amount of DU in airborne dust and, therefore, the amount of DU on the vegetation surface, controlled the amount of DU ingested by deer and by humans. Human doses from the RESRAD estimates ranged from less than 1 mrem/y to about 6.5 mrem/y in a hunting scenario and subsistence fanning scenario, respectively. The human doses exceeded the 100 mrem/y dose limit when drinking water for the farming scenario was obtained from the on-site aquifer that was presumably contaminated with DU. The two farming scenarios were unrealistic land uses because the additional risk to humans due to unexploded ordnance in the impact area was not figured into the risk estimate. The doses estimated with RESRAD translated to less than 1 {times} 10{sup {minus}6} detriments to about 1 {times} 10{sup {minus}3} detriments. The higher risks were associated only with the farming scenario in which drinking water was obtained on-site.

  5. Lessons Learned Concerning the Human Element in Events and Training

    SciTech Connect (OSTI)

    Michael D. Sandvig

    2006-02-01

    As the number and complexity of responses to hazardous material incidents have increased, government regulators have implemented a national incident command system, bolstered by a host of protective measures and response equipment. Special advanced technical equipment has also been developed and made available to on-scene responders and command staff. Yet with all the investment in organizational and technical advance, the human element of emergency response remains critical and also needs our continued attention to ensure effective operation and success. This paper focuses on lessons learned from radiological events and training exercises that pertain to these human elements.

  6. Ethical issues in international collaborative research on the human genome: The HGP and the HGDP

    SciTech Connect (OSTI)

    Knoppers, B.M.; Hirtle, M.; Lormeau, S.

    1996-06-01

    This special feature describes the ethical issues in international collaborative research on the human genome, both regarding the Human Genome Project (HGP), which is concerned with genetic mapping, and the Human Genome Diversity Project (HGDP), which is an effort to document the genetic variation of the human species worldwide. 88 refs.

  7. Psychosocial and Cultural Modeling in Human Computation Systems: A Gamification Approach

    SciTech Connect (OSTI)

    Sanfilippo, Antonio P.; Riensche, Roderick M.; Haack, Jereme N.; Butner, R. Scott

    2013-11-20

    “Gamification”, the application of gameplay to real-world problems, enables the development of human computation systems that support decision-making through the integration of social and machine intelligence. One of gamification’s major benefits includes the creation of a problem solving environment where the influence of cognitive and cultural biases on human judgment can be curtailed through collaborative and competitive reasoning. By reducing biases on human judgment, gamification allows human computation systems to exploit human creativity relatively unhindered by human error. Operationally, gamification uses simulation to harvest human behavioral data that provide valuable insights for the solution of real-world problems.

  8. The human factors of quality and QA in R D environments

    SciTech Connect (OSTI)

    Hill, S.G.

    1990-01-01

    Achieving quality is a human activity. It is therefore important to consider the human in the design, development and evaluation of work processes and environments in an effort to enhance human performance and minimize error. It is also important to allow for individual differences when considering human factors issues. Human Factors is the field of study which can provide information on integrating the human into the system. Human factors and quality are related for the customer of R D work, R D personnel who perform the work, and the quality professional who overviews the process of quality in the work. 18 refs., 1 fig.

  9. Low Dose IR Creates an Oncogenic Microenvironment by Inducing Premature

    SciTech Connect (OSTI)

    Yuan, Zhi-Min

    2013-04-28

    Introduction Much of the work addressing ionizing radiation-induced cellular response has been carried out mainly with the traditional cell culture technique involving only one cell type, how cellular response to IR is influenced by the tissue microenvironment remains elusive. By use of a three-dimensional (3D) co-culture system to model critical interactions of different cell types with their neighbors and with their environment, we recently showed that low-dose IR-induced extracellular signaling via the tissue environment affects profoundly cellular responses. This proposal aims at determining the response of mammary epithelial cells in a tissue-like setting.

  10. Human performance modeling for system of systems analytics :soldier fatigue.

    SciTech Connect (OSTI)

    Lawton, Craig R.; Campbell, James E.; Miller, Dwight Peter

    2005-10-01

    The military has identified Human Performance Modeling (HPM) as a significant requirement and challenge of future systems modeling and analysis initiatives as can be seen in the Department of Defense's (DoD) Defense Modeling and Simulation Office's (DMSO) Master Plan (DoD 5000.59-P 1995). To this goal, the military is currently spending millions of dollars on programs devoted to HPM in various military contexts. Examples include the Human Performance Modeling Integration (HPMI) program within the Air Force Research Laboratory, which focuses on integrating HPMs with constructive models of systems (e.g. cockpit simulations) and the Navy's Human Performance Center (HPC) established in September 2003. Nearly all of these initiatives focus on the interface between humans and a single system. This is insufficient in the era of highly complex network centric SoS. This report presents research and development in the area of HPM in a system-of-systems (SoS). Specifically, this report addresses modeling soldier fatigue and the potential impacts soldier fatigue can have on SoS performance.

  11. Comparative mutagenesis of human cells in vivo and in vitro

    SciTech Connect (OSTI)

    Thilly, W.G.

    1992-05-01

    This report discusses measuring methods of point mutations; high density cell cultures for low dose studies; measurement and sequence determination of mutations in DNA; the mutational spectra of styrene oxide and ethlyene oxide in TK-6 cells; mutational spectrum of Cr in human lymphoblast cells; mutational spectra of radon in TK-6 cells; and the mutational spectra of smokeless tobacco. (CBS)

  12. Human genome program report. Part 1, overview and progress

    SciTech Connect (OSTI)

    1997-11-01

    This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

  13. A Research Roadmap for Computation-Based Human Reliability Analysis

    SciTech Connect (OSTI)

    Boring, Ronald; Mandelli, Diego; Joe, Jeffrey; Smith, Curtis; Groth, Katrina

    2015-08-01

    The United States (U.S.) Department of Energy (DOE) is sponsoring research through the Light Water Reactor Sustainability (LWRS) program to extend the life of the currently operating fleet of commercial nuclear power plants. The Risk Informed Safety Margin Characterization (RISMC) research pathway within LWRS looks at ways to maintain and improve the safety margins of these plants. The RISMC pathway includes significant developments in the area of thermalhydraulics code modeling and the development of tools to facilitate dynamic probabilistic risk assessment (PRA). PRA is primarily concerned with the risk of hardware systems at the plant; yet, hardware reliability is often secondary in overall risk significance to human errors that can trigger or compound undesirable events at the plant. This report highlights ongoing efforts to develop a computation-based approach to human reliability analysis (HRA). This computation-based approach differs from existing static and dynamic HRA approaches in that it: (i) interfaces with a dynamic computation engine that includes a full scope plant model, and (ii) interfaces with a PRA software toolset. The computation-based HRA approach presented in this report is called the Human Unimodels for Nuclear Technology to Enhance Reliability (HUNTER) and incorporates in a hybrid fashion elements of existing HRA methods to interface with new computational tools developed under the RISMC pathway. The goal of this research effort is to model human performance more accurately than existing approaches, thereby minimizing modeling uncertainty found in current plant risk models.

  14. Human factors evaluation of teletherapy: Literature review. Volume 5

    SciTech Connect (OSTI)

    Henriksen, K.; Kaye, R.D.; Jones, R.; Morisseau, D.S.; Serig, D.L.

    1995-07-01

    A series of human factors evaluations were undertaken to better understand the contributing factors to human error in the teletherapy environment. Teletherapy is a multidisciplinary methodology for treating cancerous tissue through selective exposure to an external beam of ionizing radiation. A team of human factors specialists, assisted by a panel of radiation oncologists, medical physicists, and radiation therapists, conducted site visits to radiation oncology departments at community hospitals, university centers, and free-standing clinics. A function and task analysis was performed initially to guide subsequent evaluations in the areas of workplace environment, system-user interfaces, procedures, training, and organizational practices. To further acquire an in-depth and up-to-date understanding of the practice of teletherapy in support of these evaluations, a systematic literature review was conducted. Factors that have a potential impact on the accuracy of treatment delivery were of primary concern. The present volume is the literature review. The volume starts with an overview of the multiphased nature of teletherapy, and then examines the requirement for precision, the increasing role of quality assurance, current conceptualizations of human error, and the role of system factors such as the workplace environment, user-system interfaces, procedures, training, and organizational practices.

  15. Human Factors Evaluation of Advanced Electric Power Grid Visualization Tools

    SciTech Connect (OSTI)

    Greitzer, Frank L.; Dauenhauer, Peter M.; Wierks, Tamara G.; Podmore, Robin

    2009-04-01

    This report describes initial human factors evaluation of four visualization tools (Graphical Contingency Analysis, Force Directed Graphs, Phasor State Estimator and Mode Meter/ Mode Shapes) developed by PNNL, and proposed test plans that may be implemented to evaluate their utility in scenario-based experiments.

  16. Advisory Committee on human radiation experiments final report

    SciTech Connect (OSTI)

    1995-10-01

    When the Advisory Committee began work in April 1994 we were charged with determining whether the radiation experiments design and administration adequately met the ethical and scientific standards, including standards of informed consent, that prevailed at the time of the experiments and that exist today and also to determine the ethical and scientific standards and criteria by which it shall evaluate human radiation experiments. Although this charge seems straightforward, it is in fact difficult to determine what the appropriate standards should be for evaluating the conduct and policies of thirty or fifty years ago. First, we needed to determine the extent to which the standards of that time are similar to the standards of today. To the extent that there were differences we needed to determine the relative roles of each in making moral evaluations. In Chapter 1 we report what we have been able to reconstruct about government rules and policies in the 1940s and 1950s regarding human experiments. We focus primarily on the Atomic Energy Commission and the Department of Defense. In Chapter 2 we turn from a consideration of government standards to an exploration of the norms and practices of physicians and medical scientists who conducted research with human subjects during this period. Using the results of our Ethics Oral History Project, and other sources, we also examine how scientists of the time viewed their moral responsibilities to human subjects as well as how this translated into the manner in which they conducted their research.

  17. Statistical Analysis of Variation in the Human Plasma Proteome

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Corzett, Todd H.; Fodor, Imola K.; Choi, Megan W.; Walsworth, Vicki L.; Turteltaub, Kenneth W.; McCutchen-Maloney, Sandra L.; Chromy, Brett A.

    2010-01-01

    Quantifying the variation in the human plasma proteome is an essential prerequisite for disease-specific biomarker detection. We report here on the longitudinal and individual variation in human plasma characterized by two-dimensional difference gel electrophoresis (2-D DIGE) using plasma samples from eleven healthy subjects collected three times over a two week period. Fixed-effects modeling was used to remove dye and gel variability. Mixed-effects modeling was then used to quantitate the sources of proteomic variation. The subject-to-subject variation represented the largest variance component, while the time-within-subject variation was comparable to the experimental variation found in a previous technical variability study where onemore » human plasma sample was processed eight times in parallel and each was then analyzed by 2-D DIGE in triplicate. Here, 21 protein spots had larger than 50% CV, suggesting that these proteins may not be appropriate as biomarkers and should be carefully scrutinized in future studies. Seventy-eight protein spots showing differential protein levels between different individuals or individual collections were identified by mass spectrometry and further characterized using hierarchical clustering. The results present a first step toward understanding the complexity of longitudinal and individual variation in the human plasma proteome, and provide a baseline for improved biomarker discovery.« less

  18. Human genome program report. Part 2, 1996 research abstracts

    SciTech Connect (OSTI)

    1997-11-01

    This report contains Part 2 of a two-part report to reflect research and progress in the US Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 2 consists of 1996 research abstracts. Attention is focused on the following: sequencing; mapping; informatics; ethical, legal, and social issues; infrastructure; and small business innovation research.

  19. Crystallization and preliminary crystallographic analysis of recombinant human galectin-1

    SciTech Connect (OSTI)

    Scott, Stacy A.; Scott, Ken; Blanchard, Helen

    2007-11-01

    Human galectin-1 has been cloned, expressed in E. coli, purified and crystallized in the presence of both lactose (ligand) and ?-mercaptoethanol under six different conditions. The X-ray diffraction data obtained have enabled the assignment of unit-cell parameters for two novel crystal forms of human galectin-1. Galectin-1 is considered to be a regulator protein as it is ubiquitously expressed throughout the adult body and is responsible for a broad range of cellular regulatory functions. Interest in galectin-1 from a drug-design perspective is founded on evidence of its overexpression by many cancers and its immunomodulatory properties. The development of galectin-1-specific inhibitors is a rational approach to the fight against cancer because although galectin-1 induces a plethora of effects, null mice appear normal. X-ray crystallographic structure determination will aid the structure-based design of galectin-1 inhibitors. Here, the crystallization and preliminary diffraction analysis of human galectin-1 crystals generated under six different conditions is reported. X-ray diffraction data enabled the assignment of unit-cell parameters for crystals grown under two conditions, one belongs to a tetragonal crystal system and the other was determined as monoclinic P2{sub 1}, representing two new crystal forms of human galectin-1.

  20. Framework for Human-Automation Collaboration: Conclusions from Four Studies

    SciTech Connect (OSTI)

    Johanna Oxstrand; Katya L. Le Blanc; John O'Hara; Jeffrey C. Joe; April M. Whaley; Heather Medema

    2013-11-01

    The Human Automation Collaboration (HAC) research project is investigating how advanced technologies that are planned for Advanced Small Modular Reactors (AdvSMR) will affect the performance and the reliability of the plant from a human factors and human performance perspective. The HAC research effort investigates the consequences of allocating functions between the operators and automated systems. More specifically, the research team is addressing how to best design the collaboration between the operators and the automated systems in a manner that has the greatest positive impact on overall plant performance and reliability. Oxstrand et al. (2013 - March) describes the efforts conducted by the researchers to identify the research needs for HAC. The research team reviewed the literature on HAC, developed a model of HAC, and identified gaps in the existing knowledge of human-automation collaboration. As described in Oxstrand et al. (2013 – June), the team then prioritized the research topics identified based on the specific needs in the context of AdvSMR. The prioritization was based on two sources of input: 1) The preliminary functions and tasks, and 2) The model of HAC. As a result, three analytical studies were planned and conduced; 1) Models of Teamwork, 2) Standardized HAC Performance Measurement Battery, and 3) Initiators and Triggering Conditions for Adaptive Automation. Additionally, one field study was also conducted at Idaho Falls Power.

  1. DOE Human Genome Program contractor-grantee workshop

    SciTech Connect (OSTI)

    1996-01-01

    This volume contains the proceedings for the DOE Human Genome Program`s Contractor-Grantee Workshop V held in Sante Fe, New Mexico January 28, February 1, 1996. Presentations were divided into sessions entitled Sequencing; Mapping; Informatics; Ethical, Legal, and Social Issues; and Infrastructure. Reports of individual projects described herein are separately indexed and abstracted for the database.

  2. T-547: Microsoft Windows Human Interface Device (HID) Vulnerability

    Broader source: Energy.gov [DOE]

    Microsoft Windows does not properly warn the user before enabling additional Human Interface Device (HID) functionality over USB, which allows user-assisted attackers to execute arbitrary programs via crafted USB data, as demonstrated by keyboard and mouse data sent by malware on a Smartphone that the user connected to the computer.

  3. Ganodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA

    SciTech Connect (OSTI)

    Jiang, Jiahua; Jedinak, Andrej; Sliva, Daniel; Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN; Indiana University Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, IN

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Ganodermanontriol (GDNT), a Ganoderma mushroom alcohol, inhibits growth of breast cancer cells. Black-Right-Pointing-Pointer CDC20 is over-expressed in tumors but not in the tumor surrounding tissue in breast cancer patients. Black-Right-Pointing-Pointer GDNT inhibits expression of CDC20 in breast cancer cells. Black-Right-Pointing-Pointer GDNT inhibits cell adhesion, cell migration and cell invasion of breast cancer cells. Black-Right-Pointing-Pointer GDNT inhibits secretion of uPA and down-regulates expression of uPAR in breast cancer cells. -- Abstract: Ganoderma lucidum is a medicinal mushroom that has been recognized by Traditional Chinese Medicine (TCM). Although some of the direct anticancer activities are attributed to the presence of triterpenes-ganoderic and lucidenic acids-the activity of other compounds remains elusive. Here we show that ganodermanontriol (GDNT), a Ganoderma alcohol, specifically suppressed proliferation (anchorage-dependent growth) and colony formation (anchorage-independent growth) of highly invasive human breast cancer cells MDA-MB-231. GDNT suppressed expression of the cell cycle regulatory protein CDC20, which is over-expressed in precancerous and breast cancer cells compared to normal mammary epithelial cells. Moreover, we found that CDC20 is over-expressed in tumors when compared to the tissue surrounding the tumor in specimens from breast cancer patients. GDNT also inhibited invasive behavior (cell adhesion, cell migration, and cell invasion) through the suppression of secretion of urokinase-plasminogen activator (uPA) and inhibited expression of uPA receptor. In conclusion, mushroom GDNT is a natural agent that has potential as a therapy for invasive breast cancers.

  4. Integrated Experimental and Model-based Analysis Reveals the Spatial Aspects of EGFR Activation Dynamics

    SciTech Connect (OSTI)

    Shankaran, Harish; Zhang, Yi; Chrisler, William B.; Ewald, Jonathan A.; Wiley, H. S.; Resat, Haluk

    2012-10-02

    The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases, and controls a diverse set of cellular responses relevant to development and tumorigenesis. ErbB activation is a complex process involving receptor-ligand binding, receptor dimerization, phosphorylation, and trafficking (internalization, recycling and degradation), which together dictate the spatio-temporal distribution of active receptors within the cell. The ability to predict this distribution, and elucidation of the factors regulating it, would help to establish a mechanistic link between ErbB expression levels and the cellular response. Towards this end, we constructed mathematical models for deconvolving the contributions of receptor dimerization and phosphorylation to EGFR activation, and to examine the dependence of these processes on sub-cellular location. We collected experimental datasets for EGFR activation dynamics in human mammary epithelial cells, with the specific goal of model parameterization, and used the data to estimate parameters for several alternate models. Model-based analysis indicated that: 1) signal termination via receptor dephosphorylation in late endosomes, prior to degradation, is an important component of the response, 2) less than 40% of the receptors in the cell are phosphorylated at any given time, even at saturating ligand doses, and 3) receptor dephosphorylation rates at the cell surface and early endosomes are comparable. We validated the last finding by measuring EGFR dephosphorylation rates at various times following ligand addition both in whole cells, and in endosomes using ELISAs and fluorescent imaging. Overall, our results provide important information on how EGFR phosphorylation levels are regulated within cells. Further, the mathematical model described here can be extended to determine receptor dimer abundances in cells co-expressing various levels of ErbB receptors. This study demonstrates that an iterative cycle of

  5. Secondary structure of rat and human amylin across force fields

    SciTech Connect (OSTI)

    Hoffmann, Kyle Quynn; McGovern, Michael; Chiu, Chi -cheng; de Pablo, Juan J.; Paci, Emanuele

    2015-07-29

    The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin was determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable

  6. Secondary structure of rat and human amylin across force fields

    DOE Public Access Gateway for Energy & Science Beta (PAGES Beta)

    Hoffmann, Kyle Quynn; McGovern, Michael; Chiu, Chi -cheng; de Pablo, Juan J.; Paci, Emanuele

    2015-07-29

    The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin wasmore » determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states

  7. A Human Factors Perspective on Alarm System Research and Development 2000 to 2010

    SciTech Connect (OSTI)

    Curt Braun; John Grimes; Eric Shaver; Ronald Boring

    2011-09-01

    By definition, alarms serve to notify human operators of out-of-parameter conditions that could threaten equipment, the environment, product quality and, of course, human life. Given the complexities of industrial systems, human machine interfaces, and the human operator, the understanding of how alarms and humans can best work together to prevent disaster is continually developing. This review examines advances in alarm research and development from 2000 to 2010 and includes the writings of trade professionals, engineering and human factors researchers, and standards organizations with the goal of documenting advances in alarms system design, research, and implementation.

  8. Human AZU-1 gene, variants thereof and expressed gene products

    DOE Patents [OSTI]

    Chen, Huei-Mei; Bissell, Mina

    2004-06-22

    A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

  9. Single-friction-surface triboelectric generator with human body conduit

    SciTech Connect (OSTI)

    Meng, Bo; Cheng, Xiaoliang; Zhang, Xiaosheng; Han, Mengdi; Liu, Wen; Zhang, Haixia

    2014-03-10

    We present a transparent single-friction-surface triboelectric generator (STEG) employing human body as the conduit, making the applications of STEG in portable electronics much more practical and leading to a significant output improvement. The STEG with micro-patterned polydimethylsiloxane surface achieved an output voltage of over 200 V with a current density of 4.7 ?A/cm{sup 2}. With human body conduit, the output current increased by 39% and the amount of charge that transferred increased by 34% compared to the results with grounded electrode. A larger increment of 210% and 81% was obtained in the case of STEG with a large-size flat polyethylene terephthalate surface.

  10. Measuring Human Performance within Computer Security Incident Response Teams

    SciTech Connect (OSTI)

    McClain, Jonathan T.; Silva, Austin Ray; Avina, Glory Emmanuel; Forsythe, James C.

    2015-09-01

    Human performance has become a pertinen t issue within cyber security. However, this research has been stymied by the limited availability of expert cyber security professionals. This is partly attributable to the ongoing workload faced by cyber security professionals, which is compound ed by the limited number of qualified personnel and turnover of p ersonnel across organizations. Additionally, it is difficult to conduct research, and particularly, openly published research, due to the sensitivity inherent to cyber ope rations at most orga nizations. As an alternative, the current research has focused on data collection during cyb er security training exercises. These events draw individuals with a range of knowledge and experience extending from seasoned professionals to recent college gradu ates to college students. The current paper describes research involving data collection at two separate cyber security exercises. This data collection involved multiple measures which included behavioral performance based on human - machine transactions and questionnaire - based assessments of cyber security experience.

  11. Issues in benchmarking human reliability analysis methods : a literature review.

    SciTech Connect (OSTI)

    Lois, Erasmia; Forester, John Alan; Tran, Tuan Q.; Hendrickson, Stacey M. Langfitt; Boring, Ronald L.

    2008-04-01

    There is a diversity of human reliability analysis (HRA) methods available for use in assessing human performance within probabilistic risk assessment (PRA). Due to the significant differences in the methods, including the scope, approach, and underlying models, there is a need for an empirical comparison investigating the validity and reliability of the methods. To accomplish this empirical comparison, a benchmarking study is currently underway that compares HRA methods with each other and against operator performance in simulator studies. In order to account for as many effects as possible in the construction of this benchmarking study, a literature review was conducted, reviewing past benchmarking studies in the areas of psychology and risk assessment. A number of lessons learned through these studies are presented in order to aid in the design of future HRA benchmarking endeavors.

  12. Clock-like mutational processes in human somatic cells

    SciTech Connect (OSTI)

    Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

    2015-11-09

    During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This paper provides the first survey of clock-like mutational processes operating in human somatic cells.

  13. Decade of the Brain 1990--2000: Maximizing human potential

    SciTech Connect (OSTI)

    Not Available

    1991-04-01

    The US Decade of the Brain offers scientists throughout the Federal Government a unique opportunity to advance and apply scientific knowledge about the brain and nervous system. During the next 10 years, scientists hope to maximize human potential through studies of human behavior, senses and communication, learning and memory, genetic/chemical alterations, and environmental interactions. Progress in these areas should lead to reductions in mortality from brain and nervous system disorders and to improvements in the quality of life. This report identifies nine research areas that could form the basis of an integrated program in the brain and behavioral sciences. A chart summarizing the Federal activities in these nine areas may be found at the back of the report. In addition, three areas that span the nine research areas -- basic research, technology and international activities -- are considered.

  14. Levels of chlordane, oxychlordane, and nonachlor in human adipose tissues

    SciTech Connect (OSTI)

    Hirai, Yukio; Tomokuni, Katsumaro )

    1991-08-01

    Chlordane was used as a termiticide for more than twenty years in Japan. Chlordane is stable in the environment such as sediment and its bioaccumulation in some species of bacteria, freshwater invertebrates, and marine fish is large. Many researches were done to elucidate the levels of chlordane and/or its metabolite oxychlordane in human adipose tissues. A comprehensive review concerning chlordane was recently provided by USEPA. On the other hand, Japan authorities banned the use of chlordane in September 1986. In the last paper, the authors reported that both water and sediment of the rivers around Saga city were slightly contaminated with chlordane. In the present study, they investigated the levels of chlordane, oxychlordane and nonachlor in human adipose tissues.

  15. Syntenic conservation of HSP70 genes in cattle and humans

    SciTech Connect (OSTI)

    Grosz, M.D.; Womack, J.E.; Skow, L.C. )

    1992-12-01

    A phage library of bovine genomic DNA was screened for hybridization with a human HSP70 cDNA probe, and 21 positive plaques were identified and isolated. Restriction mapping and blot hybridization analysis of DNA from the recombinant plaques demonstrated that the cloned DNAs were derived from three different regions of the bovine genome. Ore region contains two tandemly arrayed HSP70 sequences, designated HSP70-1 and HSP70-2, separated by approximately 8 kb of DNA. Single HSP70 sequences, designated HSP70-3 and HSP70-4, were found in two other genomic regions. Locus-specific probes of unique flanking sequences from representative HSP70 clones were hybridized to restriction endonuclease-digested DNA from bovine-hamster and bovine-mouse somatic cell hybrid panels to determine the chromosomal location of the HSP70 sequences. The probe for the tandemly arrayed HSP70-1 and HSP70-2 sequences mapped to bovine chromosome 23, syntenic with glyoxalase 1, 21 steroid hydroxylase, and major histocompatibility class I loci. HSP70-3 sequences mapped to bovine chromosome 10, syntenic with nucleoside phosphorylase and murine osteosarcoma viral oncogene (v-fos), and HSP70-4 mapped to bovine syntenic group U6, syntenic with amylase 1 and phosphoglucomutase 1. On the basis of these data, the authors propose that bovine HSP70-1,2 are homologous to human HSPA1 and HSPA1L on chromosome 6p21.3, bovine HSP70-3 is the homolog of an unnamed human HSP70 gene on chromosome 14q22-q24, and bovine HSP70-4 is homologous to one of the human HSPA-6,-7 genes on chromosome 1. 34 refs., 2 figs., 1 tab.

  16. Assessing human health risk in the USDA forest service

    SciTech Connect (OSTI)

    Hamel, D.R.

    1990-12-31

    This paper identifies the kinds of risk assessments being done by or for the US Department of Agriculture (USDA) Forest Service. Summaries of data sources currently in use and the pesticide risk assessments completed by the agency or its contractors are discussed. An overview is provided of the agency`s standard operating procedures for the conduct of toxicological, ecological, environmental fate, and human health risk assessments.

  17. Human dimensions in cyber operations research and development priorities.

    SciTech Connect (OSTI)

    Forsythe, James Chris; Silva, Austin Ray; Stevens-Adams, Susan Marie; Bradshaw, Jeffrey

    2012-11-01

    Within cyber security, the human element represents one of the greatest untapped opportunities for increasing the effectiveness of network defenses. However, there has been little research to understand the human dimension in cyber operations. To better understand the needs and priorities for research and development to address these issues, a workshop was conducted August 28-29, 2012 in Washington DC. A synthesis was developed that captured the key issues and associated research questions. Research and development needs were identified that fell into three parallel paths: (1) human factors analysis and scientific studies to establish foundational knowledge concerning factors underlying the performance of cyber defenders; (2) development of models that capture key processes that mediate interactions between defenders, users, adversaries and the public; and (3) development of a multi-purpose test environment for conducting controlled experiments that enables systems and human performance measurement. These research and development investments would transform cyber operations from an art to a science, enabling systems solutions to be engineered to address a range of situations. Organizations would be able to move beyond the current state where key decisions (e.g. personnel assignment) are made on a largely ad hoc basis to a state in which there exist institutionalized processes for assuring the right people are doing the right jobs in the right way. These developments lay the groundwork for emergence of a professional class of cyber defenders with defined roles and career progressions, with higher levels of personnel commitment and retention. Finally, the operational impact would be evident in improved performance, accompanied by a shift to a more proactive response in which defenders have the capacity to exert greater control over the cyber battlespace.

  18. Using Genomics to Study Human Biology and Disease

    SciTech Connect (OSTI)

    Myers, Ricard M.

    2005-04-06

    The Human Genome Project culminated in April 2003 with the finished DNA sequence of all of the human chromosomes. This book of information, particularly in conjunction with the genome sequences of many other organisms, has already begun to revolutionize the way that biomedical scientists study our species. The identification of essentially all of our genes has provided a template upon which researchers can discover basic processes that govern cells, organs, and the whole organism, and to understand the fundamental causes of the diseases that occur when something goes wrong with a gene or a set of genes. The Genome Project has already made it possible to identify the genes that are defective in more than 1,000 rare inherited diseases, and these discoveries have helped to understand the mechanisms of the more common forms of these disorders. This understanding of primary defects in diseases - which is translated as mutations in genes that encode proteins that serve specific functions - is transforming the way that biotechnology and pharmaceutical companies identify drug targets, and a few notable cases have already had a striking impact on specific diseases. In addition, it has become clear that the differential response to drugs in human populations is heavily influenced by genes, and a whole field called pharmacogenetics has begun to identify these genetic factors. Such knowledge will allow physicians to prescribe drugs targeted to each individual, with the potential to increase efficacy and decrease side-effects. Determining the DNA sequence of the human genome and identifying the genes has been an exciting endeavor, but we are only just beginning to understand the treasures present in all of our DNA. My presentation will briefly describe the road we took to get the sequence, as well as the tools that we are developing to unlock its secrets.

  19. Human Capital: The Role of Ombudsmen in Dispute Resolution

    Office of Environmental Management (EM)

    the Ranking Member, Subcommittee on International Security, Proliferation, and Federal Services, Committee on Government Affairs, U.S. Senate United States General Accounting Office GAO April 2001 HUMAN CAPITAL The Role of Ombudsmen in Dispute Resolution GAO-01-466 Page i GAO-01-466 The Role of Ombudsmen in Dispute Resolution Letter 1 Results in Brief 2 Background 5 Objectives, Scope, and Methodology 12 Some Agencies Use Ombudsmen to Deal With Workplace Issues 14 The Case Illustrations: Varied

  20. Computational Human Performance Modeling For Alarm System Design

    SciTech Connect (OSTI)

    Jacques Hugo

    2012-07-01

    The introduction of new technologies like adaptive automation systems and advanced alarms processing and presentation techniques in nuclear power plants is already having an impact on the safety and effectiveness of plant operations and also the role of the control room operator. This impact is expected to escalate dramatically as more and more nuclear power utilities embark on upgrade projects in order to extend the lifetime of their plants. One of the most visible impacts in control rooms will be the need to replace aging alarm systems. Because most of these alarm systems use obsolete technologies, the methods, techniques and tools that were used to design the previous generation of alarm system designs are no longer effective and need to be updated. The same applies to the need to analyze and redefine operators alarm handling tasks. In the past, methods for analyzing human tasks and workload have relied on crude, paper-based methods that often lacked traceability. New approaches are needed to allow analysts to model and represent the new concepts of alarm operation and human-system interaction. State-of-the-art task simulation tools are now available that offer a cost-effective and efficient method for examining the effect of operator performance in different conditions and operational scenarios. A discrete event simulation system was used by human factors researchers at the Idaho National Laboratory to develop a generic alarm handling model to examine the effect of operator performance with simulated modern alarm system. It allowed analysts to evaluate alarm generation patterns as well as critical task times and human workload predicted by the system.