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Sample records for lesanded hes sellega

  1. Hypereosinophilic Syndrome (HES)

    MedlinePlus

    ... and is part of the larger group of Myeloproliferative Neoplasms. Closely related disease to HES is chronic eosinophilic ... long-term therapy. Overall experience with IFNa in myeloproliferative neoplasms is that about 25-30% of patients require ...

  2. HES6 enhances the motility of alveolar rhabdomyosarcoma cells

    SciTech Connect

    Wickramasinghe, Caroline M; Domaschenz, Renae; Amagase, Yoko; Williamson, Daniel; Missiaglia, Edoardo; Shipley, Janet; Murai, Kasumi; Jones, Philip H

    2013-01-01

    Absract: HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.

  3. HES6 promotes prostate cancer aggressiveness independently of Notch signalling.

    PubMed

    Carvalho, Filipe L F; Marchionni, Luigi; Gupta, Anuj; Kummangal, Basheer A; Schaeffer, Edward M; Ross, Ashley E; Berman, David M

    2015-07-01

    Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high-grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer-specific up-regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up- and down-regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor-independent manner. Using a Notch-sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell-autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression.

  4. [Abnormal Notch-Hes Signaling Pathways and Acute Leukemia -Review].

    PubMed

    Gu, Zhen-Yang; Wang, Li; Gao, Chun-Ji

    2017-02-01

    The abnormal activation of Notch signaling is closely related to the development of acute leukemia (AL). The core elements of the Notch signaling system include Notch receptors, Notch ligands, CSL DNA-binding proteins, and effectors like target genes. Any factors, which affect ligands, receptors, signal transducers and effectors, can influence the signal transduction of Notch signaling greatly. Based on the role of Notch signaling in AL, several targeted drugs against Notch upstream signaling have been developed. However, due to the complexity and pleiotropic effects of Notch upstream signaling, these targeted drugs display strong side effects. Thus, Hes (Hairy Enhancer of Split) factors as a primary Notch effector, also play an important role in the pathogenesis of AL. This review summarizes recent progresses on Notch-Hes signaling in AL, hopping to provide references for further excavation of the Notch-Hes signaling, and lay foundations for developing the next generation of targeted drugs.

  5. Results of NASA/NOAA HES Trade Studies

    NASA Technical Reports Server (NTRS)

    Susskind, Joel

    2011-01-01

    This slide presentation reviews the trade studies that were done for the Hyperspectral Environmental Suite (HES). The goal of the trade studies was to minimize instrument cost and risk while producing scientifically useful products. Three vendors were selected to perform the trade study, and were to conduct 11 studies, with the first study a complete wish list of things that scientists would like from GEO orbit to the 11th study which was for a Reduced Accommodation Sounder (RAS) which would still result in useful scientific products, within constrains compatible with flight on GEOS-R. The RAS's from each vendor and one other HES sounders designs are reviewed.

  6. Expression dynamics and functions of Hes factors in development and diseases.

    PubMed

    Kobayashi, Taeko; Kageyama, Ryoichiro

    2014-01-01

    Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1-7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences, while the HLH region forms homo- and heterodimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits corepressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate-determination steps of embryonic stem cells and neural progenitor cells. Here, we discuss some key features of Hes factors in development and diseases.

  7. Identification of small molecule Hes1 modulators as potential anticancer chemotherapeutics.

    PubMed

    Sail, Vibhavari; Hadden, M Kyle

    2013-03-01

    Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.

  8. The Hospice Environmental Survey (HES): Pilot Test of a New Measurement Instrument.

    ERIC Educational Resources Information Center

    Taylor, Jean H.; Perrill, Norman K.

    1988-01-01

    Describes development of the Hospice Environmental Survey (HES) to measure user's perception of the homelike atmosphere provided by a hospital inpatient unit called Hospice House. Presents the HES instrument, methodology, and pilot study data. (Author/NB)

  9. Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development.

    PubMed

    Tateya, Tomoko; Imayoshi, Itaru; Tateya, Ichiro; Ito, Juichi; Kageyama, Ryoichiro

    2011-04-15

    Notch-mediated lateral inhibition has been reported to regulate auditory hair cell and supporting cell development from common precursors. While the Notch effector genes Hes1, Hes5 and Hey1 are expressed in the developing cochlea, inactivation of either of them causes only mild abnormality, suggesting their functional redundancy. To explore the roles of Hes/Hey genes in cochlear development, we examined compound heterozygous or homozygous mutant mice that lacked Hes1, Hes5 and Hey1 alleles. We found that a reduction in Hes/Hey gene dosage led to graded increase of hair cell formation. However, if at least one allele of Hes1, Hes5 or Hey1 was intact, excessive hair cells were accompanied by overproduction of supporting cells, suggesting that the hair cell increase does not occur at the expense of supporting cells, and that each Hes/Hey gene functions to induce supporting cells. By contrast, when all alleles of Hes1, Hes5 and Hey1 were inactivated, the number of hair cells increased more drastically, whereas that of supporting cells was unchanged compared with control, suggesting that supporting cell formation was balanced by their overproduction and fate conversion into hair cells. The increase of the cell numbers seemed to occur after the prosensory domain formation in the mutants because the proliferation state and the size of the prosensory domain were not affected. Thus, Hes1, Hes5 and Hey1 cooperatively inhibit hair cell formation, and one allele of Hes1, Hes5 or Hey1 is sufficient for supporting cell production probably by lateral inhibition in the sensory epithelium. Strikingly, Hes/Hey mutations lead to disorganized cell alignment and polarity and to hearing loss despite hair cell overproduction. These results suggest that Hes/Hey gene dosage is essential not only for generation of appropriate numbers of hair cells and supporting cells by controlling cell proliferation and lateral inhibition but also for the hearing ability by regulating the cell alignment

  10. Differential regulation of Hes/Hey genes during inner ear development.

    PubMed

    Petrovic, Jelena; Gálvez, Hector; Neves, Joana; Abelló, Gina; Giraldez, Fernando

    2015-07-01

    Notch signaling plays a crucial role during inner ear development and regeneration. Hes/Hey genes encode for bHLH transcription factors identified as Notch targets. We have studied the expression and regulation of Hes/Hey genes during inner ear development in the chicken embryo. Among several Hes/Hey genes examined, only Hey1 and Hes5 map to the sensory regions, although with salient differences. Hey1 expression follows Jag1 expression except at early prosensory stages while Hes5 expression corresponds well to Dl1 expression throughout otic development. Although Hey1 and Hes5 are direct Notch downstream targets, they differ in the level of Notch required for activation. Moreover, they also differ in mRNA stability, showing different temporal decays after Notch blockade. In addition, Bmp, Wnt and Fgf pathways also modify Hey1 and Hes5 expression in the inner ear. Particularly, the Wnt pathway modulates Hey1 and Jag1 expression. Finally, gain of function experiments show that Hey1 and Hes5 cross-regulate each other in a complex manner. Both Hey1 and Hes5 repress Dl1 and Hes5 expression, suggesting that they prevent the transition to differentiation stages, probably by preventing Atoh1 expression. In spite of its association with Jag1, Hey1 does not seem to be instrumental for lateral induction as it does not promote Jag1 expression. We suggest that, besides being both targets of Notch, Hey1 and Hes5 are subject to a rather complex regulation that includes the stability of their transcripts, cross regulation and other signaling pathways.

  11. History of a prolific family: the Hes/Hey-related genes of the annelid Platynereis

    PubMed Central

    2014-01-01

    Background The Hes superfamily or Hes/Hey-related genes encompass a variety of metazoan-specific bHLH genes, with somewhat fuzzy phylogenetic relationships. Hes superfamily members are involved in a variety of major developmental mechanisms in metazoans, notably in neurogenesis and segmentation processes, in which they often act as direct effector genes of the Notch signaling pathway. Results We have investigated the molecular and functional evolution of the Hes superfamily in metazoans using the lophotrochozoan Platynereis dumerilii as model. Our phylogenetic analyses of more than 200 Metazoan Hes/Hey-related genes revealed the presence of five families, three of them (Hes, Hey and Helt) being pan-metazoan. Those families were likely composed of a unique representative in the last common metazoan ancestor. The evolution of the Hes family was shaped by many independent lineage specific tandem duplication events. The expression patterns of 13 of the 15 Hes/Hey-related genes in Platynereis indicate a broad functional diversification. Nevertheless, a majority of these genes are involved in two crucial developmental processes in annelids: neurogenesis and segmentation, resembling functions highlighted in other animal models. Conclusions Combining phylogenetic and expression data, our study suggests an unusual evolutionary history for the Hes superfamily. An ancestral multifunctional annelid Hes gene may have undergone multiples rounds of duplication-degeneration-complementation processes in the lineage leading to Platynereis, each gene copies ensuring their maintenance in the genome by subfunctionalisation. Similar but independent waves of duplications are at the origin of the multiplicity of Hes genes in other metazoan lineages. PMID:25250171

  12. The transcriptional repressor Hes1 attenuates inflammation via regulating transcriptional elongation

    PubMed Central

    Shang, Yingli; Coppo, Maddalena; He, Teng; Ning, Fei; Yu, Li; Kang, Lan; Zhang, Bin; Ju, Chanyang; Qiao, Yu; Zhao, Baohong; Gessler, Manfred; Rogatsky, Inez; Hu, Xiaoyu

    2016-01-01

    Most of the known regulatory mechanisms that curb inflammatory gene expression target pre-transcription initiation steps and evidence for regulation of inflammatory gene expression post initiation remains scarce. Here we show that transcription repressor hairy and enhancer of split 1 (Hes1) suppresses production of CXCL1, a chemokine crucial for recruiting neutrophils. Hes1 negatively regulates neutrophil recruitment in vivo in a manner that is dependent on macrophage-produced CXCL1 and attenuates severity of inflammatory arthritis. Mechanistically, inhibition of Cxcl1 expression by Hes1 does not involve modification of transcription initiation. Instead, Hes1 inhibits signal-induced recruitment of positive transcription elongation complex P-TEFb, thereby preventing phosphorylation of RNA polymerase II on serine-2 and productive elongation. Thus, our results identify Hes1 as a homeostatic suppressor of inflammatory responses which exerts its suppressive function by regulating transcription elongation. PMID:27322654

  13. Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

    PubMed Central

    Markenstein, Lisa; Appelt-Menzel, Antje; Metzger, Marco

    2014-01-01

    Summary The mono-6-deoxy-6-azides of 2,6-di-O-methyl-β-cyclodextrin (DIMEB) and randomly methylated-β-cyclodextrin (RAMEB) were conjugated to propargylated hydroxyethyl starch (HES) by Cu+-catalysed [2 + 3] cycloaddition. The resulting water soluble polymers showed lower critical solution temperatures (LCST) at 52.5 °C (DIMEB-HES) and 84.5 °C (RAMEB-HES), respectively. LCST phase separations could be completely avoided by the introduction of a small amount of carboxylate groups at the HES backbone. The methylated CDs conjugated to the HES backbone exhibited significantly lower cytotoxicities than the corresponding monomeric CD derivatives. Since the binding potentials of these CD conjugates were very high, they are promising candidates for new oral dosage forms of anaesthetic actives. PMID:25670977

  14. Hes1: a key role in stemness, metastasis and multidrug resistance

    PubMed Central

    Liu, Zi-Hao; Dai, Xiao-Meng; Du, Bin

    2015-01-01

    Hes1 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability. Recent studies have shown that Hes1 functions in the maintenance of cancer stem cells (CSCs), metastasis and antagonizing drug-induced apoptosis. Pathways that are involved in the up-regulation of Hes1 level canonically or non-canonically, such as the Hedgehog, Wnt and hypoxia pathways are frequently aberrant in cancer cells. Here, we summarize the recent data supporting the idea that Hes1 may have an important function in the maintenance of cancer stem cells self-renewal, cancer metastasis, and epithelial–mesenchymal transition (EMT) process induction, as well as chemotherapy resistance, and conclude with the possible mechanisms by which Hes1 functions have their effect, as well as their crosstalk with other carcinogenic signaling pathways. PMID:25781910

  15. HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression

    PubMed Central

    Revollo, Javier R.; Oakley, Robert H.; Lu, Nick Z.; Kadmiel, Mahita; Gandhavadi, Maheer; Cidlowski, John A.

    2014-01-01

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the genome. We now establish a genome wide molecular link between HES1 and glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This glucocorticoid-dependent repression of HES1 was necessary for the glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper glucocorticoid signaling. PMID:24300895

  16. Hes1 Is Expressed in the Second Heart Field and Is Required for Outflow Tract Development

    PubMed Central

    Mesbah, Karim; Jarry, Thérèse; Mattei, Marie-Geneviève; Kelly, Robert G.

    2009-01-01

    Background Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation of this process leads to congenital heart defects. In order to provide further insight into second heart field development we characterized the insertion site of a transgene expressed in the second heart field and outflow tract as the result of an integration site position effect. Results Here we show that the integration site of the A17-Myf5-nlacZ-T55 transgene lies upstream of Hes1, encoding a basic helix-loop-helix containing transcriptional repressor required for the maintenance of diverse progenitor cell populations during embryonic development. Transgene expression in a subset of Hes1 expression sites, including the CNS, pharyngeal epithelia, pericardium, limb bud and lung endoderm suggests that Hes1 is the endogenous target of regulatory elements trapped by the transgene. Hes1 is expressed in pharyngeal endoderm and mesoderm including the second heart field. Analysis of Hes1 mutant hearts at embryonic day 15.5 reveals outflow tract alignment defects including ventricular septal defects and overriding aorta. At earlier developmental stages, Hes1 mutant embryos display defects in second heart field proliferation, a reduction in cardiac neural crest cells and failure to completely extend the outflow tract. Conclusions Hes1 is expressed in cardiac progenitor cells in the early embryo and is required for development of the arterial pole of the heart. PMID:19609448

  17. Dynamic expression and essential functions of Hes7 in somite segmentation.

    PubMed

    Bessho, Y; Sakata, R; Komatsu, S; Shiota, K; Yamada, S; Kageyama, R

    2001-10-15

    The basic helix-loop-helix (bHLH) gene Hes7, a putative Notch effector, encodes a transcriptional repressor. Here, we found that Hes7 expression oscillates in 2-h cycles in the presomitic mesoderm (PSM). In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. As a result, the somite derivatives such as vertebrae and ribs are severely disorganized. Although expression of Notch and its ligands is not affected significantly, the oscillator and Notch modulator lunatic fringe is expressed continuously throughout the mutant PSM. These results indicate that Hes7 controls the cyclic expression of lunatic fringe and is essential for coordinated somite segmentation.

  18. The viscous characterization of hydroxyethyl starch (HES) plasma volume expanders in a non-Newtonian blood analog.

    PubMed

    Walker, Andrew M; Xiao, Yao; Johnston, Clifton R; Rival, David E

    2013-01-01

    Although information pertaining to the viscous characterization of HES 130/0.4 Voluven® and HES 260/0.45 Pentaspan® is available, quantification is limited to 100% concentrations. We focus here on the quantification of their viscous behavior along with HES 130/0.4 Volulyte® in a shear thinning non-Newtonian blood analog of aqueous xanthan gum and glycerol. Dynamic viscosities of multiple batches of HES fluids were measured through capillary viscometry. The viscous behavior of 100%, 25% and 12.5% concentrations were then measured through a closed flow loop across physiologically relevant flow rates. Measured viscosities were 2.57 millipascal second (mPa·s) 6.52 mPa·s and 2.48 mPa·s for HES 130/0.4 Voluven®, HES 260/0.45 and HES 130/0.4 Volulyte®, respectively. Pipe flow analysis found that all HES fluids displayed Newtonian behavior at 100% concentrations. 25% concentrations of both HES 130/0.4 fluids decreased analog viscosity 23%-29% at a flow rate of 1.0 ml/s and 16%-21% at a flow rate of 22.5 ml/s. At a flow rate of 22.5 ml/s, 25% and 12.5% concentrations of HES 260/0.45 resulted in analog viscosity changes of 3.9%-4.5%. Capillary viscosity reductions of approximately 7% and 14.5% in HES 130/0.4 Voluven® and HES 260/0.45 suggest changes in molecular composition to batches previously measured. Maintenance of analog viscosity suggests that HES 260/0.45 would be suitable as a high viscosity plasma expander in extreme hemodilution through preservation of microcirculatory function and wall shear stress (WSS).

  19. Hes4 controls proliferative properties of neural stem cells during retinal ontogenesis.

    PubMed

    El Yakoubi, Warif; Borday, Caroline; Hamdache, Johanna; Parain, Karine; Tran, Hong Thi; Vleminckx, Kris; Perron, Muriel; Locker, Morgane

    2012-12-01

    The retina of fish and amphibian contains genuine neural stem cells located at the most peripheral edge of the ciliary marginal zone (CMZ). However, their cell-of-origin as well as the mechanisms that sustain their maintenance during development are presently unknown. We identified Hes4 (previously named XHairy2), a gene encoding a bHLH-O transcriptional repressor, as a stem cell-specific marker of the Xenopus CMZ that is positively regulated by the canonical Wnt pathway and negatively by Hedgehog signaling. We found that during retinogenesis, Hes4 labels a small territory, located first at the pigmented epithelium (RPE)/neural retina (NR) border and later in the retinal margin, that likely gives rise to adult retinal stem cells. We next addressed whether Hes4 might impart this cell subpopulation with retinal stem cell features: inhibited RPE or NR differentiation programs, continuous proliferation, and slow cell cycle speed. We could indeed show that Hes4 overexpression cell autonomously prevents retinal precursor cells from commitment toward retinal fates and maintains them in a proliferative state. Besides, our data highlight for the first time that Hes4 may also constitute a crucial regulator of cell cycle kinetics. Hes4 gain of function indeed significantly slows down cell division, mainly through the lengthening of G1 phase. As a whole, we propose that Hes4 maintains particular stemness features in a cellular cohort dedicated to constitute the adult retinal stem cell pool, by keeping it in an undifferentiated and slowly proliferative state along embryonic retinogenesis.

  20. Hes1 is involved in the self-renewal and tumourigenicity of stem-like cancer cells in colon cancer.

    PubMed

    Gao, Fei; Zhang, YuQin; Wang, ShengChun; Liu, YuanQiang; Zheng, Lin; Yang, JianQuan; Huang, Wei; Ye, YanFen; Luo, WeiRen; Xiao, Dong

    2014-02-04

    A small subpopulation of cancer cells with stem cell-like features might be responsible for tumour generation, progression, and chemoresistance. Hes1 influences the maintenance of certain stem cells and progenitor cells and the digestive systems. We found upregulated Hes1 in poorly differentiated cancer samples compared with well-differentiated tumour samples, and most of the adenocarcinomas exhibited significantly higher levels of Hes1 mRNA compared with that observed in matched normal colon samples. Moreover, Hes1 expression was found to be correlated with the expression of stem cell markers in colon cancer samples, and Hes1 upregulates the expression of stemness-related genes in colon cancer cells. In addition, Hes1 enhances the self-renewal properties of the stem-like cells by increasing the sizes of CD133+ cells and SP cells and the ability of tumour sphere formation. Additionally, the Hes1-overexpressing cells formed significantly larger and higher number of colonies, as determined through the colony and the soft agar assays. More importantly, Hes1 enhances the tumourigenicity of colon cancer cell lines in nude mice and exhibits a strong tumour-formation ability at a cell density of 1 × 10(3). Taken together, our data indicate that Hes1 induces stem-like cell self-renewal and increases the number of tumour-initiating cells in colon cancer.

  1. Hes1 Desynchronizes Differentiation of Pluripotent Cells by Modulating STAT3 Activity

    PubMed Central

    Zhou, Xinzhi; Smith, Andrew JH; Waterhouse, Anna; Blin, Guillaume; Malaguti, Mattias; Lin, Chia-Yi; Osorno, Rodrigo; Chambers, Ian; Lowell, Sally

    2013-01-01

    Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously. Stem Cells 2013;31:1511–1522 PMID:23649667

  2. Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity.

    PubMed

    Zhou, Xinzhi; Smith, Andrew J H; Waterhouse, Anna; Blin, Guillaume; Malaguti, Mattias; Lin, Chia-Yi; Osorno, Rodrigo; Chambers, Ian; Lowell, Sally

    2013-08-01

    Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously.

  3. HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion

    SciTech Connect

    Ball, Andrew J.; Abrahamsson, Annelie E.; Tyrberg, Bjoern; Itkin-Ansari, Pamela; Levine, Fred; E-mail: flevine@ucsd.edu

    2007-04-06

    To examine the mechanism by which growth-stimulated pancreatic {beta}-cells dedifferentiate, somatic cell fusions were performed between MIN6, a highly differentiated mouse insulinoma, and {beta}lox5, a cell line derived from human {beta}-cells which progressively dedifferentiated in culture. MIN6/{beta}lox5 somatic cells hybrids underwent silencing of insulin expression and a marked decline in PDX1, NeuroD, and MafA, indicating that {beta}lox5 expresses a dominant transacting factor(s) that represses {beta}-cell differentiation. Expression of Hes1, which inhibits endocrine differentiation was higher in hybrid cells than in parental MIN6 cells. Hes6, a repressor of Hes1, was highly expressed in primary {beta}-cells as well as MIN6, but was repressed in hybrids. Hes6 overexpression using a retroviral vector led to a decrease in Hes1 levels, an increase in {beta}-cell transcription factors and partial restoration of insulin expression. We conclude that the balance of Notch activators and inhibitors may play an important role in maintaining the {beta}-cell differentiated state.

  4. Geostationary Operational Environmental Satellites (GOES): R series hyperspectral environmental suite (HES) overview

    NASA Astrophysics Data System (ADS)

    Martin, Gene; Criscione, Joseph C.; Cauffman, Sandra A.; Davis, Martin A.

    2004-11-01

    The Hyperspectral Environmental Suite (HES) instrument is currently under development by the NASA GOES-R Project team within the framework of the GOES Program to fulfill the future needs and requirements of the National Environmental Satellite, Data, and Information Service (NESDIS) Office. As part of the GOES-R instrument complement, HES will provide measurements of the traditional temperature and water vapor vertical profiles with higher accuracy and vertical resolution than obtained through current sounder technologies. HES will provide measurements of the properties of the shelf and coastal waters and back up imaging (at in-situ resolution) for the GOES-R Advanced Baseline Imager (ABI). The HES team is forging the future of remote environmental monitoring with the development of an operational instrument with high temporal, spatial and spectral-resolution and broad hemispheric coverage. The HES development vision includes threshold and goal requirements that encompass potential system solutions. The HES team has defined tasks for the instrument(s) that include a threshold functional complement of Disk Sounding (DS), Severe Weather/Mesoscale Sounding (SW/M), and Shelf and Coastal Waters imaging (CW) and a goal functional complement of Open Ocean (OO) imaging, and back up imaging (at in-situ resolution) for the GOES-R Advanced Baseline Imager (ABI). To achieve the best-value procurement, the GOES-R Project has base-lined a two-phase procurement approach to the HES design and development; a Formulation/study phase and an instrument Implementation phase. During Formulation, currently slated for the FY04-05 timeframe, the developing team(s) will perform Systems Requirements Analysis and evaluation, System Trade and Requirements Baseline Studies, Risk Assessment and Mitigation Strategy and complete a Preliminary Conceptual Design of the HES instrument. The results of the formulation phase will be leveraged to achieve an effective and efficient system solution during

  5. Delta-1 Activation of Notch-1 Signaling Results in HES-1 Transactivation

    PubMed Central

    Jarriault, Sophie; Le Bail, Odile; Hirsinger, Estelle; Pourquié, Olivier; Logeat, Frédérique; Strong, Clare F.; Brou, Christel; Seidah, Nabil G.; Israël, Alain

    1998-01-01

    The Notch receptor is involved in many cell fate determination events in vertebrates and invertebrates. It has been shown in Drosophila melanogaster that Delta-dependent Notch signaling activates the transcription factor Suppressor of Hairless, leading to an increased expression of the Enhancer of Split genes. Genetic evidence has also implicated the kuzbanian gene, which encodes a disintegrin metalloprotease, in the Notch signaling pathway. By using a two-cell coculture assay, we show here that vertebrate Dl-1 activates the Notch-1 cascade. Consistent with previous data obtained with active forms of Notch-1 a HES-1-derived promoter construct is transactivated in cells expressing Notch-1 in response to Dl-1 stimulation. Impairing the proteolytic maturation of the full-length receptor leads to a decrease in HES-1 transactivation, further supporting the hypothesis that only mature processed Notch is expressed at the cell surface and activated by its ligand. Furthermore, we observed that Dl-1-induced HES-1 transactivation was dependent both on Kuzbanian and RBP-J activities, consistent with the involvement of these two proteins in Notch signaling in Drosophila. We also observed that exposure of Notch-1-expressing cells to Dl-1 results in an increased level of endogenous HES-1 mRNA. Finally, coculture of Dl-1-expressing cells with myogenic C2 cells suppresses differentiation of C2 cells into myotubes, as previously demonstrated for Jagged-1 and Jagged-2, and also leads to an increased level of endogenous HES-1 mRNA. Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do. PMID:9819428

  6. Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity

    PubMed Central

    Wall, Dana S.; Mears, Alan J.; McNeill, Brian; Mazerolle, Chantal; Thurig, Sherry; Wang, Yaping; Kageyama, Ryoichiro; Wallace, Valerie A.

    2009-01-01

    Sonic hedgehog (Shh) is an indispensable, extrinsic cue that regulates progenitor and stem cell behavior in the developing and adult mammalian central nervous system. Here, we investigate the link between the Shh signaling pathway and Hes1, a classical Notch target. We show that Shh-driven stabilization of Hes1 is independent of Notch signaling and requires the Shh effector Gli2. We identify Gli2 as a primary mediator of this response by showing that Gli2 is required for Hh (Hedgehog)-dependent up-regulation of Hes1. We also show using chromatin immunoprecipitation that Gli2 binds to the Hes1 promoter, which suggests that Hes1 is a Hh-dependent direct target of Gli2 signaling. Finally, we show that Shh stimulation of progenitor proliferation and cell diversification requires Gli2 and Hes1 activity. This paper is the first demonstration of the mechanistic and functional link between Shh, Gli, and Hes1 in the regulation of progenitor cell behavior. PMID:19124651

  7. Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells

    SciTech Connect

    Murano, Tatsuro; Okamoto, Ryuichi; Ito, Go; Nakata, Toru; Hibiya, Shuji; Shimizu, Hiromichi; Fujii, Satoru; Kano, Yoshihito; Mizutani, Tomohiro; Yui, Shiro; Akiyama-Morio, Junko; Nemoto, Yasuhiro; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Watanabe, Mamoru

    2014-01-17

    Highlights: •Hes1 enhances IL-22-STAT3 signaling in human intestinal epithelial cells. •Hes1 enhances REG family gene induction by IL-22-STAT3 signaling. •Protein level of Hes1 restricts the response to IL-22. •Present regulation of a cytokine signal represents a new mode of Hes1 function. -- Abstract: Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a γ-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs.

  8. Effects of different types of hydroxyethyl starch (HES) on microcirculation perfusion and tissue oxygenation in patients undergoing liver surgery.

    PubMed

    Cui, Yinghua; Sun, Bo; Wang, Changsong; Liu, Shujuan; Li, Peng; Shi, Jinghui; Li, Enyou

    2014-01-01

    To compare the effects of hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5, which have different molecular weights and degrees of substitution, on microcirculation perfusion and tissue oxygenation in patients undergoing liver surgery. Thirty patients with an American Society of Anesthesiologists status I/II who were scheduled for liver surgery were randomly divided into two groups: one received an intraoperative HES 130/0.4 infusion equal to the amount of blood loss (HES 130/0.4 group, n=15), and the other received HES 200/0.5 equal to the amount of blood loss (HES 200/0.5 group, n=15). Gastric mucosal perfusion and tissue oxygenation were monitored by measuring the gastric mucosal pH (pHi), which was determined using a carbon dioxide tonometer inserted through a nasogastric tube. Gastric mucosal pHi , hemodynamic parameters, body temperature, and blood gas parameters were recorded upon entering the operating room, before skin incision, one hour and two hours after skin incision, and at the end of surgery. The intraoperative pHi decreased in both groups of patients, but the decline in the HES 130/0.4 group was smaller than that of the HES 200/0.5 group. The pHi of the HES 130/0.4 group was significantly higher than that of the HES 200/0.5 group two hours after skin incision and at the end of surgery (P<0.05). A multivariate analysis showed that the type of colloid used intraoperatively was the only variant that affected pHi (F=0.626, P<0.05). Moreover, there were good correlation between pHi at the end of surgery and the length of postoperative hospital stay (r=-0.536, P<0.05) and the time intervals from surgery to the passage of flatus (r=-0.547, P<0.05). Compared with HES 200/0.5, the use of HES 130/0.4 (with a relatively lower molecular weight and lower degree of substitution) could significantly improve internal organ perfusion and tissue oxygenation in patients undergoing liver surgery with a relatively large amount of blood loss.

  9. Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development.

    PubMed

    Ichi, Shunsuke; Costa, Fabricio F; Bischof, Jared M; Nakazaki, Hiromichi; Shen, Yueh-Wei; Boshnjaku, Vanda; Sharma, Saurabh; Mania-Farnell, Barbara; McLone, David G; Tomita, Tadanori; Soares, Marcelo B; Mayanil, Chandra S K

    2010-11-19

    The mechanism(s) behind folate rescue of neural tube closure are not well understood. In this study we show that maternal intake of folate prior to conception reverses the proliferation potential of neural crest stem cells in homozygous Splotch embryos (Sp(-/-)) via epigenetic mechanisms. It is also shown that the pattern of differentiation seen in these cells is similar to wild-type (WT). Cells from open caudal neural tubes of Sp(-/-) embryos exhibit increased H3K27 methylation and decreased expression of KDM6B possibly due to up-regulation of KDM6B targeting micro-RNAs such as miR-138, miR-148a, miR-185, and miR-339-5p. In our model, folate reversed these epigenetic marks in folate-rescued Sp(-/-) embryos. Using tissue from caudal neural tubes of murine embryos we also examined H3K27me2 and KDM6B association with Hes1 and Neurog2 promoters at embryonic day E10.5, the proliferative stage, and E12.5, when neural differentiation begins. In Sp(-/-) embryos compared with WT, levels of H3K27me2 associated with the Hes1 promoter were increased at E10.5, and levels associated with the Neurog2 promoter were increased at E12.5. KDM6B association with Hes1 and Neurog2 promoters was inversely related to H3K27me2 levels. These epigenetic changes were reversed in folate-rescued Sp(-/-) embryos. Thus, one of the mechanisms by which folate may rescue the Sp(-/-) phenotype is by increasing the expression of KDM6B, which in turn decreases H3K27 methylation marks on Hes1 and Neurog2 promoters thereby affecting gene transcription.

  10. Re: Coagulation and Fluid Resuscitation by HyperHES in Severe Hemorrhage

    DTIC Science & Technology

    2013-08-01

    pigs after resuscitation from hem- orrhagic shock using the small-volume con- cept with hypertonic saline/hydroxyethyl starch as compared to...administration of 4% gelatin or 6% hydroxyethyl starch solution. Anesth Analg. 2008;106:1078Y1086, table of contents. 5. Kramer GC. Hypertonic resuscitation...hydroxyethyl starch .1Y4 However, we are unaware of studies evaluating the effects of HyperHES on coagulation after hemorrhagic shock. With well-documented

  11. Qingyihuaji Formula Inhibits Pancreatic Cancer and Prolongs Survival by Downregulating Hes-1 and Hey-1.

    PubMed

    Xu, Yanli; Xu, Shan; Cai, Yueqin; Liu, Luming

    2015-01-01

    The dire prognosis of pancreatic cancer has not markedly improved during past decades. The present study was carried out to explore the effect of Qingyihuaji formula (QYHJ) on inhibiting pancreatic cancer and prolonging survival in related Notch signaling pathway. Proliferation of pancreatic cancer cells (SW1990 and PANC-1) was detected by MTT assay at 24, 48, and 72 h with exposure to various concentrations (0.08-50 mg/mL) of QYHJ water extract. Pancreatic tumor models of nude mice were divided into three groups randomly (control, QYHJ, and gemcitabine). mRNA and protein expression of Notch target genes (Hes-1, Hey-1, Hey-2, and Hey-L) in dissected tumor tissue were detected. Results showed that proliferation of SW1990 cells and PANC-1 cells was inhibited by QYHJ water extract in a dose-dependent and time-dependent manner. QYHJ effectively inhibited tumor growth and prolonged survival time in nude mice. Expression of both Hes-1 and Hey-1 was decreased significantly in QYHJ group, suggesting that Hes-1 and Hey-1 in Notch signaling pathway might be potential targets for QYHJ treatment. This research could help explain the clinical effectiveness of QYHJ and may provide advanced pancreatic cancer patients with a new therapeutic option.

  12. Leak testing of IR sensor dewars to 1E-15 std He/s

    NASA Astrophysics Data System (ADS)

    Sasaki, Y. Tito; Bergquist, Lyle E.

    1990-09-01

    The results of tests for leakage performed on ten IR sensor dewars are presented, and the design principles of the new testing devices are discussed. The ultrasensitive leak detector used for testing is compared to conventional detectors. The superfine leak calibrator consisting of a tracer gas supply, an aliquot volume, a pressure transducer, temperature gage, and valves was used to measure leak rates in the E-4 to E-12 std cc He/s range. The testing method is explained, including the gases used, the quadrupole mass analyzer, the reference leak calibration, and the temperature coefficient of the reference leak. The test results of the IR sensor dewars are shown: seven showed leak rates in the E-15 std cc He/s range, two had no detectable leaks, and one had a mid-range E-14 leak. The shelf lives of the dewars are calculated based on the results. The vacuum integrity of small IR sensor dewars can be reliably tested to the range of 1E-15 std cc He/s using the ultrasensitive leak detector and the superfine leak calibrator.

  13. Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains

    PubMed Central

    Bai, Guang; Cheung, Iris; Shulha, Hennady P.; Coelho, Joana E.; Li, Ping; Dong, Xianjun; Jakovcevski, Mira; Wang, Yumei; Grigorenko, Anastasia; Jiang, Yan; Hoss, Andrew; Patel, Krupal; Zheng, Ming; Rogaev, Evgeny; Myers, Richard H.; Weng, Zhiping; Akbarian, Schahram; Chen, Jiang-Fan

    2015-01-01

    To investigate epigenetic contributions to Huntington's disease (HD) pathogenesis, we carried out genome-wide mapping of the transcriptional mark, trimethyl-histone H3-lysine 4 (H3K4me3) in neuronal nuclei extracted from prefrontal cortex of HD cases and controls using chromatin immunoprecipitation followed by deep-sequencing. Neuron-specific mapping of the genome-wide distribution of H3K4me3 revealed 136 differentially enriched loci associated with genes implicated in neuronal development and neurodegeneration, including GPR3, TMEM106B, PDIA6 and the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2, supporting the view that the neuronal epigenome is affected in HD. Importantly, loss of H3K4me3 at CpG-rich sequences on the HES4 promoter was associated with excessive DNA methylation, reduced binding of nuclear proteins to the methylated region and altered expression of HES4 and HES4 targeted genes MASH1 and P21 involved in striatal development. Moreover, hypermethylation of HES4 promoter sequences was strikingly correlated with measures of striatal degeneration and age-of-onset in a cohort of 25 HD brains (r = 0.56, P = 0.006). Lastly, shRNA knockdown of HES4 in human neuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates and cell death. These findings, taken together, suggest that epigenetic dysregulation of HES4 could play a critical role in modifying HD disease pathogenesis and severity. PMID:25480889

  14. T cell development requires constraint of the myeloid regulator C/EBPa by the Notch target and transcriptional repressor Hes1

    PubMed Central

    De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin; Harly, Christelle; Yashiro-Ohtani, Yumi; DeLong, Jonathan H; Zlotoff, Daniel A; Sultana, Dil Afroz; Pear, Warren S; Bhandoola, Avinash

    2014-01-01

    Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBPa restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development. PMID:24185616

  15. Systematic analysis of hydroxyethyl starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses

    PubMed Central

    Hartog, Christiane S.; Skupin, Helga; Natanson, Charles; Sun, Junfeng; Reinhart, Konrad

    2013-01-01

    Purpose Hydroxyethyl starch (HES) is a synthetic colloid used widely for resuscitation despite the availability of safer, less costly fluids. Numerous HES reviews have been published that may have influenced clinicians’ practice. We have therefore examined the relationship between the methodological quality of published HES reviews, authors’ potential conflicts of interest (pCOI) and the recommendations made. Methods Systematic analysis of reviews on HES use. Results Between 1975 and 2010, 165 reviews were published containing recommendations for or against HES use. From the 1990s onwards, favorable reviews increased from two to eight per year and HES’s share of the artificial colloid market tripled from 20 to 60 %. Only 7 % (12/165) of these reviews of HES use contained meta-analyses; these 7 % had higher Overview Quality Assessment Questionnaire (OQAQ) scores [median (range) 6.5 (3–7)] than reviews without meta-analysis [2 (1–4); p < 0.001]. The rates of recommending against HES use are 83 % (10/12) in meta-analyses and 20 % (31/153) in reviews without meta-analysis (p < 0.0001). Fourteen authors published the majority (70/124) of positive reviews, and ten of these 14 had or have since developed a pCOI with various manufacturers of HES. Conclusions Low-quality HES reviews reached different conclusions than high-quality meta-analyses from independent entities, such as Cochrane Reviews. The majority of these low-quality positive HES reviews were written by a small group of authors, most of whom had or have since established ties to industry. The proliferation of positive HES reviews has been associated with increased utilization of an expensive therapy despite the lack of evidence for meaningful clinical benefit and increased risks. Clinicians need to be more informed that marketing efforts are potentially influencing scientific literature. PMID:22790311

  16. The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt.

    PubMed

    Kay, Sophie K; Harrington, Heather A; Shepherd, Sarah; Brennan, Keith; Dale, Trevor; Osborne, James M; Gavaghan, David J; Byrne, Helen M

    2017-02-28

    The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its

  17. The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

    PubMed Central

    Harrington, Heather A.; Dale, Trevor; Gavaghan, David J.

    2017-01-01

    The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch’s interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain

  18. Inflammatory Kidney and Liver Tissue Response to Different Hydroxyethylstarch (HES) Preparations in a Rat Model of Early Sepsis

    PubMed Central

    Schimmer, Ralph C.; Urner, Martin; Voigtsberger, Stefanie; Booy, Christa; Roth Z’Graggen, Birgit; Beck-Schimmer, Beatrice; Schläpfer, Martin

    2016-01-01

    Background Tissue hypoperfusion and inflammation in sepsis can lead to organ failure including kidney and liver. In sepsis, mortality of acute kidney injury increases by more than 50%. Which type of volume replacement should be used is still an ongoing debate. We investigated the effect of different volume strategies on inflammatory mediators in kidney and liver in an early sepsis model. Material and Methods Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) and assigned to three fluid replenishment groups. Animals received 30mL/kg of Ringer’s lactate (RL) for 2h, thereafter RL (75mL/kg), hydroxyethyl starch (HES) balanced (25mL/kg), containing malate and acetate, or HES saline (25mL/kg) for another 2h. Kidney and liver tissue was assessed for inflammation. In vitro rat endothelial cells were exposed to RL, HES balanced or HES saline for 2h, followed by stimulation with tumor necrosis factor-α (TNF-α) for another 4h. Alternatively, cells were exposed to malate, acetate or a mixture of malate and acetate, reflecting the according concentration of these substances in HES balanced. Pro-inflammatory cytokines were determined in cell supernatants. Results Cytokine mRNA in kidney and liver was increased in CLP animals treated with HES balanced compared to RL, but not after application of HES saline. MCP-1 was 3.5fold (95% CI: 1.3, 5.6) (p<0.01) and TNF-α 2.3fold (95% CI: 1.2, 3.3) (p<0.001) upregulated in the kidney. Corresponding results were seen in liver tissue. TNF-α-stimulated endothelial cells co-exposed to RL expressed 3529±1040pg/mL MCP-1 and 59±23pg/mL CINC-1 protein. These cytokines increased by 2358pg/mL (95% CI: 1511, 3204) (p<0.001) and 29pg/ml (95% CI: 14, 45) (p<0.01) respectively when exposed to HES balanced instead. However, no further upregulation was observed with HES saline. PBS supplemented with acetate increased MCP-1 by 1325pg/mL (95% CI: 741, 1909) (p<0.001) and CINC-1 by 24pg/mL (95% CI: 9, 38) (p<0

  19. TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells.

    PubMed

    Lee, Sung Hee; Hong, Hannah S; Liu, Zi Xiao; Kim, Reuben H; Kang, Mo K; Park, No-Hee; Shin, Ki-Hyuk

    2012-07-20

    Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.

  20. Hes1 is required for the development of the superior cervical ganglion of sympathetic trunk and the carotid body.

    PubMed

    Kameda, Yoko; Saitoh, Takayoshi; Nemoto, Noriko; Katoh, Tokio; Iseki, Sachiko

    2012-08-01

    Hes1 gene represses the expression of proneural basic helix-loop-helix (bHLH) factor Mash1, which is essential for the differentiation of the sympathetic ganglia and carotid body glomus cells. The sympathetic ganglia, carotid body, and common carotid artery in Wnt1-Cre/R26R double transgenic mice were intensely labeled by X-gal staining, i.e., the neural crest origin. The deficiency of Hes1 caused severe hypoplasia of the superior cervical ganglion (SCG). At embryonic day (E) 17.5-E18.5, the volume of the SCG in Hes1 null mutants was reduced to 26.4% of the value in wild-type mice. In 4 of 30 cases (13.3%), the common carotid artery derived from the third arch artery was absent in the null mutants, and the carotid body was not formed. When the common carotid artery was retained, the organ grew in the wall of the third arch artery and glomus cell precursors were provided from the SCG in the null mutants as well as in wild-types. However, the volume of carotid body in the null mutants was only 52.5% of the value in wild-types at E17.5-E18.5. These results suggest that Hes1 plays a critical role in regulating the development of neural crest derivatives in the mouse cervical region.

  1. Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice

    PubMed Central

    Hosokawa, Shinichi; Furuyama, Kenichiro; Horiguchi, Masashi; Aoyama, Yoshiki; Tsuboi, Kunihiko; Sakikubo, Morito; Goto, Toshihiko; Hirata, Koji; Tanabe, Wataru; Nakano, Yasuhiro; Akiyama, Haruhiko; Kageyama, Ryoichiro; Uemoto, Shinji; Kawaguchi, Yoshiya

    2015-01-01

    In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions. PMID:25687338

  2. The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia.

    PubMed

    Espinosa, Lluis; Cathelin, Severine; D'Altri, Teresa; Trimarchi, Thomas; Statnikov, Alexander; Guiu, Jordi; Rodilla, Veronica; Inglés-Esteve, Julia; Nomdedeu, Josep; Bellosillo, Beatriz; Besses, Carles; Abdel-Wahab, Omar; Kucine, Nicole; Sun, Shao-Cong; Song, Guangchan; Mullighan, Charles C; Levine, Ross L; Rajewsky, Klaus; Aifantis, Iannis; Bigas, Anna

    2010-09-14

    It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.

  3. The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

    PubMed Central

    Espinosa, Lluis; Cathelin, Severine; D’Altri, Teresa; Trimarchi, Thomas; Statnikov, Alexander; Guiu, Jordi; Rodilla, Veronica; Inglés-Esteve, Julia; Nomdedeu, Josep; Bellosillo, Beatriz; Besses, Carles; Abdel-Wahab, Omar; Kucine, Nicole; Sun, Shao-Cong; Song, Guangchan; Mullighan, Charles C.; Levine, Ross L.; Rajewsky, Klaus; Aifantis, Iannis; Bigas, Anna

    2010-01-01

    SUMMARY It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo. PMID:20832754

  4. Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells.

    PubMed

    Lee, Jung Bok; Werbowetski-Ogilvie, Tamra E; Lee, Jong-Hee; McIntyre, Brendan A S; Schnerch, Angelique; Hong, Seok-Ho; Park, In-Hyun; Daley, George Q; Bernstein, Irwin D; Bhatia, Mickie

    2013-08-15

    Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and small interfering RNA to Notch receptors we have demonstrated that Notch1, but not Notch2, activation induced hairy and enhancer of split 1 (HES1) expression and generation of committed hematopoietic progenitors. Using gain- and loss-of-function approaches, this was shown to be attributed to Notch-signaling regulation through HES1, which dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs endothelial fate specification.

  5. Discovery of HeLa Cell Contamination in HES Cells: Call for Cell Line Authentication in Reproductive Biology Research.

    PubMed

    Kniss, Douglas A; Summerfield, Taryn L

    2014-08-01

    Continuous cell lines are used frequently in reproductive biology research to study problems in early pregnancy events and parturition. It has been recognized for 50 years that many mammalian cell lines contain inter- or intraspecies contaminations with other cells. However, most investigators do not routinely test their culture systems for cross-contamination. The most frequent contributor to cross-contamination of cell lines is the HeLa cell isolated from an aggressive cervical adenocarcinoma. We report on the discovery of HeLa cell contamination of the human endometrial epithelial cell line HES isolated in our laboratory. Short tandem repeat analysis of 9 unique genetic loci demonstrated molecular identity between HES and HeLa cells. In addition, we verified that WISH cells, isolated originally from human amnion epithelium, were also contaminated with HeLa cells. Inasmuch as our laboratory did not culture HeLa cells at the time of HES cell derivations, the source of contamination was the WISH cell line. These data highlight the need for continued diligence in authenticating cell lines used in reproductive biology research.

  6. Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats

    PubMed Central

    Xu, Xiao; Sun, Xin; Hu, Xue-Song; Zhuang, Yan; Liu, Yue-Chen; Meng, Hao; Miao, Lin; Yu, He; Luo, Shu-Jin

    2016-01-01

    Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits. PMID:27560986

  7. Delta–Notch—and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors

    PubMed Central

    Fischer, Andreas; Gessler, Manfred

    2007-01-01

    Hes and Hey genes are the mammalian counterparts of the Hairy and Enhancer-of-split type of genes in Drosophila and they represent the primary targets of the Delta–Notch signaling pathway. Hairy-related factors control multiple steps of embryonic development and misregulation is associated with various defects. Hes and Hey genes (also called Hesr, Chf, Hrt, Herp or gridlock) encode transcriptional regulators of the basic helix-loop-helix class that mainly act as repressors. The molecular details of how Hes and Hey proteins control transcription are still poorly understood, however. Proposed modes of action include direct binding to N- or E-box DNA sequences of target promoters as well as indirect binding through other sequence-specific transcription factors or sequestration of transcriptional activators. Repression may rely on recruitment of corepressors and induction of histone modifications, or even interference with the general transcriptional machinery. All of these models require extensive protein–protein interactions. Here we review data published on protein–protein and protein–DNA interactions of Hairy-related factors and discuss their implications for transcriptional regulation. In addition, we summarize recent progress on the identification of potential target genes and the analysis of mouse models. PMID:17586813

  8. Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats.

    PubMed

    Xu, Xiao; Sun, Xin; Hu, Xue-Song; Zhuang, Yan; Liu, Yue-Chen; Meng, Hao; Miao, Lin; Yu, He; Luo, Shu-Jin

    2016-08-25

    Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits.

  9. Regulation of the Notch target gene Hes-1 by TGF{alpha} induced Ras/MAPK signaling in human neuroblastoma cells

    SciTech Connect

    Stockhausen, Marie-Therese; Sjoelund, Jonas; Axelson, Hakan . E-mail: hakan.axelson@molmed.mas.lu.se

    2005-10-15

    Ras and Notch signaling have recently been shown to cooperate in the maintenance of neoplastic transformation. Here, we show that TGF{alpha}, a known activator of Ras signaling, can drive cell proliferation and at the same time induce the expression of the Notch target Hes-1 in the neuroblastoma cell line SK-N-BE(2)c. The up-regulation of Hes-1 occurred both at the transcriptional and protein levels and by use of EGFR and MEK inhibitors we could show that the Hes-1 response was dependent on activation of the MAP kinase ERK. Blocking Notch activation by {gamma}-secretase inhibition did not profoundly affect the Hes-1 levels, neither in untreated nor in TGF{alpha} treated cells. The up-regulation of Hes-1 was associated with down-regulation of its pro-neuronal target gene Hash-1. Taken together, these results show that TGF{alpha} is a potent mitogen of neuroblastoma cells and suggest a connection between activation of ERK and Hes-1, thus providing a link between the Ras and Notch signaling pathways.

  10. The Evaluation of Hydroxyethyl Starch (6% HES 130/0.4) Solution’s Potential Preventive Effects on Coagulation Status in Women with Gynecologic Malignancies Using Rotation Thromboelastography

    PubMed Central

    Akay, Meltem Olga; Bilir, Ayten; Öge, Tufan; Kuş, Gökhan; Mutlu, Fezan Şahin

    2014-01-01

    Objective: The aim of this study was to determine the effects of in vitro hemodilution with 6% hydroxyethyl starch (HES) 130/0.4 solution on the coagulation status of women with gynecologic malignancies by using rotation thromboelastogram (ROTEM®). Materials and Methods: Twenty-two patients with gynecological tumors scheduled for anesthesia were enrolled. Blood samples were diluted by 20% with 6% HES (130/0.4) solution. Results: In the INTEM assay, clotting time (CT) (p<0.01) and clot formation time (CFT) (p<0.001) were significantly increased and maximum maximum clot formation (MCF) (p< 0.001) was significantly decreased in HES hemodilution compared with the undiluted control samples. In the EXTEM assay, there was a similar significant increase in increase in CFT (p<0.01) and a decrease in maximum a decrease in MCF (p<0.01) in HES hemodilution when compared with control samples. Conclusion: HES 130/0.4 solution causes significant hypocoagulable changes in the thromboelastographic profile of gynecologic cancer patients in vitro. PMID:25330518

  11. Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1.

    PubMed

    Keohane, Aoife; Ryan, Sinead; Maloney, Eimer; Sullivan, Aideen M; Nolan, Yvonne M

    2010-01-01

    Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1.

  12. RNAi for contactin 2 inhibits proliferation of U87-glioma stem cells by downregulating AICD, EGFR, and HES1

    PubMed Central

    Guo, Yang; Zhang, Peidong; Zhang, Hongtian; Zhang, Peng; Xu, Ruxiang

    2017-01-01

    Glioblastoma is the most common form of malignant brain tumors and has a poor prognosis. Glioma stem cells (GSCs) are thought to be responsible for the aberrant proliferation and invasion. Targeting the signaling pathways that promote proliferation in GSCs is one of the strategies for glioma treatment. In this study, we found increased expression of contactin 2 (CNTN2) and amyloid β precursor protein (APP) in U87-derived GSCs (U87-GSCs). RNA interference (RNAi) for CNTN2 downregulated the expression of APP intracellular domain (AICD), which is the proteolytic product of APP. Treatment with CNTN2 RNAi inhibited the proliferation of U87-GSCs. CNTN2 RNAi decreased the expression of epidermal growth factor receptor and HES1, which are potential targets of AICD. In summary, inhibition of the CNTN2/APP signaling pathway may repress the proliferation in U87-GSCs via downregulating the expression of HES1 and epidermal growth factor receptor. CNTN2/APP/AICD signaling pathway plays an important role in U87 glial tumorigenesis. Further studies are warranted to elucidate the role of these signaling pathways in other sources of GSCs. Depending on their role in proliferation in other sources of GSCs, members of the CNTN2/APP/AICD signaling pathway may provide novel targets for the development of therapy for glioblastomas. PMID:28243115

  13. The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease.

    PubMed

    Yamada, Yoshiyuki; Rothenberg, Marc E; Lee, Andrew W; Akei, Hiroko Saito; Brandt, Eric B; Williams, David A; Cancelas, Jose A

    2006-05-15

    Dysregulated tyrosine kinase activity by the Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRA) (F/P) fusion gene has been identified as a cause of clonal hypereosinophilic syndrome (HES), called F/P-positive chronic eosinophilic leukemia (CEL) in humans. However, transplantation of F/P-transduced hematopoietic stem cells/progenitors (F/P(+) HSCs/Ps) into mice results in a chronic myelogenous leukemia-like disease, which does not resemble HES. Because a subgroup of patients with HES show T-cell-dependent interleukin-5 (IL-5) overexpression, we determined if expression of the F/P fusion gene in the presence of transgenic T-cell IL-5 overexpression in mice induces HES-like disease. Mice that received a transplant of CD2-IL-5-transgenic F/P(+) HSC/Ps (IL-5Tg-F/P) developed intense leukocytosis, strikingly high eosinophilia, and eosinophilic infiltration of nonhematopoietic as well as hematopoietic tissues, a phenotype resembling human HES. The disease phenotype was transferable to secondary transplant recipients of a high cell dose, suggesting involvement of a short-term repopulating stem cell or an early myeloid progenitor. Induction of significant eosinophilia was specific for F/P since expression of another fusion oncogene, p210-BCR/ABL, in the presence of IL-5 overexpression was characterized by a significantly lower eosinophilia than IL-5Tg-F/P recipients. These results suggest that F/P is not sufficient to induce a HES/CEL-like disease but requires a second event associated with IL-5 overexpression.

  14. CDKN1C/P57 is regulated by the Notch target gene Hes1 and induces senescence in human hepatocellular carcinoma.

    PubMed

    Giovannini, Catia; Gramantieri, Laura; Minguzzi, Manuela; Fornari, Francesca; Chieco, Pasquale; Grazi, Gian Luca; Bolondi, Luigi

    2012-08-01

    CDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers, including hepatocellular carcinoma (HCC); however, little is known regarding the role of CDKN1C/P57 and its regulation in HCC. In this study, we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation, CDKN1C/P57 up-regulation, and reduced cell growth. In line with these data, we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector, Hes1. We found that the up-regulation of CDKN1C/P57 by cDNA transfection decreased tumor growth, as determined by growth curve, flow cytometry analysis, and cyclin D1 down-regulation, without affecting the apoptosis machinery. Indeed, the expression of Bax, Noxa, PUMA, BNIP(3), and cleaved caspase-3 was not affected by CDKN1C/P57 induction. Morphologically CDKN1C/p57-induced HCC cells became flat and lengthened in shape, accumulated the senescence-associated β-galactosidase marker, and increased P16 protein expression. Evaluation of senescence in cells depleted both for Hes1 and CDKN1C/P57 revealed that the senescent state really depends on the accumulation of CDKN1C/p57. Finally, we validated our in vitro results in primary HCCs, showing that Hes1 protein expression inversely correlates with CDKN1C/P57 mRNA levels. In addition, reduced Hes1 protein expression is accompanied by a shorter time to recurrence after curative resection, suggesting that Hes1 may represent a biomarker for prediction of patients with poor prognosis.

  15. Effects of 10% hydroxyethyl starch (HES 200/0.5) solution in intraoperative fluid therapy management of horses undergoing elective surgical procedures.

    PubMed

    Brünisholz, H P; Schwarzwald, C C; Bettschart-Wolfensberger, R; Ringer, S K

    2015-12-01

    The aim of the present study was to investigate the effect of pentastarch on colloid osmotic pressure (COP) and cardiopulmonary function during and up to 24 h after anaesthesia in horses. Twenty-five systemically healthy horses were anaesthetised using isoflurane-medetomidine balanced anaesthesia. Twelve were assigned to treatment with hydroxyethyl starch (HES) (H group) and 13 to no HES (NH group). In the H group, 6 mL/kg of pentastarch 10% HES (200/0.5) was infused over 1 h starting 30 min after induction of anaesthesia. Horses of the NH group received an equal amount of lactated Ringer's solution (LRS). COP and blood biochemical, cardiopulmonary and anaesthesia-related variables were measured at different time points before and after treatment. Pentastarch was effective in correcting the decrease in COP observed with LRS administration. No differences between treatments were detected for blood glucose, lactate, total proteins and electrolytes. Packed cell volume was lower with the H group immediately after finishing HES-administration and for an additional 30 min. In all horses, all blood biochemical variables other than lactate returned to normal after 12 h. No clinically relevant differences between treatments were detected for cardiopulmonary variables, although 23.1% of the NH-horses needed rescue-HES to maintain cardiovascular function, while none of the H-horses needed additional colloids. Overall, 6 mL/kg HES (200/0.5) was found to be effective in maintaining COP during anaesthesia in systemically healthy horses. Intermediate and long-term effects were below the limit of detection. The potentially beneficial effects on cardiovascular function need further investigation, especially in critically ill horses.

  16. The interference of Notch1 target Hes1 affects cell growth, differentiation and invasiveness of glioblastoma stem cells through modulation of multiple oncogenic targets.

    PubMed

    Cenciarelli, Carlo; Marei, Hany E; Zonfrillo, Manuela; Casalbore, Patrizia; Felsani, Armando; Giannetti, Stefano; Trevisi, Gianluca; Althani, Asma; Mangiola, Annunziato

    2017-02-02

    The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.

  17. Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression.

    PubMed

    Takata, Takehiko; Ishikawa, Fuyuki

    2003-01-31

    The Hairy-related bHLH proteins function as transcriptional repressors in most cases and play important roles in diverse aspects of metazoan development. Recently, it was shown that the Drosophila bHLH repressor proteins, Hairy and Deadpan, bind to and function with the NAD(+)-dependent histone deacetylase, Sir2. Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo. Moreover, using the reporter assay, we show that both SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions mediated by these bHLH repressors. These results indicate that the molecular association between bHLH proteins and Sir2-related proteins is conserved among metazoans, from Drosophila to human, and suggest that the Sir2-bHLH interaction also plays important roles in human cells.

  18. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

    PubMed Central

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-01-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies. PMID:24737870

  19. The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance

    PubMed Central

    Schreck, Karisa C.; Taylor, Pete; Marchionni, Luigi; Gopalakrishnan, Vidya; Bar, Eli E.; Gaiano, Nicholas; Eberhart, Charles G.

    2010-01-01

    Purpose Multiple developmental pathways including Notch, Hedgehog, and Wnt are active in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating a different one. We investigated whether brain tumors show resistance to therapies against Notch, and whether targeting multiple pathways simultaneously would kill brain tumor cells more effectively than monotherapy. Experimental Design We used GBM neurosphere lines to investigate the effects of a gamma-secretase inhibitor (MRK-003) on tumor growth, and chromatin immunoprecipitation (ChIP) to study the regulation of other genes by Notch targets. We also evaluated the effect of combined therapy with a Hedgehog inhibitor (cyclopamine) in GBM and medulloblastoma lines, and primary human GBM cultures. Results GBM cells are at least partially resistant to long-term MRK-003 treatment, despite ongoing Notch pathway suppression, and show concomitant upregulation of Wnt and Hedgehog activity. The Notch target Hes1, a repressive transcription factor, bound the Gli1 first intron, and may inhibit its expression. Similar results were observed in a melanoma-derived cell line. Targeting Notch and Hedgehog simultaneously induced apoptosis, decreased cell growth, and inhibited colony-forming ability more dramatically than monotherapy. Low-passage neurospheres isolated from freshly resected human GBMs were also highly susceptible to co-inhibition of the two pathways, indicating that targeting multiple developmental pathways can be more effective than monotherapy at eliminating glioblastoma-derived cells. Conclusion Notch may directly suppress Hedgehog via Hes1 mediated inhibition of Gli1 transcription, and targeting both pathways simultaneously may be more effective at eliminating GBMs cells. PMID:21169257

  20. Effect of rapid set binder on early strength and permeability of HES latex modified road repair pre-packed concrete

    NASA Astrophysics Data System (ADS)

    Han, J. W.; Lee, S. K.; Yu, C.; Park, C. G.

    2015-12-01

    The early strength development characteristics and permeability resistance of high early strength (HES) pre-packed road repair concrete incorporating a rapid-set binder material were evaluated for emergency repairs to road pavement. The rapid-set binder is a mixture of rapid-set cement and silica sands whose fluidity improves with the addition of styrene butadiene latex (latex). The resulting mixture has a compressive strength of 21 MPa or higher and a flexural strength of greater than 3.5 MPa after 4 hours, the maximum curing age allowed for emergency repair materials. This study examines the strength development properties and permeability resistance of HES latex-modified pre-packed road repair concrete using a rapid- set binder as a function of the latex-to-binder mixing ratio at values of 0.40, 0.33, 0.29 and 0.25. Both early strength development properties and permeability resistance increased as the ratio of latex to rapid-set binder decreased. The mixture showed a compressive strength of 21 MPa or higher after 4 hours, which is the design standard of emergency repair concrete, only when this ratio was 0.29 or lower. A flexural strength of 3.5 MPa or greater was observed after hours only when this ratio was 0.33 or lower. The standard for permeability resistance, less than 2,000 C of chloride after 7 days of curing, was satisfied by all ratios. The ratio of latex to rapid-set binder satisfying all of the conditions for an emergency road repair material was 0.29 or less.

  1. Aberrant expression of Notch1, HES1, and DTX1 genes in glioblastoma formalin-fixed paraffin-embedded tissues.

    PubMed

    Narayanappa, Rajeswari; Rout, Pritilata; Aithal, Madhuri G S; Chand, Ashis Kumar

    2016-05-01

    Glioblastoma is the most common malignant brain tumor accounting for more than 54 % of all gliomas. Despite aggressive treatments, median survival remains less than 1 year. This might be due to the unavailability of effective molecular diagnostic markers and targeted therapy. Thus, it is essential to discover molecular mechanisms underlying disease by identifying dysregulated pathways involved in tumorigenesis. Notch signaling is one such pathway which plays an important role in determining cell fates. Since it is found to play a critical role in many cancers, we investigated the role of Notch genes in glioblastoma with an aim to identify biomarkers that can improve diagnosis. Using real-time PCR, we assessed the expression of Notch genes including receptors (Notch1, Notch2, Notch3, and Notch4), ligands (JAG1, JAG2, and DLL3), downstream targets (HES1 and HEY2), regulator Deltex1 (DTX1), inhibitor NUMB along with transcriptional co-activator MAML1, and a component of gamma-secretase complex APH1A in 15 formalin-fixed paraffin-embedded (FFPE) patient samples. Relative quantification was done by the 2(-ΔΔCt) method; the data are presented as fold change in gene expression normalized to an internal control gene and relative to the calibrator. The data revealed aberrant expression of Notch genes in glioblastoma compared to normal brain. More than 85 % of samples showed high Notch1 (P = 0.0397) gene expression and low HES1 (P = 0.011) and DTX1 (P = 0.0001) gene expression. Our results clearly show aberrant expression of Notch genes in glioblastoma which can be used as putative biomarkers together with histopathological observation to improve diagnosis, therapeutic strategies, and patient prognosis.

  2. Murine leukemia provirus-mediated activation of the Notch1 gene leads to induction of HES-1 in a mouse T lymphoma cell line, DL-3.

    PubMed

    Lee, J S; Ishimoto, A; Honjo, T; Yanagawa, S

    1999-07-23

    Constitutive activation of Notch signaling is known to be associated with tumorigenesis. In a mouse T lymphoma cell line, DL-3, we found that a murine leukemia provirus was inserted in the Notch1 locus, which led to marked expression of a virus-Notch1 fusion mRNA encoding an intracellular portion of the Notch1 protein. Furthermore, expression and nuclear localization of this constitutively active form of Notch1 protein were confirmed. Corresponding to this finding, the transcription of the hairy/enhancer of split (HES-1) gene, a known target of Notch1 signaling, was elevated in this cell line. A potential role for overexpressed HES-1 in the development of the lymphoma was discussed.

  3. Notch-Hes-1 axis controls TLR7-mediated autophagic death of macrophage via induction of P62 in mice with lupus

    PubMed Central

    Li, Xiaojing; Liu, Fei; Zhang, Xuefang; Shi, Guoping; Ren, Jing; Ji, Jianjian; Ding, Liang; Fan, Hongye; Dou, Huan; Hou, Yayi

    2016-01-01

    The increased death of macrophages has been considered as a pathogenic factor for systemic lupus erythematosus (SLE), and dysfunction of autophagy may contribute to improper cell death. However, the effect of autophagy on macrophage during the pathogenesis of SLE is still unclear. Here we found that the death rate and autophagy level of macrophages significantly increased in MRL/lpr lupus-prone mice. Activation of toll-like receptor 7 (TLR7) triggered macrophage death in an autophagy-dependent but caspase-independent way in vitro. Moreover, P62/SQSTM1 is thought to have an essential role in selective autophagy. We also demonstrated that P62/SQSTM1 was required for TLR7-induced autophagy, and knockdown of P62 suppressed R848-induced cell death and LC3II protein accumulation. As an important mediator for cell–cell communication, Notch signaling is responsible for cell-fate decisions. Our results showed that activation of TLR7 also upregulated the expression of Notch1, especially its downstream target gene Hairy and enhancer of split 1 (Hes-1) in macrophages. Of note, we found that Hes-1, as a transcriptional factor, controlled TLR7-induced autophagy by regulating P62 expression. Furthermore, to confirm the above results in vivo, TLR7 agonist imiquimod (IMQ)-induced lupus mouse model was prepared. Splenic macrophages from IMQ-treated mice exhibited increased autophagy and cell death as well as enhanced expressions of Notch1 and Hes-1. Our results indicate that Notch1-Hes-1 signaling controls TLR7-induced autophagic death of macrophage via regulation of P62 in mice with lupus. PMID:27537524

  4. NF-κB-inducing kinase (NIK) prevents the development of hypereosinophilic syndrome (HES)-like disease in mice independent of IKKα activation

    PubMed Central

    Häcker, Hans; Chi, Liying; Rehg, Jerold E.; Redecke, Vanessa

    2012-01-01

    Immune cell-mediated tissue injury is the common feature of different inflammatory diseases, yet the pathogenetic mechanisms and cell types involved vary significantly. Hypereosinophilic Syndrome (HES) represents a group of inflammatory diseases that are characterized by increased numbers of pathogenic eosinophilic granulocytes in the peripheral blood and diverse organs. Based on clinical and laboratory findings, various forms of HES have been defined, yet the molecular mechanism and potential signaling pathways that drive eosinophil expansion remain largely unknown. Here we show that mice deficient of the serine/ threonine-specific protein kinase NF-κB inducing kinase (NIK) develop a HES-like disease, reflected by progressive blood and tissue eosinophilia, tissue injury and premature death at around 25–30 weeks of age. Similar to the lymphocytic form of HES, CD4+ T-cells from NIK-deficient mice express increased levels of T-helper 2 (Th2)-associated cytokines, and eosinophilia and survival of NIK deficient mice could completely be prevented by genetic ablation of CD4+ T-cells. Experiments based on bone marrow chimeric mice, however, demonstrated that inflammation in NIK-deficient mice depended on radiation-resistant tissues, implicating that NIK-deficient immune cells mediate inflammation in a non-autonomous manner. Surprisingly, disease development was independent of NIKs known function as IkappaB kinase (IKK)-α kinase, as mice carrying a mutation in the activation loop of IKKα, which is phosphorylated by NIK, did not develop inflammatory disease. Our data show that NIK activity in non-hematopoietic cells controls Th2-cell development and prevents eosinophil-driven inflammatory disease, most likely using a signaling pathway that operates independent of the known NIK substrate IKKα. PMID:22474019

  5. Minor physical anomalies in bipolar I and bipolar II disorders - Results with the Méhes Scale.

    PubMed

    Berecz, Hajnalka; Csábi, Györgyi; Jeges, Sára; Herold, Róbert; Simon, Maria; Halmai, Tamás; Trixler, Dániel; Hajnal, András; Tóth, Ákos Levente; Tényi, Tamás

    2017-03-01

    Minor physical anomalies (MPAs) are external markers of abnormal brain development, so the more common appearence of these signs among bipolar I and bipolar II patients can confirm the possibility of a neurodevelopmental deficit in these illnesses. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in patients with bipolar I and - first in literature - with bipolar II disorders compared to matched healthy control subjects. Using a list of 57 minor physical anomalies (the Méhes Scale), 30 bipolar I and 30 bipolar II patients, while as a comparison 30 matched healthy control subjects were examined. Significant differences were detected between the three groups comparing the total number of minor physical anomalies, minor malformations and phenogenetic variants and in the cases of the ear and the mouth regions. The individual analyses of the 57 minor physical anomalies by simultaneous comparison of the three groups showed, that in the cases of furrowed tongue and high arched palate were significant differences between the three groups. The results can promote the concept, that a neurodevelopmental deficit may play a role in the etiology of both bipolar I and bipolar II disorders.

  6. Data compression studies for NOAA Hyperspectral Environmental Suite (HES) using 3D integer wavelet transforms with 3D set partitioning in hierarchical trees

    NASA Astrophysics Data System (ADS)

    Huang, Bormin; Huang, Hung-Lung; Chen, Hao; Ahuja, Alok; Baggett, Kevin; Schmit, Timothy J.; Heymann, Roger W.

    2004-02-01

    The next-generation NOAA/NESDIS GOES-R hyperspectral sounder, now referred to as the HES (Hyperspectral Environmental Suite), will have hyperspectral resolution (over one thousand channels with spectral widths on the order of 0.5 wavenumber) and high spatial resolution (less than 10 km). Hyperspectral sounder data is a particular class of data requiring high accuracy for useful retrieval of atmospheric temperature and moisture profiles, surface characteristics, cloud properties, and trace gas information. Hence compression of these data sets is better to be lossless or near lossless. Given the large volume of three-dimensional hyperspectral sounder data that will be generated by the HES instrument, the use of robust data compression techniques will be beneficial to data transfer and archive. In this paper, we study lossless data compression for the HES using 3D integer wavelet transforms via the lifting schemes. The wavelet coefficients are processed with the 3D set partitioning in hierarchical trees (SPIHT) scheme followed by context-based arithmetic coding. SPIHT provides better coding efficiency than Shapiro's original embedded zerotree wavelet (EZW) algorithm. We extend the 3D SPIHT scheme to take on any size of 3D satellite data, each of whose dimensions need not be divisible by 2N, where N is the levels of the wavelet decomposition being performed. The compression ratios of various kinds of wavelet transforms are presented along with a comparison with the JPEG2000 codec.

  7. Nonsteroidal anti-inflammatory drugs suppress cancer stem cells via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1 and activating PPARG in colorectal cancer.

    PubMed

    Moon, Chang Mo; Kwon, Ji-Hee; Kim, Ji Suk; Oh, Sun-Hee; Jin Lee, Kyoung; Park, Jae Jun; Pil Hong, Sung; Cheon, Jae Hee; Kim, Tae Il; Kim, Won Ho

    2014-02-01

    Cancer stem cells (CSCs) play a pivotal role in cancer relapse or metastasis. We investigated the CSC-suppressing effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and the relevant mechanisms in colorectal cancer. We measured the effect of NSAIDs on CSC populations in Caco-2 or SW620 cells using colosphere formation and flow cytometric analysis of PROM1 (CD133)(+) CD44(+) cells after indomethacin treatment with/without prostaglandin E2 (PGE2) or peroxisome proliferator-activated receptor γ (PPARG) antagonist, and examined the effect of indomethacin on transcriptional activity and protein expression of NOTCH/HES1 and PPARG. These effects of indomethacin were also evaluated in a xenograft mouse model. NSAIDs (indomethacin, sulindac and aspirin), celecoxib, γ-secretase inhibitor and PPARG agonist significantly decreased the number of colospheres formation compared to controls. In Caco-2 and SW620 cells, compared to controls, PROM1 (CD133)(+) CD44(+) cells were significantly decreased by indomethacin treatment, and increased by 5-fluorouracil (5-FU) treatment. This 5-FU-induced increase of PROM1 (CD133)(+) CD44(+) cells was significantly attenuated by combination with indomethacin. This CSC-inhibitory effect of indomethacin was reversed by addition of PGE2 and PPARG antagonist. Indomethacin significantly decreased CBFRE and increased PPRE transcriptional activity and their relative protein expressions. In xenograft mouse experiments using 5-FU-resistant SW620 cells, the 5-FU treatment combined with indomethacin significantly reduced tumor growth, compared to 5-FU alone. In addition, treatment of indomethacin alone or combination of 5-FU and indomethacin decreased the expressions of PROM1 (CD133), CD44, PTGS2 (cyclooxygenase 2) and HES1, and increased PPARG expression. NSAIDs could selectively reduce the colon CSCs and suppress 5-FU-induced increase of CSCs via inhibiting PTGS2 (cyclooxygenase 2) and NOTCH/HES1, and activating PPARG.

  8. Identification of a new clock-related element EL-box involved in circadian regulation by BMAL1/CLOCK and HES1.

    PubMed

    Ueshima, Taichi; Kawamoto, Takeshi; Honda, Kiyomasa K; Noshiro, Mitsuhide; Fujimoto, Katsumi; Nakao, Sanae; Ichinose, Natsuhiro; Hashimoto, Seiichi; Gotoh, Osamu; Kato, Yukio

    2012-12-01

    Several cis-acting elements play critical roles in maintaining circadian expression of clock and clock-controlled genes. Using in silico analysis, we identified 10 sequence motifs that are correlated with the circadian phases of gene expression in the cartilage. One of these motifs, an E-box-like clock-related element (EL-box; GGCACGAGGC), can mediate BMAL1/CLOCK-induced transcription, which is typically regulated through an E-box or E'-box. Expression of EL-box-containing genes, including Ank, Dbp, and Nr1d1 (Rev-erbα), was induced by BMAL1/CLOCK or BMAL1/NPAS2. Compared with the E-box, the EL-box elements had distinct responsiveness to DEC1, DEC2, and HES1: suppressive actions of DEC1 and DEC2 on the EL-box were less potent than those on the E-box. HES1, which is known to bind to the N-box (CACNAG), suppressed enhancer activity of the EL-box, but not the E-box. In the Dbp promoter, an EL-box worked cooperatively with a noncanonical (NC) E-box to mediate BMAL1/CLOCK actions. These findings suggest that in addition to known clock elements, the EL-box element may contribute to circadian regulation of clock and clock-controlled genes.

  9. Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation

    PubMed Central

    Phillips, Nick E; Manning, Cerys S; Pettini, Tom; Biga, Veronica; Marinopoulou, Elli; Stanley, Peter; Boyd, James; Bagnall, James; Paszek, Pawel; Spiller, David G; White, Michael RH; Goodfellow, Marc; Galla, Tobias; Rattray, Magnus; Papalopulu, Nancy

    2016-01-01

    Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted. DOI: http://dx.doi.org/10.7554/eLife.16118.001 PMID:27700985

  10. Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression

    PubMed Central

    2014-01-01

    Background PTOV1 is an adaptor protein with functions in diverse processes, including gene transcription and protein translation, whose overexpression is associated with a higher proliferation index and tumor grade in prostate cancer (PC) and other neoplasms. Here we report its interaction with the Notch pathway and its involvement in PC progression. Methods Stable PTOV1 knockdown or overexpression were performed by lentiviral transduction. Protein interactions were analyzed by co-immunoprecipitation, pull-down and/or immunofluorescence. Endogenous gene expression was analyzed by real time RT-PCR and/or Western blotting. Exogenous promoter activities were studied by luciferase assays. Gene promoter interactions were analyzed by chromatin immunoprecipitation assays (ChIP). In vivo studies were performed in the Drosophila melanogaster wing, the SCID-Beige mouse model, and human prostate cancer tissues and metastasis. The Excel package was used for statistical analysis. Results Knockdown of PTOV1 in prostate epithelial cells and HaCaT skin keratinocytes caused the upregulation, and overexpression of PTOV1 the downregulation, of the Notch target genes HEY1 and HES1, suggesting that PTOV1 counteracts Notch signaling. Under conditions of inactive Notch signaling, endogenous PTOV1 associated with the HEY1 and HES1 promoters, together with components of the Notch repressor complex. Conversely, expression of active Notch1 provoked the dismissal of PTOV1 from these promoters. The antagonist role of PTOV1 on Notch activity was corroborated in the Drosophila melanogaster wing, where human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed the effects of constitutively active Notch. PTOV1 was required for optimal in vitro invasiveness and anchorage-independent growth of PC-3 cells, activities counteracted by Notch, and for their efficient growth and metastatic spread in vivo. In prostate tumors, the overexpression of PTOV1 was associated with decreased expression

  11. Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter.

    PubMed

    Abdolazimi, Yassan; Stojanova, Zlatka; Segil, Neil

    2016-03-01

    Determination of cell fate within the prosensory domain of the developing cochlear duct relies on the temporal and spatial regulation of the bHLH transcription factor Atoh1. Auditory hair cells and supporting cells arise in a wave of differentiation that patterns them into discrete rows mediated by Notch-dependent lateral inhibition. However, the mechanism responsible for selecting sensory cells from within the prosensory competence domain remains poorly understood. We show in mice that rather than being upregulated in rows of cells, Atoh1 is subject to transcriptional activation in groups of prosensory cells, and that highly conserved sites for Hes/Hey repressor binding in the Atoh1 promoter are needed to select the hair cell and supporting cell fate. During perinatal supporting cell transdifferentiation, which is a model of hair cell regeneration, we show that derepression is sufficient to induce Atoh1 expression, suggesting a mechanism for priming the 3' Atoh1 autoregulatory enhancer needed for hair cell expression.

  12. Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aβ metabolism.

    PubMed

    Leal, María C; Surace, Ezequiel I; Holgado, María P; Ferrari, Carina C; Tarelli, Rodolfo; Pitossi, Fernando; Wisniewski, Thomas; Castaño, Eduardo M; Morelli, Laura

    2012-02-01

    Cerebral amyloid β (Aβ) accumulation is pathogenically associated with sporadic Alzheimer's disease (SAD). BACE-1 is involved in Aβ generation while insulin-degrading enzyme (IDE) partakes in Aβ proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular Aβ accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at -379/-372 and -310-303 from the first translation start site in the -575/-19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on Aβ metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD.

  13. Acid-Base and Electrolyte Status during Normovolemic Hemodilution with Succinylated Gelatin or HES-Containing Volume Replacement Solutions in Rats

    PubMed Central

    Teloh, Johanna K.; Ferenz, Katja B.; Petrat, Frank; Mayer, Christian; de Groot, Herbert

    2013-01-01

    Background In the past, several studies have compared different colloidal replacement solutions, whereby the focus was usually on the respective colloid. We therefore systematically studied the influence of the carrier solution’s composition of five approved colloidal volume replacement solutions (Gelafundin, Gelafusal, Geloplasma, Voluven and Volulyte) on acid-base as well as electrolyte status during and following acute severe normovolemic hemodilution. The solutions differed in the colloid used (succinylated gelatin vs. HES) and in the presence and concentration of metabolizable anions as well as in their electrolyte composition. Methods Anesthetized Wistar rats were subjected to a stepwise normovolemic hemodilution with one of the solutions until a final hematocrit of 10%. Subsequent to dilution (162 min), animals were observed for an additional period (150 min). During dilution and observation time blood gas analyses were performed eight times in total. Additionally, in the Voluven and Volulyte groups as well as in 6 Gelafundin animals, electrolyte concentrations, glucose, pH and succinylated gelatin were measured in urine and histopathological evaluation of the kidney was performed. Results All animals survived without any indications of injury. Although the employed solutions differed in their respective composition, comparable results in all plasma acid-base and electrolyte parameters studied were obtained. Plasma pH increased from approximately 7.28 to 7.39, the plasma K+ concentration decreased from circa 5.20 mM to 4.80-3.90 mM and the plasma Cl− concentration rose from approximately 105 mM to 111–120 mM. Urinary analysis revealed increased excretion of K+, H+ and Cl−. Conclusions The present data suggest that the carrier solution’s composition with regard to metabolizable anions as well as K+, Ca2+ only has a minor impact on acid-base and electrolyte status after application of succinylated gelatin or HES-containing colloidal volume

  14. Minor physical anomalies are more common among the first-degree unaffected relatives of schizophrenia patients - Results with the Méhes Scale.

    PubMed

    Hajnal, András; Csábi, Györgyi; Herold, Róbert; Jeges, Sára; Halmai, Tamás; Trixler, Dániel; Simon, Maria; Tóth, Ákos Levente; Tényi, Tamás

    2016-03-30

    Minor physical anomalies are external markers of abnormal brain development,so the more common appearance of these signs among the relatives of schizophrenia patients can confirm minor physical anomalies as intermediate phenotypes. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in the first-degree unaffected relatives of patients with schizophrenia compared to matched normal control subjects. Using a list of 57 minor physical anomalies (the Méhes Scale), 20 relatives of patients with the diagnosis of schizophrenia and as a comparison 20 matched normal control subjects were examined. Minor physical anomalies were more common in the head and mouth regions among the relatives of schizophrenia patients compared to normal controls. By the differentiation of minor malformations and phenogenetic variants, we have found that only phenogenetic variants were more common in the relatives of schizophrenia patients compared to the control group, however individual analyses showed, that one minor malformation (flat forehead) was more prevalent in the relative group. The results can promote the concept, that minor physical anomalies can be endophenotypic markers of the illness.

  15. An essential role for RAX homeoprotein and NOTCH-HES signaling in Otx2 expression in embryonic retinal photoreceptor cell fate determination.

    PubMed

    Muranishi, Yuki; Terada, Koji; Inoue, Tatsuya; Katoh, Kimiko; Tsujii, Toshinori; Sanuki, Rikako; Kurokawa, Daisuke; Aizawa, Shinichi; Tamaki, Yasuhiro; Furukawa, Takahisa

    2011-11-16

    The molecular mechanisms underlying cell fate determination from common progenitors in the vertebrate CNS remain elusive. We previously reported that the OTX2 homeoprotein regulates retinal photoreceptor cell fate determination. While Otx2 transactivation is a pivotal process for photoreceptor cell fate determination, its transactivation mechanism in the retina is unknown. Here, we identified an evolutionarily conserved Otx2 enhancer of ∼500 bp, named embryonic enhancer locus for photoreceptor Otx2 transcription (EELPOT), which can recapitulate initial Otx2 expression in the embryonic mouse retina. We found that the RAX homeoprotein interacts with EELPOT to transactivate Otx2, mainly in the final cell cycle of retinal progenitors. Conditional inactivation of Rax results in downregulation of Otx2 expression in vivo. We also showed that NOTCH-HES signaling negatively regulates EELPOT to suppress Otx2 expression. These results suggest that the integrated activity of cell-intrinsic and -extrinsic factors on EELPOT underlies the molecular basis of photoreceptor cell fate determination in the embryonic retina.

  16. Quality of water used during cage cultivation of rainbow trout (Oncorhynchus mykiss) in Bereket HES IV Dam Lake (Muğla, Turkey).

    PubMed

    Ozdemir, Nedim; Demirak, Ahmet; Keskin, Feyyaz

    2014-12-01

    A thorough investigation of the impact of rainbow trout (Oncorhynchus mykiss) cultivation on surface water quality in the area known as Bereket HES IV Dam Lake was conducted. Water samples were collected from October 2009 to June 2010 from four stations in the Dam Lake and analyzed for water temperature, pH, dissolved oxygen, electrical conductivity, nitrite nitrogen, nitrate nitrogen, and orthophosphate. Surface water quality was then evaluated based on the comparison of samples collected from three stations located near fish cages to those collected from a reference station outside the cultivation area as well as by the comparison with standards specified in the Water Pollution Registration Act. According to the Water Pollution Registration Act, the surface water quality of the Dam Lake was class I. Additionally, there were no significant differences in water quality within the Dam Lake among any of the sampling stations, including the reference station. Overall, these findings indicate that cage cultivation of rainbow trout may have a negative impact on the entire Dam Lake.

  17. HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44(+)/CD24(-/low) tumor-initiating subpopulation in basal-like breast cancer.

    PubMed

    So, Jae Young; Wahler, Joseph; Das Gupta, Soumyasri; Salerno, David M; Maehr, Hubert; Uskokovic, Milan; Suh, Nanjoo

    2015-04-01

    Tumor-initiating cells (also known as cancer stem cells) are the subpopulation of cells shown to be responsible for tumor initiation, maintenance and recurrence. In breast cancer, CD44(+)/CD24(-/low) cells were identified as tumor-initiating cells. We previously reported that a Gemini vitamin D analog, 1,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), reduced CD44(+)/CD24(-/low) cells in MCF10DCIS basal-like breast cancer cells. Since Notch has been identified as one of the key signaling pathways involved in breast cancer stem cells, the effect of BXL0124 on the Notch signaling pathway was investigated in breast cancer. The CD44(+)/CD24(-/low) subpopulation of MCF10DCIS cells showed elevated Notch1 signaling and increased cell proliferation compared to the CD44(+)/CD24(high) subpopulation. Treatment with the Gemini vitamin D analog BXL0124 decreased the level of activated Notch1 receptor. In addition, mRNA and protein levels of the Notch ligands, Jagged-1, Jagged-2 and DLL1, were significantly reduced by treatment with BXL0124, which was followed by repression of c-Myc, a key downstream target of Notch signaling. Interestingly, HES1, a known downstream target of Notch signaling, was rapidly induced by treatment with BXL0124. The inhibitory effect of BXL0124 on Notch signaling was reversed by knockdown of HES1. Overexpression of HES1 inhibited Notch1 signaling and reduced the CD44(+)/CD24(-/low) subpopulation, confirming a role of HES1 in Notch1 signaling. In conclusion, the Gemini vitamin D analog, BXL0124, represses the tumor-initiating subpopulation by HES1-mediated inhibition of Notch1 signaling. The present study demonstrates BXL0124 as a potent inhibitor of Notch signaling to target tumor-initiating cells in basal-like breast cancer. This article is part of a Special Issue entitled "17th Vitamin D Workshop".

  18. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress

    PubMed Central

    Zhang, Meng; Yu, Li-ming; Zhao, Hang; Zhou, Xuan-xuan; Yang, Qian; Song, Fan; Yan, Li; Zhai, Meng-en; Li, Bu-ying; Zhang, Bin; Jin, Zhen-xiao; Duan, Wei-xun; Wang, Si-wang

    2017-01-01

    2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg−1·d−1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1–1000 μmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis. PMID:28112174

  19. Methylprednisolone inhibits the proliferation and affects the differentiation of rat spinal cord-derived neural progenitor cells cultured in low oxygen conditions by inhibiting HIF-1α and Hes1 in vitro.

    PubMed

    Wang, Wenhao; Wang, Peng; Li, Shiyuan; Yang, Jiewen; Liang, Xinjun; Tang, Yong; Li, Yuxi; Yang, Rui; Wu, Yanfeng; Shen, Huiyong

    2014-09-01

    Although there is much controversy over the use of methylprednisolone (MP), it is one of the main drugs used in the treatment of acute spinal cord injury (SCI). The induction of the proliferation and differentiation of endogenous neural progenitor cells (NPCs) is considered a promising mode of treatment for SCI. However, the effects of MP on spinal cord-derived endogenous NPCs in a low oxygen enviroment remain to be delineated. Thus, the aim of this study was to investigate the potential effects of MP on NPCs cultured under low oxygen conditions in vitro and to elucidate the molecular mechanisms involved. Fetal rat spinal cord-derived NPCs were harvested and divided into 4 groups: 2 groups of cells cultured under normal oxygen conditions and treated with or without MP, and 2 groups incubated in 3% O2 (low oxygen) treated in a similar manner. We found that MP induced suppressive effects on NPC proliferation even under low oxygen conditions (3% O2). The proportion of nestin-positive NPCs decreased from 51.8±2.46% to 36.17±3.55% following the addition of MP and decreased more significantly to 27.20±2.68% in the cells cultured in 3% O2. In addition, a smaller number of glial fibrillary acidic protein (GFAP)-positive cells and a greater number of microtubule-associated protein 2 (MAP2)-positive cells was observed following the addition of MP under both normal (normoxic) and low oxygen (hypoxic) conditions. In response to MP treatment, hypoxia-inducible factor-1α (HIF-1α) and the Notch signaling pathway downstream protein, Hes1, but not the upstream Notch-1 intracelluar domain (NICD), were inhibited. After blocking NICD with a γ-secretase inhibitor (DAPT) MP still inhibited the expression of Hes1. Our results provide insight into the molecular mechanisms responsible for the MP-induced inhibition of proliferation and its effects on differentiation and suggest that HIF-1α and Hes1 play an important role in this effect.

  20. Hematology Expert System (HES) For Tonsillectomy/Adenoidectomy Patients

    NASA Astrophysics Data System (ADS)

    Pizzi, Nicolino J.; Kapoor, Sandhya; Gerrard, Jon M.

    1989-03-01

    The purpose of this expert system is to assess a predisposition to bleeding in a patient undergoing a tonsillectomy and/or adenoidectomy as may occur with patients who have certain blood conditions such as hemophilia and von Willebrand's disease. This goal is achieved by establishing a correlation between the patients' responses to a medical questionnaire and the relative quantities of blood lost during the operation.

  1. Technical Education in 2-Year Colleges. HES Survey Number 17.

    ERIC Educational Resources Information Center

    Burton, Lawrence; Celebuski, Carin A.

    Based on a January 1993 survey of 347 two-year colleges nationwide, this report describes aspects of engineering technology and science technology education and training in the nation's two-year colleges. Following introductory materials, the first chapter estimates the number of colleges offering engineering and science programs, reviews types of…

  2. Hydrogen Energy Storage (HES) and Power-to-Gas Economic Analysis; NREL (National Renewable Energy Laboratory)

    SciTech Connect

    Eichman, Joshua

    2015-07-30

    This presentation summarizes opportunities for hydrogen energy storage and power-to-gas and presents the results of a market analysis performed by the National Renewable Energy Laboratory to quantify the value of energy storage. Hydrogen energy storage and power-to-gas systems have the ability to integrate multiple energy sectors including electricity, transportation, and industrial. On account of the flexibility of hydrogen systems, there are a variety of potential system configurations. Each configuration will provide different value to the owner, customers and grid system operator. This presentation provides an economic comparison of hydrogen storage, power-to-gas and conventional storage systems. The total cost is compared to the revenue with participation in a variety of markets to assess the economic competitiveness. It is found that the sale of hydrogen for transportation or industrial use greatly increases competitiveness. Electrolyzers operating as demand response devices (i.e., selling hydrogen and grid services) are economically competitive, while hydrogen storage that inputs electricity and outputs only electricity have an unfavorable business case. Additionally, tighter integration with the grid provides greater revenue (e.g., energy, ancillary service and capacity markets are explored). Lastly, additional hours of storage capacity is not necessarily more competitive in current energy and ancillary service markets and electricity markets will require new mechanisms to appropriately compensate long duration storage devices.

  3. Hydrogen Energy Storage (HES) Activities at NREL; NREL (National Renewable Energy Laboratory)

    SciTech Connect

    Eichman, J.

    2015-04-21

    This presentation provides an overview of hydrogen and energy storage, including hydrogen storage pathways and international power-to-gas activities, and summarizes the National Renewable Energy Laboratory's hydrogen energy storage activities and results.

  4. Pu-nvt-tv E-ten-hes-se (Animal Friends).

    ERIC Educational Resources Information Center

    Dissemination and Assessment Center for Bilingual Education, Austin, TX.

    This reader in Maskoke (Muskokee) is developed to help elementary school children begin simple reading. Black-and-white drawings personifying animals illustrate the text. An English translation is included. (NCR)

  5. Transition metal HE`s - VII ACP. Progress report, August 1971--October 1971

    SciTech Connect

    Clink, G.L.

    1998-12-31

    Physical and physicochemical properties of hexaamminechromium III perchlorate (ACP) were investigated to determine its potentiality for HE and/or HE component application. Physicochemical properties obtained through investigation of isothermally aged ACP under conditions of various system and boundary restrictions (open and closed; 50 and 80 C; 0.65 and 0.85 g/cc) show the material to be substantially stable under these simulated isothermal storage conditions from a standpoint of infrared and DTA thermal pattern behavior and chemical analysis of aged residues. Spark sensitivity was 0.25 joules at 5 kv (by LASL type test) and impact sensitivity was about 23 and 14 cm on sandpaper (12A) and steel (12B), respectively.

  6. "HES Presidential Address": Confessions of a Positivist--How Foucault Led Me to a Meta-Narrative about School Desegregation

    ERIC Educational Resources Information Center

    Hutcheson, Philo

    2012-01-01

    This address derives from the intellectual contributions of young scholars and doctoral students, in faded memory of the author's life as a doctoral student and young scholar. This address has three purposes: (1) to define school desegregation; (2) to place--albeit briefly--that definition within the larger context of the literature on school…

  7. Low-energy R -matrix fits for the 6Li(d ,α ) 4HeS factor

    NASA Astrophysics Data System (ADS)

    Grineviciute, J.; Lamia, L.; Mukhamedzhanov, A. M.; Spitaleri, C.; La Cognata, M.

    2015-01-01

    Background: Information about the 6Li(d ,α ) 4He reaction rates of astrophysical interest can be obtained by extrapolating direct data to lower energies, or by indirect methods. The indirect Trojan horse method, as well as various R -matrix and polynomial fits to direct data, estimate electron screening energies much larger than the adiabatic limit. Calculations that include the subthreshold resonance estimate smaller screening energies. Purpose: Obtain the 6Li(d,α ) 4He reaction R -matrix parameters and the bare astrophysical S factor for energies relevant to the stellar plasmas by fitting R -matrix formulas for the subthreshold resonances to the S -factor data above 60 keV. Methods: The bare S factor is calculated using the single- and the two-level R -matrix formulas for the closest to the threshold 0+ and 2+ subthreshold states at 22.2 ,20.2 , and 20.1 MeV. The electron screening potential U e is then obtained by fitting it as a single parameter to the low-energy data. The calculations are also done by fitting U e simultaneously with other parameters. Results: The low-energy S factor is dominated by the 2+ subthreshold resonance at 22.2 MeV. The influence of the other two subthreshold states is small. The resultant electron screening is smaller than the adiabatic value. The fits that neglect the electron screening above 60 keV produce a significantly smaller electron screening potential. The calculations show a large ambiguity associated with a choice of the initial channel radius. Conclusions: The R -matrix fits do not show a significantly larger Ue than predicted by the atomic physics models. The R -matrix best fit provides U e=149.5 eV and Sb(0 ) =21.7 MeV b.

  8. Physical plugging does not account for attenuation of capillary leakage by hydroxyethyl starch 130/0.4: a synthetic gel layer model.

    PubMed

    Tatara, Tsuneo; Itani, Motoi; Sugi, Takashi; Fujita, Kimihiko

    2013-01-01

    Hydroxyethyl starch (HES) solutions, widely used plasma substitutes, reportedly attenuate capillary leakage via physical plugging of capillary defects. We investigated how 2% HES solutions of different molecular weights (HES(70): 70 kDa, HES(130): 130 kDa, HES(200): 200 kDa, and HES(670): 670 kDa) affect dye release from polyacrylamide gels (PAGs) as a model of endothelial glycocalyx. We assessed dye release from 4% PAG with varying concentrations of albumin [0, 1, 2, 4, and 8% (w/v)] by measuring the change in dye absorbance (ΔAbs) at 5 h for each HES solution. For PAG containing no albumin, ΔAbs for HES(130) was 30% lower than that for HES(70) and HES(200), and 50% lower than that for HES(670). At concentrations of 1-8% albumin, ΔAbs at 5 h with HES(70), HES(130), and HES(200) solutions were almost half that with the HES(670) solution, but no significant differences were noted in ΔAbs at 5 h among HES(70), HES(130), and HES(200) solutions. The inhibition of dye release by HES(670) is likely due to the hindering effect of HES molecules partitioned into gel pores. However, a unique property of HES(130) , including the heavy hydroxyethylation at the C(2) position, may promote specific interactions with PAG and thereby inhibit solute release.

  9. A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells

    PubMed Central

    Kjartansdóttir, Kristín Rós; Reda, Ahmed; Panula, Sarita; Day, Kelly; Hultenby, Kjell; Söder, Olle; Hovatta, Outi; Stukenborg, Jan-Bernd

    2015-01-01

    Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro. PMID:26630562

  10. Drosophila CK2 phosphorylates Deadpan, a member of the HES family of basic-helix-loop-helix (bHLH) repressors.

    PubMed

    Karandikar, Umesh C; Shaffer, Jonathan; Bishop, Clifton P; Bidwai, Ashok P

    2005-06-01

    In Drosophila, protein kinase CK2 regulates a diverse array of developmental processes. One of these is cell-fate specification (neurogenesis) wherein CK2 regulates basic-helix-loop-helix (bHLH) repressors encoded by the Enhancer of Split Complex (E(spl)C). Specifically, CK2 phosphorylates and activates repressor functions of E(spl)M8 during eye development. In this study we describe the interaction of CK2 with an E(spl)-related bHLH repressor, Deadpan (Dpn). Unlike E(spl)-repressors which are expressed in cells destined for a non-neural cell fate, Dpn is expressed in the neuronal cells and is thought to control the activity of proneural genes. Dpn also regulates sex-determination by repressing sxl, the primary gene involved in sex differentiation. We demonstrate that Dpn is weakly phosphorylated by monomeric CK2alpha, whereas it is robustly phosphorylated by the embryo-holoenzyme, suggesting a positive role for CK2beta. The weak phosphorylation by CK2alpha is markedly stimulated by the activator polylysine to levels comparable to those with the holoenzyme. In addition, pull down assays indicate a direct interaction between Dpn and CK2. This is the first demonstration that Dpn is a partner and target of CK2, and raises the possibility that its repressor functions might also be regulated by phosphorylation.

  11. Effect of 6% Hydroxyethyl Starch 130/0.4 as a Priming Solution on Coagulation and Inflammation Following Complex Heart Surgery

    PubMed Central

    Cho, Jang-Eun; Shim, Jae-Kwang; Song, Jong-Won; Lee, Hye-Won; Kim, Dong-Hwan

    2014-01-01

    Purpose Prolonged duration of cardiopulmonary bypass aggravates the degree of inflammation and coagulopathy. We investigated the influence of 6% hydroxyethyl starch (HES) 130/0.4 on coagulation and inflammation compared with albumin when used for both cardiopulmonary bypass priming and perioperative fluid therapy in patients undergoing complex valvular heart surgery. Materials and Methods Fifty four patients were randomly allocated into albumin-HES, albumin-nonHES, and HES-HES groups. The cardiopulmonary bypass circuit was primed with 5% albumin in the albumin-HES and albumin-nonHES group, and with HES in the HES-HES group. As perioperative fluid, only plasmalyte was used in the albumin-nonHES group whereas HES was used up to 20 mL/kg in the albumin-HES and albumin-HES group. Serial assessments of coagulation profiles using the rotational thromboelastometry and inflammatory markers (tissue necrosis factor-α, interleukin-6, and interleukin-8) were performed. Results Patients' characteristics and the duration of cardiopulmonary bypass (albumin-HES; 137±34 min, HES-HES; 136±47 min, albumin-nonHES; 132±39 min) were all similar among the groups. Postoperative coagulation profiles demonstrated sporadic increases in clot formation time and coagulation time, without any differences in the actual amount of perioperative bleeding and transfusion requirements among the groups. Also, inflammatory markers showed significant activation after cardiopulmonary bypass without any differences among the groups. Conclusion Even in the presence of prolonged duration of cardiopulmonary bypass, HES seemed to yield similar influence on the ensuing coagulopathy and inflammatory response when used for priming and perioperative fluid therapy following complex valvular heart surgery compared with conventional fluid regimen including albumin and plasmalyte. PMID:24719128

  12. Gastrointestinal and Hepatic Involvement in Hypereosinophilic Syndrome

    PubMed Central

    Hurairah, Abu

    2016-01-01

    The objective of this investigation was to study the gastrointestinal and hepatic involvement in hypereosinophilic syndrome (HES). Gastrointestinal or hepatic involvement is estimated to affect up to one-third of patients with HES, although most of the clinical evidence has been derived from case reports. In literature, HES presenting with hepatitis and jaundice with subsequent development of colitis is a rare clinicopathologic entity. Given the clinical implications, physicians should include HES among differentials in these types of presentations. PMID:27733964

  13. Role of ICT in Shaping the Future of Pakistani Higher Education System

    ERIC Educational Resources Information Center

    Shaikh, Zaffar Ahmed; Khoja, Shakeel Ahmed

    2011-01-01

    This study examined the challenges faced by the Pakistani higher education system (HES) in integrating information and communication technology (ICT); it aimed at understanding ICT needs, measuring the increase in ICT demand, determining the relationship between ICT and HES performance, and understanding how the HES copes with the challenges of…

  14. Higher Education for Sustainability: Developing a Comprehensive Research Agenda

    ERIC Educational Resources Information Center

    Wright, Tarah

    2007-01-01

    From 27 to 29 October 2005, 35 experts in higher education for sustainability (HES) representing 17 countries, gathered in Halifax, Nova Scotia. This consultation represents the first gathering of HES researchers in Canada, and brought Canadian and international researchers together to further intellectual understanding of HES research and to…

  15. Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients

    PubMed Central

    Vuiblet, Vincent; Fere, Michael; Bankole, Ezechiel; Wynckel, Alain; Gobinet, Cyril; Birembaut, Philippe; Piot, Olivier; Rieu, Philippe

    2016-01-01

    In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival. PMID:27608775

  16. Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients

    NASA Astrophysics Data System (ADS)

    Vuiblet, Vincent; Fere, Michael; Bankole, Ezechiel; Wynckel, Alain; Gobinet, Cyril; Birembaut, Philippe; Piot, Olivier; Rieu, Philippe

    2016-09-01

    In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival.

  17. Hemato-endothelial differentiation from lentiviral-transduced human embryonic stem cells retains durable reporter gene expression under the control of ubiquitin promoter.

    PubMed

    Jiang, Hua; Lin, Xiaolong; Feng, Youji; Xie, Yi; Han, Jinlan; Zhang, Yueping; Wang, Zack Z; Chen, Tong

    2010-01-01

    Human embryonic stem (hES) cells are able to give rise to a variety of cell lineages under specific culture condition. An effective strategy for stable genetic modification in hES cells may provide a powerful tool for study of human embryogenesis and cell-based therapies. However, gene silences are documented in hES cells. In current study, we investigated whether genes controlled under ubiquitin promoter are expressed during hematopoietic-endothelial differentiation in hES cells. Undifferentiated hES cells (H1) were transduced by lentivirus encoding green fluorescent protein (GFP) gene under ubiquitin promoter. GFP-expressing hES cells (GFP-H1) were established after several rounds of mechanical selection under fluorescence microscope. GFP gene was stably expressed in hES cells throughout prolonged (> 50 passages) cultivation, and in differentiated embryo body (EB) and teratoma. Hematopoietic and endothelial markers, including KDR (VEGFR2), CD34, CD31, Tie-2, GATA-1 and GATA-2, were expressed at similar levels during hES cell differentiation in parent hES cells and GFP-H1 hES cells. CD34(+) cells isolated from GFP-H1 hES cells were capable to generate hematopoietic colony-forming cells and tubular structure-forming cells. Differentiated GFP-EB formed vasculature structures in a semi-solid sprouting EB model. These results indicated that a transgene under ubiquitin promoter in lentiviral transduced hES cells retained its expression in undifferentiated hES cells and in hES-derived hematopoietic and endothelial cells. With the view of embryonic mesodermal developing events in humans, genetic modification of hES cells by lentiviral vectors provides a powerful tool for study of hematopoiesis and vasculogenesis.

  18. Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model

    PubMed Central

    Hüter, Lars; Simon, Tim-Philipp; Weinmann, Lenard; Schuerholz, Tobias; Reinhart, Konrad; Wolf, Gunter; Amann, Kerstin Ute; Marx, Gernot

    2009-01-01

    Introduction The aim of the study was to evaluate some of the underlying pathomechanisms of hydroxyethylstarch (HES) induced adverse effects on renal function using 24 porcine kidneys in an isolated perfusion model over six hours. Methods Infusion of either 10% HES 200/0.5, 6% HES 130/0.42 or Ringer's lactate (RL) was performed to achieve an haematocrit of 20% in eight kidneys from four animals per group. Physiological and pathophysiological parameters were determined (including N-acetyl-beta-aminoglucosidase as a marker for lysosomal tubular damage). Histological investigations and immunohistological stainings of the kidneys were performed. Results Initially after haemodilution, HES 130/0.42 and HES 200/0.5 reduced urine output compared with RL (P < 0.01). After six hours, N-acetyl-beta-aminoglucosidase was significantly higher in HES 200/0.5 (81 ± 23 U/L) compared with HES 130/0.42 (38 ± 12 U/L) and RL (21 ± 13 U/L; P < 0.001). Osmotic nephrosis-like lesions (OL) of the tubuli were present in all groups showing a significantly lower number of OL in RL (1.1 ± 0.4; P = 0.002) compared with both HES groups (HES 200/0.5 = 2.1 ± 0.6; HES 130/0.42 = 2.0 ± 0.5). Macrophage infiltration was significantly higher in HES 200/0.5 compared with HES 130/0.42 (1.3 ± 1.0 vs. 0.2 ± 0.04; P = 0.044). There was a significant increase in interstitial cell proliferation in the HES 200/0.5 group vs. HES 130/0.42 (18.0 ± 6.9 vs. 6.5 ± 1.6; P = 0.006) with no significant difference in RL (13.5 ± 4.0). Conclusions We observed impaired diuresis and sodium excretion by HES and identified renal interstitial proliferation, macrophage infiltration and tubular damage as potential pathological mechanisms of HES-induced adverse effects on renal function using an isolated porcine renal perfusion model. Furthermore, we demonstrated that 10% HES 200/0.5 had more of a pro-inflammatory effect compared with 6% HES 130/0.42 and caused more pronounced tubular damage than 6% HES 130/0.42 and

  19. Genetic engineering of human embryonic stem cells with lentiviral vectors.

    PubMed

    Xiong, Chen; Tang, Dong-Qi; Xie, Chang-Qing; Zhang, Li; Xu, Ke-Feng; Thompson, Winston E; Chou, Wayne; Gibbons, Gary H; Chang, Lung-Ji; Yang, Li-Jun; Chen, Yuqing E

    2005-08-01

    Human embryonic stem (hES) cells present a valuable source of cells with a vast therapeutic potential. However, the low efficiency of directed differentiation of hES cells remains a major obstacle in their uses for regenerative medicine. While differentiation may be controlled by the genetic manipulation, effective and efficient gene transfer into hES cells has been an elusive goal. Here, we show stable and efficient genetic manipulations of hES cells using lentiviral vectors. This method resulted in the establishment of stable gene expression without loss of pluripotency in hES cells. In addition, lentiviral vectors were effective in conveying the expression of an U6 promoter-driven small interfering RNA (siRNA), which was effective in silencing its specific target. Taken together, our results suggest that lentiviral gene delivery holds great promise for hES cell research and application.

  20. Hall effect, edge states, and Haldane exclusion statistics in two-dimensional space

    NASA Astrophysics Data System (ADS)

    Ye, F.; Marchetti, P. A.; Su, Z. B.; Yu, L.

    2015-12-01

    We clarify the relation between two kinds of statistics for particle excitations in planar systems: the braid statistics of anyons and the Haldane exclusion statistics (HES). It is shown nonperturbatively that the HES exists for incompressible anyon liquid in the presence of a Hall response. We also study the statistical properties of a specific quantum anomalous Hall model with Chern-Simons term by perturbation in both compressible and incompressible regimes, where the crucial role of edge states to the HES is shown.

  1. Reversible Severe Eosinophilic Endomyocardial Fibrosis During Pregnancy: A Case Report.

    PubMed

    Pineton de Chambrun, Marc; Charron, Philippe; Vauthier-Brouzes, Danièle; Cluzel, Philippe; Haroche, Julien; Kahn, Jean-Emmanuel; Amoura, Zahir; Aubart, Fleur Cohen

    2015-08-01

    Idiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and have rarely been reported, particularly in the setting of heart failure.We here report on the case of a 29-year-old woman with HES who developed severe endomyocardial fibrosis with heart failure during pregnancy. Outcome was favorable under treatment with prednisone and azathioprine.This case illustrates a favorable outcome of endomyocardial fibrosis during pregnancy.

  2. Reversible Severe Eosinophilic Endomyocardial Fibrosis During Pregnancy

    PubMed Central

    Pineton de Chambrun, Marc; Charron, Philippe; Vauthier-Brouzes, Danièle; Cluzel, Philippe; Haroche, Julien; Kahn, Jean-Emmanuel; Amoura, Zahir; Aubart, Fleur Cohen

    2015-01-01

    Abstract Idiopathic hypereosinophilic syndrome (HES) is a condition of unknown origin characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. Cardiac involvement is rare and threatening accounting for 33% to 43% of death in HES. Management of pregnant patients with HES is challenging and have rarely been reported, particularly in the setting of heart failure. We here report on the case of a 29-year-old woman with HES who developed severe endomyocardial fibrosis with heart failure during pregnancy. Outcome was favorable under treatment with prednisone and azathioprine. This case illustrates a favorable outcome of endomyocardial fibrosis during pregnancy. PMID:26266372

  3. Atypical Presentation of Intracardiac Floating Thrombi in Hypereosinophilic Syndrome Complicated With Stroke and Systemic Embolization

    PubMed Central

    Lai, Chih-Hung; Chang, Szu-Ling; Lin, Wei-Wen; Hsiung, Ming-Chon; Juan, Yu-Hsiang; Wang, Tzu-Lin

    2015-01-01

    Abstract Hypereosinophilic syndrome (HES) describes a disorder characterized by persistent peripheral blood eosinophilia with evidence of multiple target organs damage caused by eosinophilia. HES most commonly involves the heart, and cardiac involvement typically presents in the form of endomyocarditis or myocarditis with apical mural thrombus formation. We present a case with atypical cardiac presentation with massive intracardiac fragile thrombi, causing peripheral emboli and strokes. HES can present as floating thrombi with thin attachment to the left ventricle, and clinicians should also be vigilant of thromboembolic complications and initiate early therapy to prevent or reduce the potential complications of HES. PMID:26512591

  4. A Case of Hypereosinophilic Syndrome Presenting With Multiorgan Infarctions Associated With Disseminated Intravascular Coagulation

    PubMed Central

    Park, Sun-Mi; Park, Ji-Won; Kim, Sung-Min; Koo, Eun-Hee; Lee, Jin-Young; Lee, Chul-Su; Choi, Dong-Chull

    2012-01-01

    Thromboembolism is one of the most critical complications of hypereosinophilic syndrome (HES). We report here a case of multi-organ infarctions related to HES. A 23-year-old woman was referred to our hospital with hemoptysis. Not only pulmonary, but also renal and splenic infarctions were detected on computed tomography images. Blood tests showed profound peripheral eosinophilia. She was diagnosed with HES with disseminated intravascular coagulation (DIC). We initiated infusion of corticosteroids, which effectively suppressed peripheral eosinophilia. However, consumptive coagulopathy did not improve and intracerebral hemorrhage related to thrombosis then developed. Addition of interferon-alpha resulted in the correction of the DIC associated with HES. PMID:22548210

  5. Distinct profiles of human embryonic stem cell metabolism and mitochondria identified by oxygen.

    PubMed

    Lees, Jarmon G; Rathjen, Joy; Sheedy, John R; Gardner, David K; Harvey, Alexandra J

    2015-10-01

    Oxygen is a powerful regulator of cell function and embryonic development. It has previously been determined that oxygen regulates human embryonic stem (hES) cell glycolytic and amino acid metabolism, but the effects on mitochondria are as yet unknown. Two hES cell lines (MEL1, MEL2) were analyzed to determine the role of 5% (physiological) and 20% (atmospheric) oxygen in regulating mitochondrial activity. In response to extended physiological oxygen culture, MEL2 hES cells displayed reduced mtDNA content, mitochondrial mass and expression of metabolic genes TFAM, NRF1, PPARa and MT-ND4. Furthermore, MEL2 hES cell glucose consumption, lactate production and amino acid turnover were elevated under physiological oxygen. In stark contrast, MEL1 hES cell amino acid and carbohydrate use and mitochondrial function were relatively unaltered in response to oxygen. Furthermore, differentiation kinetics were delayed in the MEL1 hES cell line following BMP4 treatment. Here we report the first incidence of metabolic dysfunction in a hES cell population, defined as a failure to respond to oxygen concentration through the modulation of metabolism, demonstrating that hES cells can be perturbed during culture despite exhibiting the defining characteristics of pluripotent cells. Collectively, these data reveal a central role for oxygen in the regulation of hES cell metabolism and mitochondrial function, whereby physiological oxygen promotes glucose flux and suppresses mitochondrial biogenesis and gene expression.

  6. Human embryonic stem cells: culture, differentiation, and genetic modification for regenerative medicine applications.

    PubMed

    Lebkowski, J S; Gold, J; Xu, C; Funk, W; Chiu, C P; Carpenter, M K

    2001-01-01

    Human embryonic stem (hES) cells can proliferate extensively in culture and can differentiate into representatives of all three embryonic germ layers in vitro and in vivo. The undifferentiated hES cells have now been cultured for more than 50 passages in vitro, yet maintain a normal karyotype. The hES cells express a series of specific surface antigens, as well as OCT-4 and human telomerase, proteins associated with a pluripotent and immortal phenotype. On differentiation, OCT-4 and human telomerase expression decreases with the emergence of a maturing population of cells. During hES cell differentiation, modulation of the expression of many genes has been evaluated using microarray analysis. To improve the ease, reproducibility, and scalability of hES culture, methods have been developed to propagate the cells in the absence of mouse embryonic cell feeders. hES cells maintained in culture using extracellular matrix factors together with mouse embryonic cell conditioned medium proliferate indefinitely while maintaining a normal karyotype, proliferation rate, and complement of undifferentiated cell markers. hES cells cultured without feeder layers retain their capacity to differentiate into cells of all three germ layers in vitro and in teratomas. The hES cells can also be genetically modified transiently or stably using both plasmid and viral gene transfer agents. These analyses and technological developments will aid in the realization of the full potential of hES cells for both research and therapeutic applications.

  7. Reduced mitotic activity at the periphery of human embryonic stem cell colonies cultured in vitro with mitotically-inactivated murine embryonic fibroblast feeder cells.

    PubMed

    Heng, Boon Chin; Cao, Tong; Liu, Hua; Rufaihah, Abdul Jalil

    2005-01-01

    This study attempted to investigate whether different levels of mitotic activity exist within different physical regions of a human embryonic stem (hES) cell colony. Incorporation of 5-bromo-2-deoxyuridine (BrdU) within newly-synthesized DNA, followed by immunocytochemical staining was used as a means of detecting mitotically-active cells within hES colonies. The results showed rather surprisingly that the highest levels of mitotic activity are primarily concentrated within the central regions of hES colonies, whereas the peripheral regions exhibited reduced levels of cellular proliferation. Two hypothetical mechanisms are therefore proposed for hES colony growth and expansion. Firstly, it is envisaged that the less mitotically-active hES cells at the periphery of the colony are continually migrating outwards, thereby providing space for newly-divided daughter cells within the more mitotically-active central region of the hES colony. Secondly, it is proposed that the newly-divided hES cells within the central region of the colony somehow migrate to the outer periphery. This could possibly explain why the periphery of hES colonies are less mitotically-active, since there would obviously be an extended time-lag before newly-divided daughter cells are ready again for the next cell division. Further investigations need to be carried out to characterize the atypical mechanisms by which hES colonies grow and expand in size.

  8. Hypereosinophilic syndrome and proliferative diseases.

    PubMed

    Ionescu, Marius A; Wang, Li; Janin, Anne

    2009-01-01

    Therapy principles of the last decade and recent advances in the research of polynuclear eosinophil have led to a new approach in the hypereosinophilic syndrome (HES), with important consequences on the development of new and effective therapies. HES is defined by persistent and marked eosinophilia and eosinophil-related organ damage in the absence of any evident cause of hypereosinophilia. Two variants of HES have been characterized, with different prognosis and possible associations with malignant diseases such as myeloid leukemia or T-cell lymphomas. The lymphocytic variant of HES (L-HES) is characterized by the presence of T cell clones, IL-5 expression and possible progression to T-cell lymphoma. Besides steroid therapy, the anti-IL-5 monoclonal antibody mepolizumab is considered as a target therapy for L-HES. The myeloproliferative variant of HES (M-HES) is associated with an increased risk of myeloid leukemia and good response to anti-tyrosine-kinase therapy. The imatinib target is a kinase resulting from an 800-kb deletion on chromosome 4. The fusion gene Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) has been validated as a marker of response to anti-tyrosine-kinase therapy. Early identification of HES variants is crucial for the rapid introduction of early and appropriately adjusted therapy.

  9. Osmotic virial coefficients of hydroxyethyl starch from aqueous hydroxyethyl starch-sodium chloride vapor pressure osmometry.

    PubMed

    Cheng, Jingjiang; Gier, Martin; Ross-Rodriguez, Lisa U; Prasad, Vinay; Elliott, Janet A W; Sputtek, Andreas

    2013-09-05

    Hydroxyethyl starch (HES) is an important industrial additive in the paper, textile, food, and cosmetic industries and has been shown to be an effective cryoprotectant for red blood cells; however, little is known about its thermodynamic solution properties. In many applications, in particular those in biology, HES is used in an aqueous solution with sodium chloride (NaCl). The osmotic virial solution thermodynamics approach accurately captures the dependence of osmolality on molality for many types of solutes in aqueous systems, including electrolytes, sugars, alcohols, proteins, and starches. Elliott et al. proposed mixing rules for the osmotic virial equation to be used for osmolality of multisolute aqueous solutions [Elliott, J. A. W.; et al. J. Phys. Chem. B 2007, 111, 1775-1785] and recently applied this approach to the fitting of one set of aqueous HES-NaCl solution data reported by Jochem and Körber [Cryobiology 1987, 24, 513-536], indicating that the HES osmotic virial coefficients are dependent on HES-to-NaCl mass ratios. The current study reports new aqueous HES-NaCl vapor pressure osmometry data which are analyzed using the osmotic virial equation. HES modifications were measured after dialysis (membrane cut off: 10,000 g/mol) and freeze-drying using vapor pressure osmometry at different mass ratios of HES to NaCl for HES up to 50% and NaCl up to 25% with three different HES modifications (weight average molecular weights [g/mol]/degree of substitution: 40,000/0.5; 200,000/0.5; 450,000/0.7). Equations were then fit to the data to provide a model for HES osmotic virial coefficient dependence on mass ratio of HES to NaCl. The osmolality data of the three HES modifications were accurately described over a broad range of HES-to-NaCl mass ratios using only four parameters, illustrating the power of the osmotic virial approach in analyzing complex data sets. As expected, the second osmotic virial coefficients increase with molecular weight of the HES and

  10. Heavy eye syndrome versus sagging eye syndrome in high myopia

    PubMed Central

    Tan, Roland Joseph D.; Demer, Joseph L.

    2015-01-01

    Background Heavy eye syndrome (HES) presents with esotropia and limited abduction due to superotemporal globe shift relative to the extraocular muscles. Sagging eye syndrome (SES) was originally described in nonmyopic patients exhibiting distance esotropia and cyclovertical strabismus with limited supraduction due to lateral rectus muscle inferodisplacement caused by degeneration of the lateral rectus–superior rectus (LR-SR) band. We hypothesized that SES might also cause strabismus in high myopia. Methods Eleven strabismic subjects with high myopia underwent ophthalmological examination and orbital magnetic resonance imaging (MRI) to assess quantitative orbital anatomy. Results Of 11 subjects, 5 had HES; 6, SES. Mean axial length in subjects with HES was 32 ± 5 mm; in subjects with SES, 32 ± 6 mm. Average distance esotropia in subjects with HES was 61Δ ± 39Δ; hypotropia was 26Δ ± 21Δ. Average distance esotropia in subjects with SES was 23Δ ± 57Δ; hypertropia was 2Δ ± 2Δ. All 5 subjects with HES had superotemporal globe prolapse; the LR-SR band was thinned in 6 orbits and ruptured in 2. The mean angle between the lateral rectus and superior rectus muscles in HES was 121° ± 7°. In SES the LR-SR band was thinned in 7 orbits and ruptured in 5, with superotemporal soft tissue prolapse. The mean angle between the lateral rectus and superior rectus muscles was 104° ± 11°, significantly less than in HES (P < 0.001). Conclusions SES occurs in highly myopic patients who also exhibit less relative globe dislocation than in HES. Unlike HES, SES exhibits superotemporal soft tissue prolapse that may limit superotemporal globe shift. The distinction is important because surgery for HES uniquely requires creation of a surgical connection between the superior rectus and lateral rectus muscles, whereas SES may be treated with conventional surgery. SES can cause strabismus in high axial myopia. Orbital MRI is useful in differentiating SES from HES. PMID

  11. Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England

    PubMed Central

    2012-01-01

    Background Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources. Methods Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman’s general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record. Results Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete. Conclusion Hospital admission data in England provide

  12. Chemical Reactivity Test (CRT)

    SciTech Connect

    Zaka, F.

    2016-12-13

    The Chemical Reactivity Test (CRT) is used to determine the thermal stability of High Explosives (HEs) and chemical compatibility between (HEs) and alien materials. The CRT is one of the small-scale safety tests performed on HE at the High Explosives Applications Facility (HEAF).

  13. National Innovation and Knowledge Performance: The Role of Higher Education Teaching and Training

    ERIC Educational Resources Information Center

    Saad, Mohammed; Guermat, Cherif; Brodie, Lisa

    2015-01-01

    This paper investigates the role of the higher education system (HES) in the production of national innovation. We focus on the issue of institutional diversity of HESs and its impact on national innovation systems. We identify four key HES characteristics and hypothesize their influence on the production of national innovation. The empirical…

  14. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    EPA Science Inventory

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultur...

  15. The Word from a Walrus: Five Decades of the History of Education Society

    ERIC Educational Resources Information Center

    Urban, Wayne J.

    2010-01-01

    This essay is an attempt at an institutional history of the History of Education Society (HES), from its inception in 1960 to the present day. Many of the intellectual currents and cross-currents, as well as the "History of Education Quarterly" (HEQ), the journal of the HES in which these intellectual movements were featured, are slighted in this…

  16. Moving Mexico’s Higher Education System Forward -- Potential and Challenges

    DTIC Science & Technology

    2011-10-28

    Mexican HES. The Mexican populace generally possesses a deeply embedded cultural aversion to self-assessment, especially when it comes to education...throughout the 31 states that make up the country.5 The Mexican public HES is nominally administered from Mexico City by the Secretaria de Educacion

  17. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue

    PubMed Central

    Rezaeyan, Abolhasan; Haddadi, Gholam Hassan; Hosseinzadeh, Massood; Moradi, Maryam; Najafi, Masoud

    2016-01-01

    This study was carried out to evaluate radioprotective effects of hesperidin (HES) administration before the irradiation on the cardiac oxidative stress and histopathological changes in an experimental rat model. The cardiovascular complications of radiation exposure cause morbidity and mortality in patients who received radiotherapy. HES, an antioxidant flavonoid found in citrus fruits, suggests the protection against the tissue damage. Fifty-eight rats were divided into four groups: Group 1 received phosphate buffered saline (PBS) and sham radiation; Group 2, HES and sham radiation; Group 3, PBS and radiation; and Group 4, HES and radiation. The rats were exposed to single dose of 18 Gy of 6 MV X-ray. One hundred milligrams per kilogram doses of HES was administered for 7 days before irradiation. The estimation of superoxide dismutase (SOD), malondialdehyde (MDA), and histopathological analyses was performed at 24 h and 8 weeks after radiation exposure. The irradiation of chest area resulted in an elevated MDA level and decreased SOD activity. Moreover, long-term pathological lesions of radiation were inflammation, fibrosis, the increased number of mast cells and macrophages, and development of plaque, vascular leakage, myocardial degeneration, and myocyte necrosis. Although the administration of HES decreases inflammation, fibrosis, mast cell and macrophage numbers, and myocyte necrosis, it did not result in reduced thrombus, myocardium degeneration, and vascular leakage. In conclusion, these results suggest that HES can perform a radioprotection action. The protective effect of HES may be attributable to its immunomodulatory effects and free radical-scavenging properties. PMID:27651565

  18. Renal thrombotic microangiopathy and FIP1L1/PDGFRα-associated myeloproliferative variant of hypereosinophilic syndrome

    PubMed Central

    Langlois, Anne Lyse; Shehwaro, Nathalie; Rondet, Claire; Benbrik, Youssef; Maloum, Karim; Gueutin, Victor; Rouvier, Philippe; Izzedine, Hassane

    2013-01-01

    We report a case of renal thrombotic microangiopathy (TMA) in a myeloproliferative variant of hypereosinophilic syndrome (HES) in a 24-year-old man which resolved with imatinib therapy. This is one of a few cases in the literature to date describing TMA in HES, suggesting that the pathogenesis of thrombosis is at least in part related to damage from activated eosinophils. PMID:27293571

  19. Renal thrombotic microangiopathy and FIP1L1/PDGFRα-associated myeloproliferative variant of hypereosinophilic syndrome.

    PubMed

    Langlois, Anne Lyse; Shehwaro, Nathalie; Rondet, Claire; Benbrik, Youssef; Maloum, Karim; Gueutin, Victor; Rouvier, Philippe; Izzedine, Hassane

    2013-08-01

    We report a case of renal thrombotic microangiopathy (TMA) in a myeloproliferative variant of hypereosinophilic syndrome (HES) in a 24-year-old man which resolved with imatinib therapy. This is one of a few cases in the literature to date describing TMA in HES, suggesting that the pathogenesis of thrombosis is at least in part related to damage from activated eosinophils.

  20. A hyperbolic-equation system approach for magnetized electron fluids in quasi-neutral plasmas

    SciTech Connect

    Kawashima, Rei; Komurasaki, Kimiya; Schönherr, Tony

    2015-03-01

    A new approach using a hyperbolic-equation system (HES) is proposed to solve for the electron fluids in quasi-neutral plasmas. The HES approach avoids treatments of cross-diffusion terms which cause numerical instabilities in conventional approaches using an elliptic equation (EE). A test calculation reveals that the HES approach can robustly solve problems of strong magnetic confinement by using an upwind method. The computation time of the HES approach is compared with that of the EE approach in terms of the size of the problem and the strength of magnetic confinement. The results indicate that the HES approach can be used to solve problems in a simple structured mesh without increasing computational time compared to the EE approach and that it features fast convergence in conditions of strong magnetic confinement.

  1. Mixed-layer deepening during Heinrich events: a multi-planktonic foraminiferal delta18O approach.

    PubMed

    Rashid, Harunur; Boyle, Edward A

    2007-10-19

    Proxies from Greenland ice cores and North Atlantic marine sediment cores document repeated extreme climate swings of a few decades to millennia during the last glacial cycle, including periods of intense ice rafting called Heinrich events (HEs). We have found similar oxygen isotope variations recorded in mixed-layer-and thermocline-dwelling planktonic foraminifera during HEs 0, 1, and 4, suggesting that three foraminiferal taxa calcified their shells at similar temperatures in a homogenized upperwater column. This implies that the surface mixed layer was deeper during HEs. Similar deepening occurred on the northern margin of the ice-rafted-debris belt, implying that these deep mixed layers during HEs were widespread in the region. We suggest that an increase in storminess during HEs intensified the vertical mixing of meltwater from ice rafting in the upper ocean.

  2. Hydroxyethyl starches: different products--different effects.

    PubMed

    Westphal, Martin; James, Michael F M; Kozek-Langenecker, Sibylle; Stocker, Reto; Guidet, Bertrand; Van Aken, Hugo

    2009-07-01

    With the development of a new generation of hydroxyethyl starches (HES), there has been renewed interest in their clinical potential. High doses of first- and second-generation HES were associated with adverse effects on renal function, coagulation, and tissue storage, thereby limiting their clinical applicability. Newer HES products have lower molar substitution and in vivo molecular weight, resulting in more rapid metabolism and clearance. In this review article, the differences between HES generations are highlighted, with particular emphasis on the improved safety profile of the third generation products. These improvements have been achieved with no loss of efficacy, and they contradict the assumption that efficacy of HES solutions is directly linked to plasma concentration. The impact of source material on structure and pharmacokinetics is highlighted, and the role of the carrier solution is critically assessed.

  3. Effect of perioperative crystalloid or colloid fluid therapy on hemorrhage, coagulation competence, and outcome

    PubMed Central

    Rasmussen, Kirsten C.; Secher, Niels H.; Pedersen, Tom

    2016-01-01

    Abstract Background: A meta-analysis concerning perioperative coagulation competence, hemorrhage, and outcome was conducted including the use of hydroxyethyl starches (HESs), dextran, or albumin versus administration of a crystalloid as control to assess the efficacy and safety of colloids and crystalloids for fluid administration during major elective surgery. Surgery was restricted to cardiovascular and noncardiovascular surgery, and HESs were stratified to HES 130/0.4 and HES 200/0.5. Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, ISI Web of Science, EMBASE, conference proceedings, reference lists, and databases of ongoing trials. Results: Thirty one primary clinical randomized controlled trials included 2287 patients undergoing major surgery from January 2000 to August 2015. The perioperative changes in coagulation competence were measured by thromboelastography (TEG) maximum amplitude (MA) in 9 studies administering crystalloids versus HES and in 4 studies administering albumin versus HES. All studies but 1 disclosed increased reduction in TEG-MA following HES administration (P = 0.0001 and 0.0002). The total loss of blood was reported in 17 studies in which crystalloids were compared to HES and 12 studies reported increased blood loss after administration of HES (P < 0.003). When administering albumin versus HES, 6 studies reported reduced hemorrhage associated with albumin administration (P = 0.005). Reoperation was not significantly reduced by the use of crystalloids, but may be more frequent after HESs compared to albumin (P < 0.03). In this analysis, more patients admitted to administration of HESs were exposed to decrease coagulation competence, compared to perioperative crystalloids and albumin administration. Conclusion: This stratified meta-analysis showed that increased blood loss was found in noncardiovascular surgery among patients receiving HES compared with crystalloids, followed by a marked

  4. Stable genetic modification of human embryonic stem cells by lentiviral vectors.

    PubMed

    Gropp, Michal; Itsykson, Pavel; Singer, Orna; Ben-Hur, Tamir; Reinhartz, Etti; Galun, Eithan; Reubinoff, Benjamin E

    2003-02-01

    Human embryonic stem (hES) cells are pluripotent cells derived from the inner cell mass of the early preimplantation embryo. An efficient strategy for stable genetic modification of hES cells may be highly valuable for manipulating the cells in vitro and may promote the study of hES cell biology, human embryogenesis, and the development of cell-based therapies. Here, we demonstrate that vectors derived from self-inactivating (SIN) human immunodeficiency virus type 1 (HIV-1) are efficient tools for stable genetic modification of hES cells. Transduction of hES cells by a modified vector derived from SIN HIV-1 and containing the woodchuck hepatitis regulatory element (WPRE) and the central polypurine tract (cPPT) sequence facilitated stable transgene expression during prolonged (38 weeks) undifferentiated proliferation in vitro. Southern blot analysis revealed that the viral vector had integrated into the host cells' DNA. Transgene expression was maintained throughout differentiation into progeny of all three germ layers both in vitro and in vivo in teratomas. Thus, the transduced hES cells retained the capability for self-renewal and their pluripotent potential. Genetic modification of hES cells by lentiviral vectors provides a powerful tool for basic and applied research in the area of human ES cells.

  5. Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy.

    PubMed

    McSorley, H J; Blair, N F; Smith, K A; McKenzie, A N J; Maizels, R M

    2014-09-01

    Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1-48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.

  6. Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina.

    PubMed

    Hara, Akira; Taguchi, Ayako; Aoki, Hitomi; Hatano, Yuichiro; Niwa, Masayuki; Yamada, Yasuhiro; Kunisada, Takahiro

    2010-06-25

    Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuroretinal cells. However, the transplanted ES cells also have a tumorigenic activity as they have the ability for multipotent differentiation to various types of tissues. In the present study, human ES (hES) cells were transplanted into adult nude mouse retinas by intravitreal injections 20 h after intravitreal N-methyl-D-aspartate (NMDA) administration. After the transplantation of hES cells, the folate antagonist, methotrexate (MTX) was administrated in order to control the differentiation of the transplanted hES cells. Neuronal differentiation and teratogenic potential of hES cells were examined immunohistochemically 5 weeks after transplantation. The proliferative activity of transplanted cells was determined by both the mitotic index and the Ki-67 proliferative index. Disappearance of Oct-4-positive hES cells showing undifferentiated morphology was observed after intraperitoneal MTX treatment daily, for 15 days. Decreased mitotic and Ki-67 proliferative indices, and increased neuronal differentiation were detected in the surviving hES cells after the MTX treatment. These results suggest two important effects of intraperitoneal MTX treatment for hES cells transplanted into nude mouse retina: (1) MTX treatment following transplantation induces neuronal differentiation, and (2) MTX decreases proliferative activity and tumorigenic potential.

  7. Refining the definition of hypereosinophilic syndrome

    PubMed Central

    Simon, Hans-Uwe; Rothenberg, Marc E.; Bochner, Bruce S.; Weller, Peter F.; Wardlaw, Andrew J.; Wechsler, Michael E.; Rosenwasser, Lanny J.; Roufosse, Florence; Gleich, Gerald J.; Klion, Amy D.

    2012-01-01

    Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition. PMID:20639008

  8. Idiopathic Hypereosinophilic Syndrome With Cutaneous Manifestations and Flame Figures: A Spectrum of Eosinophilic Dermatoses Whose Features Overlap With Wells' Syndrome

    PubMed Central

    Kiracofe, Elizabeth A.; Clark, Lindsey N.; Gru, Alejandro A.

    2015-01-01

    Importance: Wells syndrome (WS) (eosinophilic cellulitis) is an uncommon eosinophilic dermatitis that has been rarely described in association with, but distinct from, hypereosinophilic syndrome (HES). Observations: We report a case of an eosinophilic dermatosis with flame figures in association with idiopathic HES, manifested by inflammatory myocarditis, asthma, and peripheral blood eosinophilia. Conclusions and Relevance: The diagnoses of WS and HES, rather than being distinct findings, may represent 2 entities on a spectrum of hypereosinophilic diseases. The diagnosis of WS should be made with caution and should prompt a thorough investigation that includes a work-up for a systemic eosinophilic disorder. PMID:25839890

  9. Do we still need human embryonic stem cells for stem cell-based therapies? Epistemic and ethical aspects.

    PubMed

    Hug, Kristina; Hermerén, Göran

    2011-11-01

    While scientific community disagrees about similarities and differences between human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells, some politicians embrace translational hiPS cell research as a replacement for translational hES cell research. We examine the ethical relevance of the main differences between hES and hiPS cell-based therapies and discuss whether, given the current state of knowledge, certain differences are essential. We discuss whether well-founded preferences can be made in hypothetical scenarios with varying levels of patient safety, treatment efficacy, treatment accessibility and ethical controversy.

  10. A Hypereosinophilic Syndrome with Cardiac Involvement from Thrombotic Stage to Fibrotic Stage

    PubMed Central

    Kim, Nam Kyun; Kim, Chang-Yeon; Kim, Jae Hee; Jang, Se Yong; Bae, Myung Hwan; Lee, Jang Hoon; Yang, Dong Heon; Park, Hun Sik; Cho, Yongkeun

    2015-01-01

    Cardiac involvement is a major cause of morbidity and mortality in hypereosinophilic syndrome (HES). It is classified into 3 stages by the degree of eosinophils-mediated heart injury; acute necrotic stage, thrombotic stage, and fibrotic stage. Nonetheless, definitive evidence that each patient passes sequentially through these stages is lacking. We present a case of 48-year-old male patient with dyspnea and peripheral edema who underwent valve replacement surgery due to severe mitral regurgitation. After the valve replacement, HES with cardiac involvement in the thrombotic stage was diagnosed. In the follow-up study, the patient progressed into fibrotic stage of HES. PMID:26140152

  11. Hydrogen Energy Storage: Grid and Transportation Services (Technical Report)

    SciTech Connect

    Melaina, M.; Eichman, J.

    2015-02-01

    Proceedings of an expert workshop convened by the U.S. Department of Energy and Industry Canada, and hosted by the National Renewable Energy Laboratory and the California Air Resources Board, May 14-15, 2014, in Sacramento, California, to address the topic of hydrogen energy storage (HES). HES systems provide multiple opportunities to increase the resilience and improve the economics of energy sup supply systems underlying the electric grid, gas pipeline systems, and transportation fuels. This is especially the case when considering particular social goals and market drivers, such as reducing carbon emissions, increasing reliability of supply, and reducing consumption of conventional petroleum fuels. This report compiles feedback collected during the workshop, which focused on policy and regulatory issues related to HES systems. Report sections include an introduction to HES pathways, market demand, and the "smart gas" concept; an overview of the workshop structure; and summary results from panel presentations and breakout groups.

  12. VizieR Online Data Catalog: M5 RR Lyrae times of maxima (Arellano Ferro+, 2016)

    NASA Astrophysics Data System (ADS)

    Arellano Ferro, A.; Ahumada, J. A.; Kains, N.; Luna, A.

    2016-11-01

    Secular period changes in RR Lyrae M5 stars are analysed by means of two approac hes, taking advantage of the data long time-base of about 118 years. Few authentically evolved stars are identified. (3 data files).

  13. Nucleofection of human embryonic stem cells.

    PubMed

    Siemen, Henrike; Nix, Michael; Endl, Elmar; Koch, Philipp; Itskovitz-Eldor, Joseph; Brüstle, Oliver

    2005-08-01

    Human embryonic stem (hES) cells provide an important tool for the study of human development, disease, and tissue regeneration. Technologies for efficient genetic modification are required to exploit hES cells fully for these applications. Here we present a customized protocol for the transfection of hES cells with the Nucleofector technology and compare its efficiency with conventional electroporation and lipofection. Cell survival and transfection efficiency were quantified using an enhanced green fluorescent protein (EGFP) reporter construct. Our optimized nucleofection parameters yielded survival rates >70%. Under these conditions, 66% of the surviving cells showed transgene expression 24 h after nucleofection. Transfected cells maintained expression of the pluripotency- associated markers Tra-1-60, Tra-1-81, and Oct4 and could be expanded to stably transgene-expressing clones. The low quantities of hES cells and DNA required for nucleofection could make this method an attractive tool for miniaturized high throughput screening (HTS) applications.

  14. Hybrid Energy System Modeling in Modelica

    SciTech Connect

    William R. Binder; Christiaan J. J. Paredis; Humberto E. Garcia

    2014-03-01

    In this paper, a Hybrid Energy System (HES) configuration is modeled in Modelica. Hybrid Energy Systems (HES) have as their defining characteristic the use of one or more energy inputs, combined with the potential for multiple energy outputs. Compared to traditional energy systems, HES provide additional operational flexibility so that high variability in both energy production and consumption levels can be absorbed more effectively. This is particularly important when including renewable energy sources, whose output levels are inherently variable, determined by nature. The specific HES configuration modeled in this paper include two energy inputs: a nuclear plant, and a series of wind turbines. In addition, the system produces two energy outputs: electricity and synthetic fuel. The models are verified through simulations of the individual components, and the system as a whole. The simulations are performed for a range of component sizes, operating conditions, and control schemes.

  15. Evaluation and differential diagnosis of marked, persistent eosinophilia

    PubMed Central

    Mejia, Rojelio; Nutman, Thomas B.

    2012-01-01

    High grade eosinophilia in patients can be a diagnostic dilemma, as the etiologies are extensive and varied. Hypereosinophilic syndromes (HES) are a group of heterogeneous disorders, many of which remain ill-defined. By definition, HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, non-infectious causes must be sought including drug reactions, malignancies, and immunologic, inflammatory and allergic diseases. PMID:22449625

  16. Evaluation and differential diagnosis of marked, persistent eosinophilia

    PubMed Central

    Nutman, Thomas B.

    2007-01-01

    Synopsis: Hyperosinophilic syndromes (HES) are a group of heterogeneous disorders many of which remain ill-defined. By definition, the HES must be distinguished from other disorders with persistently elevated eosinophilia with a defined cause. Although marked eosinophilia worldwide is most commonly caused by helminth (worm) infections, the diagnostic approach must include non-infectious (non-parasitic) causes of marked eosinophilia as well. PMID:17868863

  17. Hesperidin as Radioprotector against Radiation-induced Lung Damage in Rat: A Histopathological Study

    PubMed Central

    Haddadi, Gholam Hassan; Rezaeyan, Abolhasan; Mosleh-Shirazi, Mohammad Amin; Hosseinzadeh, Massood; Fardid, Reza; Najafi, Masoud; Salajegheh, Ashkan

    2017-01-01

    Reactive oxygen species (ROS) are generated by ionizing radiation, and one of the organs commonly affected by ROS is the lung. Radiation-induced lung injury including pneumonia and lung fibrosis is a dose-limiting factor in radiotherapy (RT) of patients with thorax irradiation. Administration of antioxidants has been proved to protect against ROS. The present study was aimed to assess the protective effect of hesperidin (HES) against radiation-induced lung injury of male rats. Fifty rats were divided into three groups. G1: Received no HES and radiation (sham). G2: Underwent γ-irradiation to the thorax. G3: Received HES and underwent γ-irradiation. The rats were exposed to a single dose of 18 Gy using cobalt-60 unit and were administered HES (100 mg/kg) for 7 days before irradiation. Histopathological analysis was performed 24 h and 8 weeks after RT. Histopathological results in 24 h showed radiation-induced inflammation and presence of more inflammatory cells as compared to G1 (P < 0.05). Administration of HES significantly decreased such an effect when compared to G2 (P < 0.05). Histopathological evaluation in 8 weeks showed a significant increase in mast cells, inflammation, inflammatory cells, alveolar thickness, vascular thickness, pulmonary edema, and fibrosis in G2 when compared to G1 (P < 0.05). HES significantly decreased inflammatory response, fibrosis, and mast cells when compared to G2 (P < 0.05). Administration of HES resulted in decreased radiation pneumonitis and radiation fibrosis in the lung tissue. Thus, the present study showed HES to be an efficient radioprotector against radiation-induced damage in the lung of tissue rats.

  18. Fluid Resuscitation for Hemorrhagic Shock in Tactical Combat Casualty Care: TCCC Guidelines Change 14-01 - 2 June 2014

    DTIC Science & Technology

    2014-06-02

    and hyper-oncotic (e.g., dextrans, hydroxyethyl starches [HESs], and 20% or 25% albumin). The dose of HES used could not exceed 30 mL per kg of body...different types of starch solutions may have different physiologic ef- fects.101 Results after treatment with an assortment of HES options do not...Habicher M, Jhanji S, et al. Incidence of postoperative death and acute kidney injury associated with i.v. hydroxyethyl starch use: systematic review

  19. Investigation of urinary excretion of hydroxyethyl starch and dextran by uhplc-hrms in different acquisition modes.

    PubMed

    Esposito, S; Deventer, K; Giron, A J; Roels, K; Herregods, L; Verstraete, A; Van Eenoo, P

    2014-06-01

    Plasma volume expanders (PVEs) such as hydroxyethyl starch (HES) and dextran are misused in sports because they can prevent dehydration and reduce haematocrit values to mask erythropoietin abuse. Endogenous hydrolysis generates multiple HES and dextran oligosaccharides which are excreted in urine. Composition of the urinary metabolic profiles of PVEs varies depending on post-administration time and can have an impact on their detectability. In this work, different mass spectrometry data acquisition modes (full scan with and without in-source collision-induced dissociation) were used to study urinary excretion profiles of HES and dextran, particularly by investigating time-dependent detectability of HES and dextran urinary oligosaccharide metabolites in post-administration samples. In-source fragmentation yielded the best results in terms of limit of detection (LOD) and detection times, whereas detection of HES and dextran metabolites in full scan mode with no in-source fragmentation is related to recent administration (< 24 hours). Urinary excretion studies showed detection windows for HES and dextran respectively of 72 and 48 hours after administration. Dextran concentrations were above the previously proposed threshold of 500 µg · mL(-1) for 12 hours. A "dilute-and-shoot" method for the detection of HES and dextran in human urine by ultra-high-pressure liquid chromatography-electrospray ionization-high resolution Orbitrap™ mass spectrometry was developed for this study. Validation of the method showed an LOD in the range of 10-500 µg · mL(-1) for the most significant HES and dextran metabolites in the different modes. The method allows retrospective data analysis and can be implemented in existing high-resolution mass spectrometry-based doping control screening analysis.

  20. INVESTIGATION OF URINARY EXCRETION OF HYDROXYETHYL STARCH AND DEXTRAN BY UHPLC-HRMS IN DIFFERENT ACQUISITION MODES

    PubMed Central

    Deventer, K.; Giron, A.J.; Roels, K.; Herregods, L.; Verstraete, A.; Van Eenoo, P.

    2014-01-01

    Plasma volume expanders (PVEs) such as hydroxyethyl starch (HES) and dextran are misused in sports because they can prevent dehydration and reduce haematocrit values to mask erythropoietin abuse. Endogenous hydrolysis generates multiple HES and dextran oligosaccharides which are excreted in urine. Composition of the urinary metabolic profiles of PVEs varies depending on post-administration time and can have an impact on their detectability. In this work, different mass spectrometry data acquisition modes (full scan with and without in-source collision-induced dissociation) were used to study urinary excretion profiles of HES and dextran, particularly by investigating time-dependent detectability of HES and dextran urinary oligosaccharide metabolites in post-administration samples. In-source fragmentation yielded the best results in terms of limit of detection (LOD) and detection times, whereas detection of HES and dextran metabolites in full scan mode with no in-source fragmentation is related to recent administration (< 24 hours). Urinary excretion studies showed detection windows for HES and dextran respectively of 72 and 48 hours after administration. Dextran concentrations were above the previously proposed threshold of 500 µg · mL−1 for 12 hours. A “dilute-and-shoot” method for the detection of HES and dextran in human urine by ultra-high-pressure liquid chromatography-electrospray ionization-high resolution Orbitrap™ mass spectrometry was developed for this study. Validation of the method showed an LOD in the range of 10-500 µg · mL−1 for the most significant HES and dextran metabolites in the different modes. The method allows retrospective data analysis and can be implemented in existing high-resolution mass spectrometry-based doping control screening analysis. PMID:24899772

  1. A novel method for generating xeno-free human feeder cells for human embryonic stem cell culture.

    PubMed

    Meng, Guoliang; Liu, Shiying; Krawetz, Roman; Chan, Michael; Chernos, Judy; Rancourt, Derrick E

    2008-06-01

    Long-term cultures of human embryonic stem (hES) cells require a feeder layer for maintaining cells in an undifferentiated state and increasing karyotype stability. In routine hES cell culture, mouse embryonic fibroblast (MEF) feeders and animal component-containing media (FBS or serum replacement) are commonly used. However, the use of animal materials increases the risk of transmitting pathogens to hES cells and therefore is not optimal for use in cultures intended for human transplantation. There are other limitations with conventional feeder cells, such as MEFs, which have a short lifespan and can only be propagated five to six passages before senescing. Several groups have investigated maintaining existing hES cell lines and deriving new hES cell lines on human feeder layers. However, almost all of these human source feeder cells employed in previous studies were derived and cultured in animal component conditions. Even though one group previously reported the derivation and culture of human foreskin fibroblasts (HFFs) in human serum-containing medium, this medium is not optimal because HFFs routinely undergo senescence after 10 passages when cultured in human serum. In this study we have developed a completely animal-free method to derive HFFs from primary tissues. We demonstrate that animal-free (AF) HFFs do not enter senescence within 55 passages when cultured in animal-free conditions. This methodology offers alternative and completely animal-free conditions for hES cell culture, thus maintaining hES cell morphology, pluripotency, karyotype stability, and expression of pluripotency markers. Moreover, no difference in hES cell maintenance was observed when they were cultured on AF-HFFs of different passage number or independent derivations.

  2. Early warning signals of regime shifts in coupled human-environment systems.

    PubMed

    Bauch, Chris T; Sigdel, Ram; Pharaon, Joe; Anand, Madhur

    2016-12-20

    In complex systems, a critical transition is a shift in a system's dynamical regime from its current state to a strongly contrasting state as external conditions move beyond a tipping point. These transitions are often preceded by characteristic early warning signals such as increased system variability. However, early warning signals in complex, coupled human-environment systems (HESs) remain little studied. Here, we compare critical transitions and their early warning signals in a coupled HES model to an equivalent environment model uncoupled from the human system. We parameterize the HES model, using social and ecological data from old-growth forests in Oregon. We find that the coupled HES exhibits a richer variety of dynamics and regime shifts than the uncoupled environment system. Moreover, the early warning signals in the coupled HES can be ambiguous, heralding either an era of ecosystem conservationism or collapse of both forest ecosystems and conservationism. The presence of human feedback in the coupled HES can also mitigate the early warning signal, making it more difficult to detect the oncoming regime shift. We furthermore show how the coupled HES can be "doomed to criticality": Strategic human interactions cause the system to remain perpetually in the vicinity of a collapse threshold, as humans become complacent when the resource seems protected but respond rapidly when it is under immediate threat. We conclude that the opportunities, benefits, and challenges of modeling regime shifts and early warning signals in coupled HESs merit further research.

  3. Early warning signals of regime shifts in coupled human–environment systems

    PubMed Central

    Bauch, Chris T.; Sigdel, Ram; Pharaon, Joe; Anand, Madhur

    2016-01-01

    In complex systems, a critical transition is a shift in a system’s dynamical regime from its current state to a strongly contrasting state as external conditions move beyond a tipping point. These transitions are often preceded by characteristic early warning signals such as increased system variability. However, early warning signals in complex, coupled human–environment systems (HESs) remain little studied. Here, we compare critical transitions and their early warning signals in a coupled HES model to an equivalent environment model uncoupled from the human system. We parameterize the HES model, using social and ecological data from old-growth forests in Oregon. We find that the coupled HES exhibits a richer variety of dynamics and regime shifts than the uncoupled environment system. Moreover, the early warning signals in the coupled HES can be ambiguous, heralding either an era of ecosystem conservationism or collapse of both forest ecosystems and conservationism. The presence of human feedback in the coupled HES can also mitigate the early warning signal, making it more difficult to detect the oncoming regime shift. We furthermore show how the coupled HES can be “doomed to criticality”: Strategic human interactions cause the system to remain perpetually in the vicinity of a collapse threshold, as humans become complacent when the resource seems protected but respond rapidly when it is under immediate threat. We conclude that the opportunities, benefits, and challenges of modeling regime shifts and early warning signals in coupled HESs merit further research. PMID:27815533

  4. Efficient differentiation of human embryonic stem cells to definitive endoderm.

    PubMed

    D'Amour, Kevin A; Agulnick, Alan D; Eliazer, Susan; Kelly, Olivia G; Kroon, Evert; Baetge, Emmanuel E

    2005-12-01

    The potential of human embryonic stem (hES) cells to differentiate into cell types of a variety of organs has generated much excitement over the possible use of hES cells in therapeutic applications. Of great interest are organs derived from definitive endoderm, such as the pancreas. We have focused on directing hES cells to the definitive endoderm lineage as this step is a prerequisite for efficient differentiation to mature endoderm derivatives. Differentiation of hES cells in the presence of activin A and low serum produced cultures consisting of up to 80% definitive endoderm cells. This population was further enriched to near homogeneity using the cell-surface receptor CXCR4. The process of definitive endoderm formation in differentiating hES cell cultures includes an apparent epithelial-to-mesenchymal transition and a dynamic gene expression profile that are reminiscent of vertebrate gastrulation. These findings may facilitate the use of hES cells for therapeutic purposes and as in vitro models of development.

  5. The efficacy and safety of colloid resuscitation in the critically ill.

    PubMed

    Hartog, Christiane S; Bauer, Michael; Reinhart, Konrad

    2011-01-01

    Despite evidence from clinical studies and meta-analyses that resuscitation with colloids or crystalloids is equally effective in critically ill patients, and despite reports from high-quality clinical trials and meta-analyses regarding nephrotoxic effects, increased risk of bleeding, and a trend toward higher mortality in these patients after the use of hydroxyethyl starch (HES) solutions, colloids remain popular and the use of HES solutions is increasing worldwide. We investigated the major rationales for colloid use, namely that colloids are more effective plasma expanders than crystalloids, that synthetic colloids are as safe as albumin, that HES solutions have the best risk/benefit profile among the synthetic colloids, and that the third-generation HES 130/0.4 has fewer adverse effects than older starches. Evidence from clinical studies shows that comparable resuscitation is achieved with considerably less crystalloid volumes than frequently suggested, namely, <2-fold the volume of colloids. Albumin is safe in intensive care unit patients except in patients with closed head injury. All synthetic colloids, namely, dextran, gelatin, and HES have dose-related side effects, which are coagulopathy, renal failure, and tissue storage. In patients with severe sepsis, higher doses of HES may be associated with excess mortality. The assumption that third-generation HES 130/0.4 has fewer adverse effects is yet unproven. Clinical trials on HES 130/0.4 have notable shortcomings. Mostly, they were not performed in intensive care unit or emergency department patients, had short observation periods of 24 to 48 hours, used cumulative doses below 1 daily dose limit (50 mL/kg), and used unsuitable control fluids such as other HES solutions or gelatins. In conclusion, the preferred use of colloidal solutions for resuscitation of patients with acute hypovolemia is based on rationales that are not supported by clinical evidence. Synthetic colloids are not superior in critically ill

  6. Impairment of renal function using hyperoncotic colloids in a two hit model of shock: a prospective randomized study

    PubMed Central

    2012-01-01

    Introduction One of the therapeutic essentials in severe sepsis and septic shock is an adequate fluid replacement to restore and maintain circulating plasma volume, improve organ perfusion and nutritive microcirculatory flow. The type of solution to be used as a fluid replacement remains under discussion. The aim of the study was to evaluate the effects of clinically used fluid replacement solutions on renal function and inflammatory response. Methods A total of 23 anesthetized and ventilated female German Landrace pigs were investigated over 19 hours using a two-hit model that combined hemorrhagic and septic shock. The septic shock was induced using an Escherichia coli laden clot placed into the abdominal cavity. Infusions of 6% hydroxyethylstarch 130/0.42 in acetate (6% HES 130), 4% gelatin in acetate (4% gelatin) and 10% hydroxyethylstarch 200/0.5 in saline (10% HES200) compared to Ringer's acetate (RAc) were used for fluid replacement to maintain a central venous pressure of 12 mmHg. Ringer's acetate was also used in the sham-treated group (SHAM). Results At study end the cardiac output (10% HES200 143 ± 48 ml/kgBW; 6% HES130 171 ± 47 ml/kgBW; RAc 137 ± 32 ml/kgBW; 4% gelatin 160 ± 42 ml/kgBW), as well as mean arterial pressure did not differ between groups. N-acetyl-beta-D-glucosamidase was significantly higher in the hydroxyethylstarch 200 (157 ± 115 U/g creatinine; P < 0.05) group compared to hydroxyethylstarch 130 (24 ± 9 U/g creatinine), Ringer's acetate (2 ± 3 U/g creatinine) and SHAM (21 ± 15 U/g creatinine) at the study's end. Creatinine significantly increased by 87 ± 84 percent of baseline in the 10% HES200 group compared to RAc and 6% HES130. We demonstrated in the histology of the kidneys a significant increase in osmotic-nephrosis like lesions for 4% gelatin compared to RAc, 6% HES130 and SHAM. Urine output was lowest in the 10% HES200 and 4% gelatin group, however not significantly. Interleukin(IL)-6 levels were significantly elevated in

  7. Trace levels of mitomycin C disrupt genomic integrity and lead to DNA damage response defect in long-term-cultured human embryonic stem cells.

    PubMed

    Zhou, Di; Lin, Ge; Zeng, Si-Cong; Xiong, Bo; Xie, Ping-Yuan; Cheng, De-Hua; Zheng, Qing; Ouyang, Qi; Zhou, Xiao-Ying; Tang, Wei-Ling; Sun, Yi; Lu, Guang-Ying; Lu, Guang-Xiu

    2015-01-01

    How to maintain the genetic integrity of cultured human embryonic stem (hES) cells is raising crucial concerns for future clinical use in regenerative medicine. Mitomycin C(MMC), a DNA damage agent, is widely used for preparation of feeder cells in many laboratories. However, to what extent MMC affects the karyotypic stability of hES cells is not clear. Here, we measured residual MMC using High Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry following each step of feeder preparation and found that 2.26 ± 0.77 and 3.50 ± 0.92 ng/ml remained in mouse feeder cells and human feeder cells, respectively. In addition, different amounts of MMC caused different chromosomal aberrations in hES cells. In particular, one abnormality, dup(1)(p32p36), was the same identical to one we previously reported in another hES cell line. Using Affymetrix SNP 6.0 arrays, the copy number variation changes of the hES cells maintained on MMC-inactivated feeders (MMC-feeder) were significantly more than those cultured on γ-inactivated feeder (IR-feeder) cells. Furthermore, DNA damage response (DDR) genes were down-regulated during long-term culture in the MMC-containing system, leading to DDR defect and shortened telomeres of hES cells, a sign of genomic instability. Therefore, MMC-feeder and MMC-induced genomic variation present an important safety problem that would limit such hES from being applied for future clinic use and drug screening.

  8. Ionizing Radiation Alters Human Embryonic Stem Cell Properties and Differentiation Capacity by Diminishing the Expression of Activin Receptors.

    PubMed

    Luft, Sabine; Arrizabalaga, Onetsine; Kulish, Ireen; Nasonova, Elena; Durante, Marco; Ritter, Sylvia; Schroeder, Insa S

    2017-03-01

    Exposure of the embryo to ionizing radiation (IR) is detrimental as it can cause genotoxic stress leading to immediate and latent consequences such as functional defects, malformations, or cancer. Human embryonic stem (hES) cells can mimic the preimplantation embryo and help to assess the biological effects of IR during early development. In this study, we describe the alterations H9 hES cells exhibit after X-ray irradiation in respect to cell cycle progression, apoptosis, genomic stability, stem cell signaling, and their capacity to differentiate into definitive endoderm. Early postirradiation, hES cells responded with an arrest in G2/M phase, elevated apoptosis, and increased chromosomal aberrations. Significant downregulation of stem cell signaling markers of the TGF beta-, Wnt-, and Hedgehog pathways was observed. Most prominent were alterations in the expression of activin receptors. However, hES cells responded differently depending on the culture conditions chosen for maintenance. Enzymatically passaged cells were less sensitive to IR than mechanically passaged ones showing fewer apoptotic cells and fewer changes in the stem cell signaling 24 h after irradiation, but displayed higher levels of chromosomal aberrations. Even though many of the observed changes were transient, surviving hES cells, which were differentiated 4 days postirradiation, showed a lower efficiency to form definitive endoderm than their mock-irradiated counterparts. This was demonstrated by lower expression levels of SOX17 and microRNA miR-375. In conclusion, hES cells are a suitable tool for the IR risk assessment during early human development. However, careful choice of the culture methods and a vigorous monitoring of the stem cell quality are mandatory for the use of these cells. Exposure to IR influences the stem cell properties of hES cells even when immediate radiation effects are overcome. This warrants consideration in the risk assessment of radiation effects during the

  9. From Observation to Information: Data-Driven Understanding of on Farm Yield Variation

    PubMed Central

    Jiménez, Daniel; Dorado, Hugo; Cock, James; Prager, Steven D.; Delerce, Sylvain; Grillon, Alexandre; Andrade Bejarano, Mercedes; Benavides, Hector; Jarvis, Andy

    2016-01-01

    Agriculture research uses “recommendation domains” to develop and transfer crop management practices adapted to specific contexts. The scale of recommendation domains is large when compared to individual production sites and often encompasses less environmental variation than farmers manage. Farmers constantly observe crop response to management practices at a field scale. These observations are of little use for other farms if the site and the weather are not described. The value of information obtained from farmers’ experiences and controlled experiments is enhanced when the circumstances under which it was generated are characterized within the conceptual framework of a recommendation domain, this latter defined by Non-Controllable Factors (NCFs). Controllable Factors (CFs) refer to those which farmers manage. Using a combination of expert guidance and a multi-stage analytic process, we evaluated the interplay of CFs and NCFs on plantain productivity in farmers’ fields. Data were obtained from multiple sources, including farmers. Experts identified candidate variables likely to influence yields. The influence of the candidate variables on yields was tested through conditional forests analysis. Factor analysis then clustered harvests produced under similar NCFs, into Homologous Events (HEs). The relationship between NCFs, CFs and productivity in intercropped plantain were analyzed with mixed models. Inclusion of HEs increased the explanatory power of models. Low median yields in monocropping coupled with the occasional high yields within most HEs indicated that most of these farmers were not using practices that exploited the yield potential of those HEs. Varieties grown by farmers were associated with particular HEs. This indicates that farmers do adapt their management to the particular conditions of their HEs. Our observations confirm that the definition of HEs as recommendation domains at a small-scale is valid, and that the effectiveness of distinct

  10. Developmentally regulated HEART STOPPER, a mitochondrially targeted L18 ribosomal protein gene, is required for cell division, differentiation, and seed development in Arabidopsis

    PubMed Central

    Zhang, Hongyu; Luo, Ming; Day, Robert C.; Talbot, Mark J.; Ivanova, Aneta; Ashton, Anthony R.; Chaudhury, Abed M.; Macknight, Richard C.; Hrmova, Maria; Koltunow, Anna M.

    2015-01-01

    Evidence is presented for the role of a mitochondrial ribosomal (mitoribosomal) L18 protein in cell division, differentiation, and seed development after the characterization of a recessive mutant, heart stopper (hes). The hes mutant produced uncellularized endosperm and embryos arrested at the late globular stage. The mutant embryos differentiated partially on rescue medium with some forming callus. HES (At1g08845) encodes a mitochondrially targeted member of a highly diverged L18 ribosomal protein family. The substitution of a conserved amino residue in the hes mutant potentially perturbs mitoribosomal function via altered binding of 5S rRNA and/or influences the stability of the 50S ribosomal subunit, affecting mRNA binding and translation. Consistent with this, marker genes for mitochondrial dysfunction were up-regulated in the mutant. The slow growth of the endosperm and embryo indicates a defect in cell cycle progression, which is evidenced by the down-regulation of cell cycle genes. The down-regulation of other genes such as EMBRYO DEFECTIVE genes links the mitochondria to the regulation of many aspects of seed development. HES expression is developmentally regulated, being preferentially expressed in tissues with active cell division and differentiation, including developing embryos and the root tips. The divergence of the L18 family, the tissue type restricted expression of HES, and the failure of other L18 members to complement the hes phenotype suggest that the L18 proteins are involved in modulating development. This is likely via heterogeneous mitoribosomes containing different L18 members, which may result in differential mitochondrial functions in response to different physiological situations during development. PMID:26105995

  11. Significance of Stat3 Signaling in Epithelial Cell Differentiation of Fetal Mouse Lungs

    PubMed Central

    Kameyama, Hiroki; Kudoh, Shinji; Hatakeyama, Jun; Matuo, Akira; Ito, Takaaki

    2017-01-01

    To study the significance of signal transducer and activator of transcription (Stat) 3 in lung epithelial development of fetal mice, we examined fetal mouse lungs, focusing on the expression of Clara cell secretory protein (CCSP), Forkhead box protein J1 (Foxj1), calcitonin gene-related peptide (CGRP), phosphorylated Stat3 (Tyr705), and hairy/enhancer of split (Hes) 1, and observed cultured fetal lungs upon treatment with IL-6, a Stat3 activator, or cucurbitacin I, a Stat3 inhibitor. Moreover, the interaction of Stat3 signaling and Hes1 was studied using Hes1 gene-deficient mice. Phosphorylated Stat3 was detected in fetal lungs and, immunohistochemically, phosphorylated Stat3 was found to be co-localized in developing Clara cells, but not in ciliated cells. In the organ culture studies, upon treatment with IL-6, quantitative RT-PCR revealed that CCSP mRNA increased with increasing Stat3 phosphorylation, while cucurbitacin I decreased Hes1, CCSP, Foxj1 and CGRP mRNAs with decreasing Stat3 phosphorylation. In the lungs of Hes1 gene-deficient mice, Stat3 phosphorylation was not markedly different from wild-type mice, the expression of CCSP and CGRP was enhanced, and the treatment of IL-6 or cucurbitacin I induced similar effects on mouse lung epithelial differentiation regardless of Hes1 expression status. Stat3 signaling acts in fetal mouse lung development, and seems to regulate Clara cell differentiation positively. Hes1 could regulate Clara cell differentiation in a manner independent from Stat3 signaling. PMID:28386145

  12. A chimeric vitronectin: IGF-I protein supports feeder-cell-free and serum-free culture of human embryonic stem cells.

    PubMed

    Manton, Kerry J; Richards, Sean; Van Lonkhuyzen, Derek; Cormack, Luke; Leavesley, David; Upton, Zee

    2010-09-01

    The therapeutic use of human embryonic stem (hES) cells is severely limited by safety concerns regarding their culture in media containing animal-derived or nondefined factors and on animal-derived feeder cells. Thus, there is a pressing need to develop culture techniques that are xeno-free, fully defined, and synthetic. Our laboratory has discovered that insulin-like growth factor (IGF) and vitronectin (VN) bind to each other resulting in synergistic short-term functional effects in several cell types, including keratinocytes and breast epithelial cells. We have further refined this complex into a single chimeric VN:IGF-I protein that functionally mimics the effects obtained upon binding of IGF-I to VN. The aim of the current study was to determine whether hES cells can be serially propagated in feeder-cell-free and serum-free conditions using medium containing our novel chimeric VN:IGF-I protein. Here we demonstrate that hES cells can be serially propagated and retain their undifferentiated state in vitro for up to 35 passages in our feeder-cell-free, serum-free, chemically defined media. We have utilized real-time polymerase chain reaction (PCR), immunofluorescence, and fluorescence-activated cell sorter (FACS) analysis to show that the hES cells have maintained an undifferentiated phenotype. In vitro differentiation assays demonstrated that the hES cells retain their pluripotent potential and the karyotype of the hES cells remains unchanged. This study demonstrates that the novel, fully defined, synthetic VN:IGF-I chimera-containing medium described herein is a viable alternative to media containing serum, and that in conjunction with laminin-coated plates facilitates feeder-cell-free and serum-free growth of hES.

  13. Efficient derivation of Chinese human embryonic stem cell lines from frozen embryos.

    PubMed

    Li, Chunliang; Yang, Ying; Lu, Xiaowei; Sun, Yijuan; Gu, Junjie; Feng, Yun; Jin, Ying

    2010-04-01

    Human embryonic stem (hES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Their unique properties of self-renewal and pluripotency make them an attractive tool for basic research as well as a potential cell resource for therapy. However, each hES cell line demonstrates different identity. It is desirable to obtain more fully characterized hES cell lines with newly developed technologies associated with hES cell culture. Here, we report our experience of efficient derivation of three new Chinese hES cell lines (SHhES2, SHhES3, and SHhES4) from in vitro fertilization discarded embryos donated by women with polycystic ovary syndrome. These cell lines were derived under conditions minimizing exposure to animal components and maintained at an undifferentiated state for long-term culture. They retained a normal karyotype and expressed ALP, OCT4, SOX2, SSEA-4, TRA-1-60 and TRA-1-81. RT-PCR analysis also revealed high expression levels of pluripotency markers such as OCT4, LEFTY A, SOX2, TDGF-1, THY1, FGF4, NANOG, and REX1. When suspended in low-attachment culture dishes, embryoid bodies formed and were comprised of various differentiated cell types from all three embryonic germ layers. However, well-shaped teratomas were only harvested from line SHhES2, not from SHhES3 and SHhES4, indicating that the differentiation ability in vivo differs among the three cell lines. Collectively, the three new hES cell lines were established and fully characterized. The effort paves the way toward generating hES cell lines without contamination by animal components. All of these cell lines are available by contact Ying Jin at yjin@sibs.ac.cn.

  14. Tracking the Fate of Surface Plasmon Resonance-Generated Hot Electrons by In Situ SERS Surveying of Catalyzed Reaction.

    PubMed

    Liu, Rui; He, Zuoliang; Sun, Jiefang; Liu, Jingfu; Jiang, Guibin

    2016-12-01

    Plasmonic catalysis is an emerging process that utilizes surface plasmon resonance (SPR) process to harnesses solar energy for the promotion of catalyzed reactions. In most cases, SPR generated hot electrons (HEs) play an indispensable role in this solar-chemical energy shift process. Therefore, understanding the effectiveness of the HEs in promoting chemical reactions, and identifying the key factors that contribute to this utilization efficiency is of profound importance. Herein, the authors outline an in situ surface enhanced Raman spectroscopy protocol to track the fate of HEs. This is based on the unheeded HEs-acceleration nature of the p-nitirothiophenol hydrogenation reaction. By this way, the authors discover that unlike Au@Pd nanostructures which experience a 20-fold increase in rate constant, HEs primary leak to surrounding H(+) /O species through Ag pinholes in Ag@Pd. This work sheds light on why Ag is seldom employed as a plasmonic cocatalyst, and provides a new viewpoint to design plasmonic nanocatalysts with efficient light utilization.

  15. Characterization of Notch Signalling Pathway Members in Normal Prostate, Prostatic Intraepithelial Neoplasia (PIN) and Prostatic Adenocarcinoma.

    PubMed

    Soylu, Hakan; Acar, Nuray; Ozbey, Ozlem; Unal, Betul; Koksal, Ismail Turker; Bassorgun, Ibrahim; Ciftcioglu, Akif; Ustunel, Ismail

    2016-01-01

    Prostate Cancer (PCa) holds the second place in terms of cancer-related mortality rate among men. The Notch signalling pathway regulates the proliferation and differentiation in embryonic and adult tissues and determines the cell fate. The body of knowledge in the present literature is currently controversial about the effect of the Notch pathway on prostatic cancer. Therefore, the present study aimed to examine the immunolocalization and expression levels of Notch1-4, Jagged1-2, Delta, HES1 and HES5 from among the members of the Notch signalling pathway in tissues of normal, prostatic intraepithelial neoplasia (PIN) and malignant prostate. The current study included a sample of 20 patients with localised prostatic adenocarcinoma, 18 patients with high grade PIN (H-PIN) and 18 normal prostatic tissue. Immunolocalisations of Notch1, 2, 3, 4, Jagged1, 2, Delta, HES1 and HES5 were identified through the immunohistochemical method. The findings of the present study showed that all in-scope members of the Notch signalling pathway were localised in PIN structures to a greater extent than in other tissues and from amongst these members, specifically Notch1, Notch4, Jagged1 and HES1 were at more significant levels. Consequently, the findings of the present study may indicate that the Notch signalling pathway can play a role especially in the formation of PIN structures.

  16. Hydroxyethyl starch-based polymers for the controlled release of biomacromolecules from hydrogel microspheres.

    PubMed

    Wöhl-Bruhn, Stefanie; Bertz, Andreas; Harling, Steffen; Menzel, Henning; Bunjes, Heike

    2012-08-01

    Hydrogels are promising delivery systems for the controlled release of biomacromolecules. Based on previous studies, hydrogels were prepared from crosslinkable hydroxyethyl starch with new linker groups to improve mechanical and release properties of the resulting hydrogels. Polyethylene glycol methacrylate with two different spacer lengths was used to obtain polymers (HES-P(EG)(n)MA) with increased hydrophilicity and degradability, whereas a polymer with methacrylate linker directly at the starch backbone (HES-MA) resulted in a less degradable polymer. Hydrogel disks were obtained by UV crosslinking and characterized by swelling and rheological measurements. The hydrogel strength was strongly influenced by the polymer concentration. Using a water-in-water emulsion process, hydrogel microspheres were prepared. The influence of the type of the linker, the degree of substitution and the phase ratio in the production process on the properties of the microspheres was investigated. Depending on the preparation parameters, particles with narrow particle size distribution and encapsulation efficiencies of up to more than 80% for FITC-dextran 70 kDa (FD70) were obtained. Incorporated FITC-labeled IgG showed a faster release from hydrogel microspheres than FD70. The release rate of incorporated FD70 could be adjusted by using different polymers (HES-P(EG)(10)MA>HES-P(EG)(6)MA>HES-MA).

  17. Stemina biomarker discovery.

    PubMed

    Cezar, Gabriela G; Donley, Elizabeth L R

    2008-09-01

    Stemina Biomarker Discovery was established in 2006 to commercialize technology developed by Dr Gabriela Cezar at the University of Wisconsin (WI, USA). Stemina's cell-based assays arise from the strategic convergence of two cutting edge technologies: metabolomics and human embryonic stem (hES) cells. Stemina analyzes the small molecules secreted by hES cells and differentiated cell types such as neural and heart cells derived from hES cells by liquid chromatography mass spectrometry at its state-of-the-art facilities in Madison, WI, USA. Stemina's first technology platform has identified a dynamic set of small molecules in the extracellular secretome of hES cells secreted in response to exposure to a library of known teratogens. Alterations to small molecules in the biochemical pathway(s) of hES cells are mapped in silico to identify biomarkers of toxicity for drug screening and development in an all human system. These small human molecules may then be translated in vivo as biomarkers of toxic response and disease.

  18. The Ultrastructural Signature of Human Embryonic Stem Cells.

    PubMed

    Underwood, Jean M; Becker, Klaus A; Stein, Gary S; Nickerson, Jeffrey A

    2017-04-01

    The epigenetics and molecular biology of human embryonic stem cells (hES cells) have received much more attention than their architecture. We present a more complete look at hES cells by electron microscopy, with a special emphasis on the architecture of the nucleus. We propose that there is an ultrastructural signature of pluripotent human cells. hES cell nuclei lack heterochromatin, including the peripheral heterochromatin, that is common in most somatic cell types. The absence of peripheral heterochromatin may be related to the absence of lamins A and C, proteins important for linking chromatin to the nuclear lamina and envelope. Lamins A and C expression and the development of peripheral heterochromatin were early steps in the development of embryoid bodies. While hES cell nuclei had abundant nuclear pores, they also had an abundance of nuclear pores in the cytoplasm in the form of annulate lamellae. These were not a residue of annulate lamellae from germ cells or the early embryos from which hES cells were derived. Subnuclear structures including nucleoli, interchromatin granule clusters, and Cajal bodies were observed in the nuclear interior. The architectural organization of human ES cell nuclei has important implications for cell structure-gene expression relationships and for the maintenance of pluripotency. J. Cell. Biochem. 118: 764-774, 2017. © 2016 Wiley Periodicals, Inc.

  19. Notch1 and its ligands Delta-like and Jagged are expressed and active in distinct cell populations in the postnatal mouse brain.

    PubMed

    Stump, Gila; Durrer, André; Klein, Anne-Laurence; Lütolf, Simone; Suter, Ueli; Taylor, Verdon

    2002-06-01

    Notch signaling plays a pivotal role in the regulation of vertebrate neurogenesis. However, in vitro experiments suggest that Notch1 may also be involved in the regulation of later stages of brain development. We have addressed putative roles in the central nervous system by examining the expression of Notch signaling cascade components in the postnatal mouse brain. In situ mRNA hybridization revealed that Notch1 is associated with cells in the subventricular zone, the dentate gyrus and the rostromigratory stream, all regions of continued neurogenesis in the postnatal brain. In addition, Notch1 is expressed at low levels throughout the cortex and olfactory bulb and shows striking expression in the cerebellar Purkinje cell layer. The Notch ligands, including Delta-like1 and 3 and Jagged1 and Jagged2, show distinct expression patterns in the developing and adult brain overlapping that of Notch1. In addition, the downstream targets of the Notch signaling cascade Hes1, Hes3, Hes5 and the intrinsic Notch regulatory proteins Numb and Numblike also show active signaling in distinct brain regions. Hes5 coincides with the majority of Notch1 expression and can be detected in the cerebral cortex, cerebellum and putative germinal zones. Hes3, on the other hand, shows a restricted expression in cerebellar Purkinje cells. The distribution of Notch1 and its putative ligands suggest distinct roles in specific subsets of cells in the postnatal brain including putative stem cells and differentiated neurons.

  20. Topology and dynamics of the zebrafish segmentation clock core circuit.

    PubMed

    Schröter, Christian; Ares, Saúl; Morelli, Luis G; Isakova, Alina; Hens, Korneel; Soroldoni, Daniele; Gajewski, Martin; Jülicher, Frank; Maerkl, Sebastian J; Deplancke, Bart; Oates, Andrew C

    2012-01-01

    During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel. To explain the observed single and double mutant phenotypes of her1, her7, and hes6 mutant embryos in our dynamic model, we postulate that the availability and effective stability of the dimers with DNA binding activity is controlled in a "dimer cloud" that contains all possible dimeric combinations between the three factors. This feature of our model predicts that Hes6 protein levels should oscillate despite constant hes6 mRNA production, which we confirm experimentally using novel Hes6 antibodies. The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks.

  1. Hypereosinophilic syndrome presenting with multiple organ infiltration and deep venous thrombosis

    PubMed Central

    Gao, Su-jun; Wei, Wei; Chen, Jiang-tao; Tan, Ye-hui; Yu, Cheng-bao; Litzow, Mark Robert; Liu, Qiu-ju

    2016-01-01

    Abstract Background: Hypereosinophilic syndrome (HES) can be fatal, particularly when eosinophils infiltrate vital organs and/or if extensive thrombosis develops. However there are no standard recommendations for the use of anticoagulant therapy of HES in the setting of thrombosis. Methods: We herein present a case of a 46-year-old female who presented with marked peripheral eosinophilia with symptoms of multi-organ infiltration and extensive deep venous thrombosis (DVT). In this case, evaluation was carried out before the diagnosis was established, and timely standard-dose corticosteroids combined with a new oral anticoagulant (NOAC) therapy were carried out. Results: These measures resulted in a rapid response and long-term disease control. Conclusion: Although there are no data to support which anticoagulant is preferred in this setting, this case indicates that the new oral anticoagulants may play an important role in the treatment of thrombosis in HES. PMID:27583887

  2. Hesperidin and rutin, antioxidant citrus flavonoids, attenuate cisplatin-induced nephrotoxicity in rats.

    PubMed

    Kamel, Kamel M; Abd El-Raouf, Ola M; Metwally, Salwa A; Abd El-Latif, Hekma A; El-sayed, Mostafa E

    2014-07-01

    This study aimed to assess the protective effect of hesperidin (HES) and rutin (RUT) against cisplatin-induced nephrotoxicity in male rats. Cisplatin (5 mg/kg, intraperitoneal) caused significant increases in serum sodium, blood urea nitrogen, serum creatinine, total sodium and potassium excreted in urine, urine volume, and lipid peroxides measured as the malondialdehyde content of kidney, with significant decreases in serum total protein, creatinine clearance, reduced glutathione content of kidney, and kidney superoxide dismutase activity as compared with the control group. On the other hand, administration of HES (200 mg/kg, per oral [p.o.]) or RUT (30 mg/kg, p.o.) for 14 days with a single cisplatin dose on the tenth day ameliorated the cisplatin-induced nephrotoxicity as indicated by the restoration of kidney function and oxidative stress biomarkers. Furthermore, the test drugs reduced the histopathological changes induced by cisplatin. In conclusion, HES and RUT showed protective effects against cisplatin-induced nephrotoxicity.

  3. NEPRO: a novel Notch effector for maintenance of neural progenitor cells in the neocortex.

    PubMed

    Saito, Tetsuichiro

    2012-01-01

    The Notch pathway is essential for maintaining neural progenitor cells (NPCs) in the developing brain. Activation of the pathway is sufficient to maintain NPCs, whereas loss-of-function mutations in the critical components of the pathway cause precocious neuronal differentiation and NPC depletion. Hairy and Enhancer of split (Hes)-type transcription factors have long been thought to be the only Notch effectors for the maintenance of NPCs. Recently, a novel nuclear protein, Nepro, has been identified as another critical effector of Notch. The Notch pathway is bifurcated into Nepro and Hes-type proteins in the early development of the neocortex. The combination of Nepro and Hes-type proteins is necessary and sufficient for maintaining NPCs downstream of Notch.

  4. U.S. Hydropower Resource Assessment Final Report

    SciTech Connect

    A. M. Conner; J. E. Francfort; B. N. Rinehart

    1998-12-01

    To provide a more accurate assessment of the domestic undeveloped hydropower capacity, the US Department of Energy's Hydropower Program developed a computer model, Hydropower Evaluation Software (HES). HES allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental, legal, and institutional attributes present, and generate reports based on these suitability factors. This report describes the development of HES, its data requirements, and its application to each state assessment; in addition, it summarizes the data derivation process and data for the states. Modeling of the undeveloped hydropower resources in the US, based on environmental, legal, and institutional constraints, has identified 5,677 sites that have a total undeveloped capacity of about 30,000 megawatts.

  5. U.S. Hydropower Resource Assessment Final Report

    SciTech Connect

    Conner, Alison M.; Francfort, James E.; Rinehart, Ben N.

    1998-12-01

    To provide a more accurate assessment of the domestic undeveloped hydropower capacity, the U.S. Department of Energy’s Hydropower Program developed a computer model, Hydropower Evaluation Software (HES). HES allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental, legal, and institutional attributes present, and generate reports based on these suitability factors. This report describes the development of HES, its data requirements, and its application to each state assessment; in addition, it summarizes the data derivation process and data for the states. Modeling of the undeveloped hydropower resources in the United States, based on environmental, legal, and institutional constraints, has identified 5,677 sites that have a total undeveloped capacity of about 30,000 megawatts.

  6. Nuclear Hybrid Energy Systems Regional Studies: West Texas & Northeastern Arizona

    SciTech Connect

    Garcia, Humberto E.; Chen, Jun; Kim, Jong Suk; McKellar, Michael George; Deason, Wesley R; Richard B. Vilim; Bragg-Sitton, Shannon M.; Boardman, Richard D.

    2015-04-01

    The primary objective of this study is to conduct a preliminary dynamic analysis of two realistic hybrid energy systems (HES) including a nuclear reactor as the main baseload heat generator (denoted as nuclear HES or nuclear hybrid energy systems [[NHES]) and to assess the local (e.g., HES owners) and system (e.g., the electric grid) benefits attainable by the application of NHES in scenarios with multiple commodity production and high penetration of renewable energy. It is performed for regional cases not generic examples based on available resources, existing infrastructure, and markets within the selected regions. This study also briefly addresses the computational capabilities developed to conduct such analyses, reviews technical gaps, and suggests some research paths forward.

  7. Nuclear Hybrid Energy Systems - Regional Studies. West Texas and Northeastern Arizona

    SciTech Connect

    Garcia, Humberto E.; Chen, Jun; Kim, Jong S.; McKellar, Michael G.; Deason, Wesley R.; Vilim, Richard B.; Bragg-Sitton, Shannon M.; Boardman, Richard D.

    2015-04-01

    The primary objective of this study is to conduct a preliminary dynamic analysis of two realistic hybrid energy systems (HES) including a nuclear reactor as the main baseload heat generator (denoted as nuclear HES or nuclear hybrid energy systems [NHES]) and to assess the local (e.g., HES owners) and system (e.g., the electric grid) benefits attainable by the application of NHES in scenarios with multiple commodity production and high penetration of renewable energy. It is performed for regional cases - not generic examples - based on available resources, existing infrastructure, and markets within the selected regions. This study also briefly addresses the computational capabilities developed to conduct such analyses, reviews technical gaps, and suggests some research paths forward.

  8. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells.

    PubMed

    Kehat, Izhak; Khimovich, Leonid; Caspi, Oren; Gepstein, Amira; Shofti, Rona; Arbel, Gil; Huber, Irit; Satin, Jonathan; Itskovitz-Eldor, Joseph; Gepstein, Lior

    2004-10-01

    Cell therapy is emerging as a promising strategy for myocardial repair. This approach is hampered, however, by the lack of sources for human cardiac tissue and by the absence of direct evidence for functional integration of donor cells into host tissues. Here we investigate whether cells derived from human embryonic stem (hES) cells can restore myocardial electromechanical properties. Cardiomyocyte cell grafts were generated from hES cells in vitro using the embryoid body differentiating system. This tissue formed structural and electromechanical connections with cultured rat cardiomyocytes. In vivo integration was shown in a large-animal model of slow heart rate. The transplanted hES cell-derived cardiomyocytes paced the hearts of swine with complete atrioventricular block, as assessed by detailed three-dimensional electrophysiological mapping and histopathological examination. These results demonstrate the potential of hES-cell cardiomyocytes to act as a rate-responsive biological pacemaker and for future myocardial regeneration strategies.

  9. US hydropower resource assessment for Colorado

    SciTech Connect

    Francfort, J.E.

    1994-05-01

    The US Department of Energy is developing an estimate of the hydropower development potential in this country. Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE, menu-driven software application. HES allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the State of Colorado.

  10. An Optimization Framework for Dynamic Hybrid Energy Systems

    SciTech Connect

    Wenbo Du; Humberto E Garcia; Christiaan J.J. Paredis

    2014-03-01

    A computational framework for the efficient analysis and optimization of dynamic hybrid energy systems (HES) is developed. A microgrid system with multiple inputs and multiple outputs (MIMO) is modeled using the Modelica language in the Dymola environment. The optimization loop is implemented in MATLAB, with the FMI Toolbox serving as the interface between the computational platforms. Two characteristic optimization problems are selected to demonstrate the methodology and gain insight into the system performance. The first is an unconstrained optimization problem that optimizes the dynamic properties of the battery, reactor and generator to minimize variability in the HES. The second problem takes operating and capital costs into consideration by imposing linear and nonlinear constraints on the design variables. The preliminary optimization results obtained in this study provide an essential step towards the development of a comprehensive framework for designing HES.

  11. Success of short-term, higher-dose imatinib mesylate to induce clinical response in FIP1L1-PDGFRalpha-negative hypereosinophilic syndrome.

    PubMed

    Butterfield, Joseph H

    2009-08-01

    Presence of the oncogenic mutation FIP1L1-PDGFRalpha in hypereosinophilic patients is predictive of hematologic response to imatinib mesylate. However, most patients with hypereosinophilic syndrome (HES) do not have this mutation and have not responded to imatinib doses traditionally successful in patients who test positive for FIP1L1-PDGFRalpha. A patient with FIP1L1-PDGFRalpha-negative HES who had intolerance of interferon alpha-2b and hydroxyurea was treated with escalating doses of imatinib. At 800 mg of imatinib daily, eosinophilia was controlled, allowing prednisone tapering and control of clinical and laboratory-detected abnormalities. HES patients who test negative for FIP1L1-PDGFRalpha may benefit from a trial of higher-dose imatinib.

  12. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.

    PubMed

    D'Amour, Kevin A; Bang, Anne G; Eliazer, Susan; Kelly, Olivia G; Agulnick, Alan D; Smart, Nora G; Moorman, Mark A; Kroon, Evert; Carpenter, Melissa K; Baetge, Emmanuel E

    2006-11-01

    Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

  13. A Rare Case of Aortic Valve Thrombosis in Patient with Idiopathic Hypereosinophilic Syndrome

    PubMed Central

    Grolla, Elisabetta; Dalla Vestra, Michele; Bonanni, Luca; Cutolo, Ada; Rigo, Fausto

    2015-01-01

    Idiopathic hypereosinophilic syndrome (HES) is characterized by persistent eosinophilia and eosinophil-mediated organ-system damage. Cardiac thrombosis and thromboembolic complications represent common causes of morbidity and mortality and usually involve cardiac ventricles or mitral and prosthetic valves, while the involvement of the aortic valve is extremely rare in HES. Here we report peculiar multimodality images of an atypical case of extended thrombosis of the aortic valve, complicated by myocardial ischemia and asymptomatic cerebral ischemia, likely due to thrombus embolization, occurring in a 48-year-old man with HES. Prompt anticoagulant and steroid therapy lead to rapid and complete resolution of the thrombotic lesions, allowing preserving the native valve and preventing further embolic events. PMID:26435854

  14. Early fluid resuscitation with hyperoncotic hydroxyethyl starch 200/0.5 (10%) in severe burn injury

    PubMed Central

    2010-01-01

    Introduction Despite large experience in the management of severe burn injury, there are still controversies regarding the best type of fluid resuscitation, especially during the first 24 hours after the trauma. Therefore, our study addressed the question whether hyperoncotic hydroxyethyl starch (HES) 200/0.5 (10%) administered in combination with crystalloids within the first 24 hours after injury is as effective as 'crystalloids only' in severe burn injury patients. Methods 30 consecutive patients were enrolled to this prospective interventional open label study and assigned either to a traditional 'crystalloids only' or to a 'HES 200/0.5 (10%)' volume resuscitation protocol. Total amount of fluid administration, complications such as pulmonary failure, abdominal compartment syndrome, sepsis, renal failure and overall mortality were assessed. Cox proportional hazard regression analysis was performed for binary outcomes and adjustment for potential confounders was done in the multivariate regression models. For continuous outcome parameters multiple linear regression analysis was used. Results Group differences between patients receiving crystalloids only or HES 200/0.5 (10%) were not statistically significant. However, a large effect towards increased overall mortality (adjusted hazard ratio 7.12; P = 0.16) in the HES 200/0.5 (10%) group as compared to the crystalloids only group (43.8% versus 14.3%) was present. Similarly, the incidence of renal failure was 25.0% in the HES 200/0.5 (10%) group versus 7.1% in the crystalloid only group (adjusted hazard ratio 6.16; P = 0.42). Conclusions This small study indicates that the application of hyperoncotic HES 200/0.5 (10%) within the first 24 hours after severe burn injury may be associated with fatal outcome and should therefore be used with caution. Trial registration NCT01120730. PMID:20584291

  15. From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

    PubMed Central

    Tiedemann, Hendrik B.; Schneltzer, Elida; Zeiser, Stefan; Hoesel, Bastian; Beckers, Johannes; Przemeck, Gerhard K. H.; de Angelis, Martin Hrabě

    2012-01-01

    The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice. PMID:22761566

  16. Hyperbranched polyglycerol as a colloid in cold organ preservation solutions.

    PubMed

    Gao, Sihai; Guan, Qiunong; Chafeeva, Irina; Brooks, Donald E; Nguan, Christopher Y C; Kizhakkedathu, Jayachandran N; Du, Caigan

    2015-01-01

    Hydroxyethyl starch (HES) is a common colloid in organ preservation solutions, such as in University of Wisconsin (UW) solution, for preventing graft interstitial edema and cell swelling during cold preservation of donor organs. However, HES has undesirable characteristics, such as high viscosity, causing kidney injury and aggregation of erythrocytes. Hyperbranched polyglycerol (HPG) is a branched compact polymer that has low intrinsic viscosity. This study investigated HPG (MW-0.5 to 119 kDa) as a potential alternative to HES for cold organ preservation. HPG was synthesized by ring-opening multibranching polymerization of glycidol. Both rat myocardiocytes and human endothelial cells were used as an in vitro model, and heart transplantation in mice as an in vivo model. Tissue damage or cell death was determined by both biochemical and histological analysis. HPG polymers were more compact with relatively low polydispersity index than HES in UW solution. Cold preservation of mouse hearts ex vivo in HPG solutions reduced organ damage in comparison to those in HES-based UW solution. Both size and concentration of HPGs contributed to the protection of the donor organs; 1 kDa HPG at 3 wt% solution was superior to HES-based UW solution and other HPGs. Heart transplants preserved with HPG solution (1 kDa, 3%) as compared with those with UW solution had a better functional recovery, less tissue injury and neutrophil infiltration in syngeneic recipients, and survived longer in allogeneic recipients. In cultured myocardiocytes or endothelial cells, significantly more cells survived after cold preservation with the HPG solution than those with the UW solution, which was positively correlated with the maintenance of intracellular adenosine triphosphate and cell membrane fluidity. In conclusion, HPG solution significantly enhanced the protection of hearts or cells during cold storage, suggesting that HPG is a promising colloid for the cold storage of donor organs and cells in

  17. Hyperbranched Polyglycerol as a Colloid in Cold Organ Preservation Solutions

    PubMed Central

    Gao, Sihai; Guan, Qiunong; Chafeeva, Irina; Brooks, Donald E.; Nguan, Christopher Y. C.; Kizhakkedathu, Jayachandran N.; Du, Caigan

    2015-01-01

    Hydroxyethyl starch (HES) is a common colloid in organ preservation solutions, such as in University of Wisconsin (UW) solution, for preventing graft interstitial edema and cell swelling during cold preservation of donor organs. However, HES has undesirable characteristics, such as high viscosity, causing kidney injury and aggregation of erythrocytes. Hyperbranched polyglycerol (HPG) is a branched compact polymer that has low intrinsic viscosity. This study investigated HPG (MW-0.5 to 119 kDa) as a potential alternative to HES for cold organ preservation. HPG was synthesized by ring-opening multibranching polymerization of glycidol. Both rat myocardiocytes and human endothelial cells were used as an in vitro model, and heart transplantation in mice as an in vivo model. Tissue damage or cell death was determined by both biochemical and histological analysis. HPG polymers were more compact with relatively low polydispersity index than HES in UW solution. Cold preservation of mouse hearts ex vivo in HPG solutions reduced organ damage in comparison to those in HES-based UW solution. Both size and concentration of HPGs contributed to the protection of the donor organs; 1 kDa HPG at 3 wt% solution was superior to HES-based UW solution and other HPGs. Heart transplants preserved with HPG solution (1 kDa, 3%) as compared with those with UW solution had a better functional recovery, less tissue injury and neutrophil infiltration in syngeneic recipients, and survived longer in allogeneic recipients. In cultured myocardiocytes or endothelial cells, significantly more cells survived after cold preservation with the HPG solution than those with the UW solution, which was positively correlated with the maintenance of intracellular adenosine triphosphate and cell membrane fluidity. In conclusion, HPG solution significantly enhanced the protection of hearts or cells during cold storage, suggesting that HPG is a promising colloid for the cold storage of donor organs and cells in

  18. Validating the use of Hospital Episode Statistics data and comparison of costing methodologies for economic evaluation: an end-of-life case study from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP)

    PubMed Central

    Thorn, Joanna C; Turner, Emma L; Hounsome, Luke; Walsh, Eleanor; Down, Liz; Verne, Julia; Donovan, Jenny L; Neal, David E; Hamdy, Freddie C; Martin, Richard M; Noble, Sian M

    2016-01-01

    Objectives To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies. Design Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes. Setting 7 UK secondary care centres. Population A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. Results Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months. Conclusions Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials. Trial registration number ISRCTN92187251

  19. Evaluation of intravenous hydroxylethyl starch, intravenous albumin 20%, and oral cabergoline for prevention of ovarian hyperstimulation syndrome in patients undergoing ovulation induction

    PubMed Central

    Ghahiri, Ataollah; Mogharehabed, Neda; Movahedi, Minoo; Hosseini, Naeimehossadat

    2015-01-01

    Background: The purpose of this study was to compare the three different strategies, intravenous (IV) hydroxylethyl starch (HES), IV human albumin (HA), and oral Cabergoline (Cb) in the prevention of ovarian hyperstimulation syndrome (OHSS). Materials and Methods: In this prospective randomized clinical trial, 91 women at high risk of developing OHSS were allocated into the three groups, group one received 2 vial (2 × 50 ml) IV HAs, in group two, 1000 ml of 6% HES was administered IV, both groups 30 min after oocyte retrieval within 4 h. Group three, 31 infertile patients received oral Cb 0.5 mg daily for 7 days after oocyte retrieval. Patients were visited 14 ± 1 days after in-vitro fertilization and if β-human chorionic gonadotropin level >10, transvaginal ultrasonography was performed 2 weeks later to confirm intrauterine pregnancy. Patients were followed up weekly for 3 months for signs of OHSS and were also informed about the signs of OHSS and asked to contact immediately if any symptoms of were detected. Results: None of the participants in group HES developed severe OHSS and only 3 patients (10%) developed mild to moderate OHSS. The incident of severe OHSS was significantly higher in albumin group compared to Cb and HES group (P = 0.033 and P < 0.001, respectively). Also, the probability of developing severe OHSS was higher in Cb group than group HES (P = 0.031). Conclusion: The findings from this study suggest that administration of 1000 ml of HES 6% has a higher prophylactic effect compared to administration of IV HA and oral Cb. PMID:26622260

  20. Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector

    PubMed Central

    2012-01-01

    Introduction Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of Aβ on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor κB (NF-κB) by impeding the tyrosine phosphorylation of I-κBα. As a result, the expression of the homologue of Enhancer-of split 1 (Hes1) gene is downregulated and ultimately, gamma-aminobutyric acid (GABA)-ergic connectivity is lost. Methods Hes1 activity was promoted in cultured hippocampal neurons by overexpressing a Hes1-encoding plasmid or by upregulating this gene by activating NF-κB through different approaches (overexpressing either the I-κB kinaseβ, or p65/RelA/NF-κB). Alternatively neurons were exposed to TGFβ1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-κB activation was measured using the dual-luciferase reporter assay. Results The expression of Hes1 abolished the effects of Aβ on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGFβ1, a known neuroprotector, could counteract the deleterious effects of Aβ by inducing NF-κB activation following the serine phosphorylation of I-κBα. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. Conclusion Our data define some of the mechanisms involved in Aβ-mediated cell death and they point to potential means to counteract this noxious activity. PMID:22849569

  1. The Implementation of an Integrated Information System for Substance Use Screening in General Medical Settings

    PubMed Central

    Sorensen-Alawad, A.; Carney, B.L.; Persand, I.; Cruz, A.; Botticelli, M.; Pressman, K.; Adams, W.G.; Brolin, M.; Alford, D.P.

    2014-01-01

    Summary The Massachusetts Screening, Brief Intervention and Referral to Treatment (MASBIRT) Program, a substance use screening program in general medical settings, created a web-based, point-of-care (POC), application – the MASBIRT Portal (the “Portal”) to meet program goals. Objectives We report on development and implementation of the Portal. Methods Five year program process outcomes recorded by an independent evaluator and an anonymous survey of Health Educator’s (HEs) adoption, perceptions and Portal use with a modified version of the Technology Readiness Index are described. [8] Specific management team members, selected based on their roles in program leadership, development and implementation of the Portal and supervision of HEs, participated in semi-structured, qualitative interviews. Results At the conclusion of the program 73% (24/33) of the HEs completed a survey on their experience using the Portal. HEs reported that the Portal made recording screening information easy (96%); improved planning their workday (83%); facilitated POC data collection (84%); decreased time dedicated to data entry (100%); and improved job satisfaction (59%). The top two barriers to use were “no or limited wireless connectivity” (46%) and “the tablet was too heavy/bulky to carry” (29%). Qualitative management team interviews identified strategies for successful HIT implementation: importance of engaging HEs in outlining specifications and workflow needs, collaborative testing prior to implementation and clear agreement on data collection purpose, quality requirements and staff roles. Discussion Overall, HEs perceived the Portal favorably with regard to time saving ability and improved workflow. Lessons learned included identifying core requirements early during system development and need for managers to institute and enforce consistent behavioral work norms. Conclusion Barriers and HEs’ views of technology impacted the utilization of the MASBIRT Portal

  2. Value-Driven Design and Sensitivity Analysis of Hybrid Energy Systems using Surrogate Modeling

    SciTech Connect

    Wenbo Du; Humberto E. Garcia; William R. Binder; Christiaan J. J. Paredis

    2001-10-01

    A surrogate modeling and analysis methodology is applied to study dynamic hybrid energy systems (HES). The effect of battery size on the smoothing of variability in renewable energy generation is investigated. Global sensitivity indices calculated using surrogate models show the relative sensitivity of system variability to dynamic properties of key components. A value maximization approach is used to consider the tradeoff between system variability and required battery size. Results are found to be highly sensitive to the renewable power profile considered, demonstrating the importance of accurate renewable resource modeling and prediction. The documented computational framework and preliminary results represent an important step towards a comprehensive methodology for HES evaluation, design, and optimization.

  3. [A propose to suspend the use of hydroxyethyl starch for fluid resuscitation in shock phase of severe burns].

    PubMed

    Luo, Gao-xing; Peng, Yi-zhi; Wu, Jun

    2013-10-01

    Based on the result of randomized controlled trials and meta-analysis recently, the infusion of hydroxyethyl starch (HES) was not shown to over match routine crystalline solution in exerting resuscitation effect against hypovolemia of patients with burn shock, severe systematic infection, or other critical conditions, on the other hand, it may induce renal toxicity and other toxic and side effects. Since the pathological mechanism underlying hypovolemia during shock phase after burn is similar to that of severe systemic infection, we propose to suspend the use of HES for fluid resuscitation during the shock phase of severe burn until further elucidation.

  4. Long Term Cryopreservation of Dog Granulocytes.

    DTIC Science & Technology

    1981-12-21

    using DINGO , HES and autologous plasma as the cryoprotectant. Our laboratory, employing CCE of whole blood and buffy coats, has also reported...cryopreservation of dog (1), baboon (3) and guinea pig granulocytes (4) using 5% DMSO, 6% HES, and 4% bovine serum albumin (BSA) formulated in Normosol-R pH 7.4...Hunt, S.M., Sehepis, R., Roy, A.J., Liss, R., Valeri, C.R.: In vitro distribution of cryopreserved guinea pig granulocytes. Cryobiology 1980; 17:1-11. S

  5. Voluven, a new colloid solution.

    PubMed

    Mizzi, Anna; Tran, Thanh; Karlnoski, Rachel; Anderson, Ashley; Mangar, Devanand; Camporesi, Enrico M

    2011-09-01

    Hydroxyethyl starch (HES) 130/0.4 (Voluven, Fresenius/Hospira, Germany) is indicated for the treatment and prophylaxis of hypovolemia. As the Voluven molecule is smaller than those of other available hydroxyethyl starch products, it is associated with less plasma accumulation and can be safely used in patients with renal impairment. Previous studies have demonstrated that Voluven has comparable effects on volume expansion and hemodynamics as other available HES products. Voluven is also associated with fewer effects on coagulation and may be an acceptable alternative to albumin for volume expansion in situations in which other starches are contraindicated secondary to risk of coagulopathy.

  6. Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and wnt-beta-catenin Pathways in CD44(+) Gastric Cancer Stem Cells.

    PubMed

    Barat, Samarpita; Chen, Xi; Cuong Bui, Khac; Bozko, Przemyslaw; Götze, Julian; Christgen, Matthias; Krech, Till; Malek, Nisar P; Plentz, Ruben R

    2017-02-03

    Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44(+) CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44(+) CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44(+) CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44(+) CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44(+) CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44(+) CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. © Stem Cells Translational Medicine 2017.

  7. Evaluation of 1066 ToxCast Chemicals in a human stem cell assay for developmental toxicity (SOT)

    EPA Science Inventory

    To increase the diversity of assays used to assess potential developmental toxicity, the ToxCast chemical library was screened in the Stemina devTOX quickPREDICT assay using human embryonic stem (hES) cells. A model for predicting teratogenicity was based on a training set of 23 ...

  8. 75 FR 6756 - Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing and Immediate Effectiveness of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-10

    .... Technologies Inc. 178 AMAT Applied Materials 155 MCO Moody's Corp. Inc. 117 AMR AMR Corp 217 MET MetLife Inc... Occidental Petroleum Corp. 190 BCRX BioCryst 158 PARD Poniard Pharmaceuticals Pharmaceuticals Inc. Inc. 218... United Technologies Corp. 170 HBC HSBC Holdings PLC. 204 WFR MEMC Electronic Materials Inc. 197 HES...

  9. 75 FR 6740 - Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing and Immediate Effectiveness of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-10

    .... 178 AMAT Applied Materials Inc. 155 MCO Moody's Corp. 117 AMR AMR Corp. 217 MET MetLife Inc. 166 ANF.... 190 BCRX BioCryst Pharmaceuticals Inc. 158 PARD Poniard Pharmaceuticals Inc. 218 BK Bank of New York... Holdings PLC. 204 WFR MEMC Electronic Materials Inc. 197 HES Hess Corp. 115 WFT Weatherford...

  10. Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis

    PubMed Central

    Shimojo, Hiromi; Isomura, Akihiro; Ohtsuka, Toshiyuki; Kori, Hiroshi; Miyachi, Hitoshi; Kageyama, Ryoichiro

    2016-01-01

    Notch signaling regulates tissue morphogenesis through cell–cell interactions. The Notch effectors Hes1 and Hes7 are expressed in an oscillatory manner and regulate developmental processes such as neurogenesis and somitogenesis, respectively. Expression of the mRNA for the mouse Notch ligand Delta-like1 (Dll1) is also oscillatory. However, the dynamics of Dll1 protein expression are controversial, and their functional significance is unknown. Here, we developed a live-imaging system and found that Dll1 protein expression oscillated in neural progenitors and presomitic mesoderm cells. Notably, when Dll1 expression was accelerated or delayed by shortening or elongating the Dll1 gene, Dll1 oscillations became severely dampened or quenched at intermediate levels, as modeled mathematically. Under this condition, Hes1 and Hes7 oscillations were also dampened. In the presomitic mesoderm, steady Dll1 expression led to severe fusion of somites and their derivatives, such as vertebrae and ribs. In the developing brain, steady Dll1 expression inhibited proliferation of neural progenitors and accelerated neurogenesis, whereas optogenetic induction of Dll1 oscillation efficiently maintained neural progenitors. These results indicate that the appropriate timing of Dll1 expression is critical for the oscillatory networks and suggest the functional significance of oscillatory cell–cell interactions in tissue morphogenesis. PMID:26728556

  11. Environmental Assessment Aerial Application of Pesticide for Mosquito Control at Tyndall Air Force Base and Vicinity

    DTIC Science & Technology

    2008-10-27

    caught or taken from osprey. Also include in the diet are crippled waterfowl, rabbits, muskrat , road killed animals and other carrion. The USFWS has...squirrel); marshland animal communities (e.g., muskrat , beaver)~ game and non~game bird specjes (e.g;, ducks, geese1 hawks, warblers); replHes and

  12. Significance of Notch1-signaling pathway in human pancreatic development and carcinogenesis.

    PubMed

    Hu, Huankai; Zhou, Lan; Awadallah, Amad; Xin, Wei

    2013-05-01

    In animal studies, Notch1-signaling pathway plays an important role in the pancreatic embryogenesis by promoting pancreatic progenitor cells self-renewal and exocrine linage development. The persistent activation of Notch pathway could arrest the organ development and keep cells at an undifferentiated stage. Studies have shown that Notch1-signaling pathway is upregulated in invasive pancreatic ductal adenocarcinoma (PDAC). Here we examined the expression pattern of Notch1 and Hes1 in human fetal pancreatic tissues to elucidate the role of Notch1 in human pancreatic embryonic development. We also compared Notch1 expression in tissues from PDAC, chronic pancreatitis and pancreatic intraepithelial neoplasm. Our data show that Notch1/Hes1-signaling pathway is activated during early pancreatic embryogenesis and reaches the highest at birth. After pancreas is fully developed, Notch1/Hes1 pathway is inactivated even though Notch1 protein cell-surface expression is upregulated. We also showed that the expression of both Notch1 and Hes1 are present in 50% (33/66) of PDACs, but not in pancreatic intraepithelial neoplasms. These findings indicate that Notch1 activation is only apparent in late stage of pancreatic carcinogenesis, suggesting that treatment with Notch-signaling inhibitors including γ-secretase should be selectively used for PDACs with confirmed Notch1-signaling activation.

  13. The Elementary and Secondary Education Act at Fifty: A Changing Federal Role in American Education

    ERIC Educational Resources Information Center

    Nelson, Adam R.

    2016-01-01

    For this first "History of Education Quarterly Policy Forum," we invited participants in the special Plenary Session at the 2015 Annual Meeting of the History of Education Society (HES) in St. Louis to publish their remarks on the historical significance of the Elementary and Secondary Education Act (ESEA) at fifty. Organized and…

  14. Investigating Students' Ideas about Buoyancy and the Influence of Haptic Feedback

    ERIC Educational Resources Information Center

    Minogue, James; Borland, David

    2016-01-01

    While haptics (simulated touch) represents a potential breakthrough technology for science teaching and learning, there is relatively little research into its differential impact in the context of teaching and learning. This paper describes the testing of a haptically enhanced simulation (HES) for learning about buoyancy. Despite a lifetime of…

  15. Hypercapnic encephalopathy syndrome: a new frontier for non-invasive ventilation?

    PubMed

    Scala, Raffaele

    2011-08-01

    According to the classical international guidelines, non-invasive ventilation is contraindicated in hypercapnic encephalopathy syndrome (HES) due to the poor compliance to ventilatory treatment of confused/agitated patients and the risk of aspirative pneumonia related to lack of airways protection. As a matter of fact, conventional mechanical ventilation has been recommended as "golden standard" in these patients. However, up to now there are not controlled data that have demonstrated in HES the advantage of conventional mechanical ventilation vs non-invasive ventilation. In fact, patients with altered mental status have been systematically excluded from the randomised and controlled trials performed with non-invasive ventilation in hypercapnic acute respiratory failure. Recent studies have clearly demonstrated that an initial cautious NPPV trial in selected HES patients may be attempt as long as there are no other contraindications and the technique is provided by experienced caregivers in a closely monitored setting where ETI is always readily available. The purpose of this review is to report the physiologic rationale, the clinical feasibility and the still open questions about the careful use of non-invasive ventilation in HES as first-line ventilatory strategy in place of conventional mechanical ventilation via endotracheal intubation.

  16. Recovering Valuable Phosphates: Chemical Biotechnology as a Problem Solver for the Environment.

    PubMed

    Heinzelmann, Elsbeth

    2015-01-01

    Researchers from the HES-SO Valais/Wallis have demonstrated how to extract phosphate from sewage sludge on the laboratory scale using renewable energy sources from a microbial fuel cell. The mobilized phosphate barely contains heavy metals and can be used to produce fertilizer of marketable quality. The necessary energy comes from a sewage treatment plant and causes no additional costs.

  17. Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro.

    PubMed

    Bruner-Tran, Kaylon L; Osteen, Kevin G; Taylor, Hugh S; Sokalska, Anna; Haines, Kaitlin; Duleba, Antoni J

    2011-01-01

    Endometriosis is a common gynecologic disorder characterized by ectopic attachment and growth of endometrial tissues. Resveratrol is a natural polyphenol with antiproliferative and anti-inflammatory properties. Our objective was to study the effects of resveratrol on human endometriotic implants in a nude mouse model and to examine its impact on human endometrial stromal (HES) cell invasiveness in vitro. Human endometrial tissues were obtained from healthy donors. Endometriosis was established in oophorectomized nude mice by intraperitoneal injection of endometrial tissues. Mice were treated with 17β-estradiol (8 mg, silastic capsule implants) alone (n = 16) or with resveratrol (6 mg/mouse; n = 20) for 10-12 and 18-20 days beginning 1 day after tissue injection. Mice were killed and endometrial implants were evaluated. A Matrigel invasion assay was used to examine the effects of resveratrol on HES cells. We assessed number and size of endometriotic implants in vivo and Matrigel invasion in vitro. Resveratrol decreased the number of endometrial implants per mouse by 60% (P < 0.001) and the total volume of lesions per mouse by 80% (P < 0.001). Resveratrol (10-30 μM) also induced a concentration-dependent reduction of invasiveness of HES by up to 78% (P < 0.0001). Resveratrol inhibits development of endometriosis in the nude mouse and reduces invasiveness of HES cells. These observations may aid in the development of novel treatments of endometriosis.

  18. High Speed Video for Airborne Instrumentation Application

    NASA Technical Reports Server (NTRS)

    Tseng, Ting; Reaves, Matthew; Mauldin, Kendall

    2006-01-01

    A flight-worthy high speed color video system has been developed. Extensive system development and ground and environmental. testing hes yielded a flight qualified High Speed Video System (HSVS), This HSVS was initially used on the F-15B #836 for the Lifting Insulating Foam Trajectory (LIFT) project.

  19. Influence of magnetic field on aqueous two-phase extraction of horse ferritin in the polyethylene glycol/hydroxyethyl starch system.

    PubMed

    Zielińska-Dawidziak, Magdalena; Błaszak, Roman; Piasecka-Kwiatkowska, Dorota

    2012-02-24

    The presented experiments show the model of expectation of equine spleen ferritin extraction in a new aqueous two-phase system which was formed by mixing polyethylene glycol (PEG) and hydroxyethyl starch (HES). The tendency of the protein to migrate in the analyzed systems was dependent on the concentrations of HES and PEG as well as PEG molecular weight. The highest concentration of ferritin in the top phase (rich in PEG) was recorded in the system composed of 6% PEG 3000 and 3% HES. The obtained concentration was 0.88 mg mL(-1). The lowest concentration was 0.42 mg mL(-1) in the system composed of 5% PEG 6000 and 1% HES. Next the influence of the magnetic field on ferritin accumulation was analyzed. Selected samples were placed between homogeneous (S/S) or heterogeneous magnetic poles (N/S and S/N). It was observed that after the application of the magnetic field the extraction of ferritin into the PEG rich phase increased in every examined system. That increase was as high as 1.67-fold ferritin concentration in the PEG phase as compared with the total concentration of ferritin in the system before separation. Introduction of the magnetic field to two-phase extraction systems is shown as an effective method of changing the partition coefficient of ferritin.

  20. Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells.

    PubMed

    Becker, Klaus A; Ghule, Prachi N; Lian, Jane B; Stein, Janet L; van Wijnen, Andre J; Stein, Gary S

    2010-02-01

    Self-renewal of pluripotent human embryonic stem (hES) cells utilizes an abbreviated cell cycle that bypasses E2F/pRB-dependent growth control. We investigated whether self-renewal is alternatively regulated by cyclin/CDK phosphorylation of the p220(NPAT)/HiNF-P complex to activate histone gene expression at the G1/S phase transition. We show that cyclin D2 is prominently expressed in pluripotent hES cells, but cyclin D1 eclipses cyclin D2 during differentiation. Depletion of cyclin D2 or p220(NPAT) causes a cell cycle defect in G1 reflected by diminished phosphorylation of p220(NPAT), decreased cell cycle dependent histone H4 expression and reduced S phase progression. Thus, cyclin D2 and p220(NPAT) are principal cell cycle regulators that determine competency for self-renewal in pluripotent hES cells. While pRB/E2F checkpoint control is relinquished in human ES cells, fidelity of physiological regulation is secured by cyclin D2 dependent activation of the p220(NPAT)/HiNF-P mechanism that may explain perpetual proliferation of hES cells without transformation or tumorigenesis.

  1. A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences

    PubMed Central

    Smith, Julianne; Grizot, Sylvestre; Arnould, Sylvain; Duclert, Aymeric; Epinat, Jean-Charles; Chames, Patrick; Prieto, Jesús; Redondo, Pilar; Blanco, Francisco J.; Bravo, Jerónimo; Montoya, Guillermo; Pâques, Frédéric; Duchateau, Philippe

    2006-01-01

    Meganucleases, or homing endonucleases (HEs) are sequence-specific endonucleases with large (>14 bp) cleavage sites that can be used to induce efficient homologous gene targeting in cultured cells and plants. These findings have opened novel perspectives for genome engineering in a wide range of fields, including gene therapy. However, the number of identified HEs does not match the diversity of genomic sequences, and the probability of finding a homing site in a chosen gene is extremely low. Therefore, the design of artificial endonucleases with chosen specificities is under intense investigation. In this report, we describe the first artificial HEs whose specificity has been entirely redesigned to cleave a naturally occurring sequence. First, hundreds of novel endonucleases with locally altered substrate specificity were derived from I-CreI, a Chlamydomonas reinhardti protein belonging to the LAGLIDADG family of HEs. Second, distinct DNA-binding subdomains were identified within the protein. Third, we used these findings to assemble four sets of mutations into heterodimeric endonucleases cleaving a model target or a sequence from the human RAG1 gene. These results demonstrate that the plasticity of LAGLIDADG endonucleases allows extensive engineering, and provide a general method to create novel endonucleases with tailored specificities. PMID:17130168

  2. THE CONTRIBUTION OF AMBIENT PM2.5 TO TOTAL PERSONAL EXPOSURES: RESULTS FROM A POPULATION EXPOSURE MODEL FOR PHILADELPHIA, PA

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) is currently developing an integrated human exposure source-to-dose modeling system (HES2D). This modeling system will incorporate population exposure modules that use a probabilistic approach to predict population exposu...

  3. Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

    EPA Science Inventory

    Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

  4. Advanced Microgrid Concepts and Technologies Workshop

    DTIC Science & Technology

    2013-04-01

    Electronic Design Automation (EDA) Tools for Efficient, Reliable, and Resilient Microgrid: Towards Energy Informed Plug-and-Play Power Systems —Prof...Integrate decomposition:  Human and control system interdependency information embedded into computational intelligence tools  Develop a control...generation. • HES process integration: o Utilize dynamic process modeling and systems design and optimization tools developed by INL. o Test beds

  5. Differences in Perceived Implementation of a Standard versus Peer-Led Interactive Substance Abuse Prevention Program

    ERIC Educational Resources Information Center

    Valente, Thomas W.; Okamoto, Janet; Pumpuang, Patchareeya; Okamoto, Paula; Sussman, Steve

    2007-01-01

    Objective: To assess perceived implementation of 2 substance-abuse prevention programs: a standard one and a peer-led interactive one. Methods: Data from 16 health educators were collected after 504 classroom sessions, 63 of which were observed by 24 monitors. Results: In the interactive program, health educators (HEs) followed the curriculum less…

  6. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome.

    PubMed

    Griffin, John H; Leung, Joey; Bruner, Rebecca J; Caligiuri, Michael A; Briesewitz, Roger

    2003-06-24

    Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha (PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe-PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.

  7. Evolution of particle size in turbid discharge plumes

    DTIC Science & Technology

    2016-06-07

    Evolution of particle size in turbid discharge plumes Paul S. Hill Department of Oceanography Dalhousie University Halifax, Nova Scotia, CANADA B3H...ES) Dalhousie University,Department of Oceanography,Halifax, Nova Scotia B3H 4J1, Canada, 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING

  8. Applying GIS to Develop a Web-Based Spatial-Person-Temporal History Educational System

    ERIC Educational Resources Information Center

    Lo, Jia-Jiunn; Chang, Chuen-Jung; Tu, Hsiao-Han; Yeh, Shiou-Wen

    2009-01-01

    Developing interactive history learning materials to facilitate historical thinking is one of the challenges in history teaching and learning. This study developed a web-based history educational system, which has used the acronym HES-SPATO (history educational system based on SPATO), to increase the understandability of history learning…

  9. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability.

    PubMed

    Ong, Chin-Tong; Cheng, Hui-Teng; Chang, Li-Wei; Ohtsuka, Toshiyuki; Kageyama, Ryoichiro; Stormo, Gary D; Kopan, Raphael

    2006-02-24

    All four mammalian Notch proteins interact with a single DNA-binding protein (RBP-jkappa), yet they are not equivalent in activating target genes. Parallel assays of three Notch-responsive promoters in several cell lines revealed that relative activation strength is dependent on protein module and promoter context more than the cellular context. Each Notch protein reads binding site orientation and distribution on the promoter differently; Notch1 performs extremely well on paired sites, and Notch3 prefers single sites in conjunction with a proximal zinc finger transcription factor. Although head-head sites can elicit a Notch response on their own, use of CBS (CSL binding site) in tail-tail orientation is context-dependent. Bias for specific DNA elements is achieved by interplay between the N-terminal RAM (RBP-jkappa-associated molecule/ankyrin region), which interprets CBS proximity and orientation, and the C-terminal transactivation domain that interacts specifically with the transcription machinery or nearby factors. To confirm the prediction that modular design underscores the evolution of functional divergence between Notch proteins, we generated a synthetic Notch protein (Notch1 ankyrin with Notch3 transactivation domain) that displayed superior signaling strength on the hes5 promoter. Consistent with the prediction that "preferred" targets (Hes1) should respond faster and at lower Notch concentration than other targets, we showed that Hes5-GFP was extinguished fast and recovered slowly, whereas Hes1-GFP was inhibited late and recovered quickly after a pulse of DAPT in metanephroi cultures.

  10. Effects of polyethylene glycol and hydroxyethyl starch in University of Wisconsin preservation solution on human red blood cell aggregation and viscosity.

    PubMed

    Mosbah, I B; Franco-Gou, R; Abdennebi, H B; Hernandez, R; Escolar, G; Saidane, D; Rosello-Catafau, J; Peralta, C

    2006-06-01

    University of Wisconsin (UW) preservation solution is considered an effective flush and cold storage liquid. However, recent studies have provided evidence of the hyperaggregating effect on human red blood cells (RBC) of hydroxyethyl starch (HES), one of the components of the UW solution. In contrast, preservation solutions containing polyethylene glycol (PEG) have been found to be effective for organ preservation. The aim of this study was to compare the effects of HES (50 g/L); PEG 20 kDa (50 and 30 g/L), and PEG35 kDa (1.05 g/L) added to UW on the rheologic parameters of human RBC at 4 degrees C. Sedimentation rate was measured by the Westergren procedure and blood viscosity evaluated at high shear rates using a cone/plate viscometer. Alterations in RBC morphology and aggregation were evaluated by light microscopy. RBC sedimentation and viscosity were not affected by the inversion of Na+ and K+ concentrations in UW, but were increased by HES. PEGs appeared to reduce RBC deformability with concomitant inhibition of RBC aggregation. These results were consistent with reduced viscosity for PEG-containing solutions. In conclusion, the use of PEG did not change the physiologic function of human RBCs and thus may be an alternative to HES in UW liquids.

  11. Alternatives to the Fish Early Life-Stage Test: A Research Strategy for Discovering and Annotating Adverse Outcome Pathways During Fish Development

    EPA Science Inventory

    The OECD 210 fish early life]stage (FELS) test is the primary guideline test used to estimate chronic fish toxicity, as well as support ecological risk assessments and chemical management programs around the world. As a step toward developing alternatives to the FELS test, a HES...

  12. microRNA input into a neural ultradian oscillator controls emergence and timing of alternative cell states.

    PubMed

    Goodfellow, Marc; Phillips, Nicholas E; Manning, Cerys; Galla, Tobias; Papalopulu, Nancy

    2014-03-04

    Progenitor maintenance, timed differentiation and the potential to enter quiescence are three fundamental processes that underlie the development of any organ system. In the nervous system, progenitor cells show short-period oscillations in the expression of the transcriptional repressor Hes1, while neurons and quiescent progenitors show stable low and high levels of Hes1, respectively. Here we use experimental data to develop a mathematical model of the double-negative interaction between Hes1 and a microRNA, miR-9, with the aim of understanding how cells transition from one state to another. We show that the input of miR-9 into the Hes1 oscillator tunes its oscillatory dynamics, and endows the system with bistability and the ability to measure time to differentiation. Our results suggest that a relatively simple and widespread network of cross-repressive interactions provides a unifying framework for progenitor maintenance, the timing of differentiation and the emergence of alternative cell states.

  13. Mineral nutrient recovery from pyrolysis systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bioenergy crops such as high-energy sorghum (HES), bioenergy rice, corn stover, and switchgrass can be thermo-chemically converted by pyrolysis to produce bio-oil, synthesis gas from non-condensable gases, and biochar. The biochar fraction can be recycled back to the production field to improve soil...

  14. Computerized system for hospital engineering service management

    NASA Astrophysics Data System (ADS)

    Centeno, C. A.; Gonzalez, E. A.; Cagnolo, F. J.; Olmos, C. E.

    2007-11-01

    When a Hospital Engineering Service (HES) is implemented within a health care environment, the idea is to improve service conditions and costs as well as to provide timely responses to equipment preventive maintenance and infrastructure requirements. An HES must, within the shortest possible period of time, meet the above requirements at the cost necessary to provide the service quality sought. In many cases there is a lack of minimal materials and staff who are qualified to attain the objectives that have been set. Therefore, external assistance becomes necessary. In this context, actions are often taken which, because they are not recorded, cannot be assessed in order to evaluate the HES. Since all action taken is appraised from the purely economic point of view, in the final analysis the contributions from staff remain invisible. This situation works against the possibility of quantifying the convenience of possessing an internal HES. The software support system we have developed here is oriented toward providing all the necessary data to address this issue.

  15. 75 FR 6233 - Self-Regulatory Organizations; NASDAQ OMX PHLX, Inc.; Notice of Filing and Immediate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... Technologies Corp. 170 HBC HSBC Holdings PLC. 204 WFR MEMC Electronic Materials Inc. 197 HES Hess Corp. 115 WFT... 176 M Macy's Inc. Inc. 178 AMAT Applied Materials 155 MCO Moody's Corp. Inc. 117 AMR AMR Corp. 217 MET... Energy Inc. Nemours & Co. 146 ERTS Electronic Arts 207 TCK Teck Resources Inc. Ltd. 121 EWJ iShares...

  16. 75 FR 6239 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... HBC HSBC Holdings PLC 204 WFR MEMC Electronic Materials Inc. 197 HES Hess Corp 115 WFT Weatherford.... 181 AKAM Akamai 176 M Macy's Inc. Technologies Inc 178 AMAT Applied Materials 155 MCO Moody's Corp... Suncor Energy Nemours & Co Inc. 146 ERTS Electronic Arts 207 TCK Teck Resources Inc Ltd. 121 EWJ...

  17. 75 FR 6424 - Self-Regulatory Organizations; NYSE Amex LLC; Notice of Filing and Immediate Effectiveness of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-09

    ... HBC HSBC Holdings PLC. 204 WFR MEMC Electronic Materials Inc. 197 HES Hess Corp. 115 WFT Weatherford.... Technologies Inc. 178 AMAT Applied Materials 155 MCO Moody's Corp. Inc. 117 AMR AMR Corp. 217 MET MetLife Inc... & Co. Inc. 146 ERTS Electronic Arts 207 TCK Teck Resources Inc. Ltd. 121 EWJ iShares MSCI Japan...

  18. 75 FR 6235 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... HSBC Holdings PLC. WFR MEMC Electronic Materials Inc. HES Hess Corp. WFT Weatherford International Ltd.... AMAT Applied Materials Inc. MCO Moody's Corp. AMR AMR Corp. MET MetLife Inc. ANF Abercrombie & Fitch Co... Seagate Technology. DD EI du Pont de Nemours & SU Suncor Energy Inc. Co. ERTS Electronic Arts Inc....

  19. Commander’s Emergency Response Program: A Flawed Metric

    DTIC Science & Technology

    2012-12-06

    24 Hamlet Evaluation System...Escalation 1962- 1967 provides great detail on the shortcomings of such metric systems as the “body count” and the HES ( Hamlet Evaluation System).17...metrics, such as body counts and hamlet evaluations, did not reflect progress towards victory. Since its introduction, CERP has experienced

  20. Spectroscopic investigation of Lambda hypernuclei in the wide mass region using the (e, e-prime K+) reaction

    SciTech Connect

    Satoshi N. Nakamura

    2011-09-01

    The third generation spectroscopic study of {Lambda} hypernuclei using (e,e'K{sup +}) reaction (JLab E05-115) was performed at JLab Hall-C in 2009. The experiment introduced the newly developed high-resolution electron spectrometer (HES) with the existing high-resolution kaon spectrometer (HKS). Experimental configuration, conditions, spectrometer designs and current status of analysis are presented.

  1. POPULATION EXPOSURES TO PARTICULATE MATTER: A COMPARISON OF EXPOSURE MODEL PREDICTIONS AND MEASUREMENT DATA

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) is currently developing an integrated human exposure source-to-dose modeling system (HES2D). This modeling system will incorporate models that use a probabilistic approach to predict population exposures to environmental ...

  2. Suppression of OVA-alum induced allergy by Heligmosomoides polygyrus products is MyD88-, TRIF-, regulatory T- and B cell-independent, but is associated with reduced innate lymphoid cell activation.

    PubMed

    McSorley, Henry J; Blair, Natalie F; Robertson, Elaine; Maizels, Rick M

    2015-11-01

    The murine intestinal nematode Heligmosomoides polygyrus exerts multiple immunomodulatory effects in the host, including the suppression of allergic inflammation in mice sensitized to allergen presented with alum adjuvant. Similar suppression is attained by co-administration of H. polygyrus excretory/secretory products (HES) with the sensitizing dose of ovalbumin (OVA) in alum. We investigated the mechanism of suppression by HES in this model, and found it was maintained in MyD88xTRIF-deficient mice, implying no role for helminth- or host-derived TLR ligands, or IL-1 family cytokines that signal in a MyD88- or TRIF-dependent manner. We also found suppression was unchanged in µMT mice, which lack B2 B cells, and that suppression was not abrogated when regulatory T cells were depleted in Foxp3.LuciDTR-4 mice. However, reduced IL-5 production was seen in the first 12 h after injection of OVA-alum when HES was co-administered, associated with reduced activation of IL-5(+) and IL-13(+) group 2 innate lymphoid cells. Thus, the suppressive effects of HES on alum-mediated OVA sensitization are reflected in the very earliest innate response to allergen exposure in vivo.

  3. 77 FR 43601 - Risks and Benefits of Hydroxyethyl Starch Solutions; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-25

    ... HUMAN SERVICES Food and Drug Administration Risks and Benefits of Hydroxyethyl Starch Solutions; Public... Administration (FDA) is announcing a public workshop entitled: ``Risks and Benefits of Hydroxyethyl Starch... FDA-approved hydroxyethyl starch (HES) solutions. The public workshop has been planned in...

  4. Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis.

    PubMed

    Zhang, Zhen; Gao, Feng; Kang, Xiaokui; Li, Jia; Zhang, Litong; Dong, Wentao; Jin, Zhangning; Li, Fan; Gao, Nannan; Cai, Xinwang; Yang, Shuyuan; Zhang, Jianning; Ren, Xinliang; Yang, Xinyu

    2015-04-01

    The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo.

  5. Reprogramming the pluripotent cell cycle: restoration of an abbreviated G1 phase in human induced pluripotent stem (iPS) cells

    PubMed Central

    Ghule, Prachi N.; Medina, Ricardo; Lengner, Chris J.; Mandeville, Matthew; Qiao, Meng; Dominski, Zbigniew; Lian, Jane B.; Stein, Janet L.; van Wijnen, Andre J.; Stein, Gary S.

    2011-01-01

    Induced pluripotent stem (iPS) cells derived from terminally differentiated human fibroblasts are re-programmed to possess stem cell like properties. However, the extent to which iPS cells exhibit unique properties of the human embryonic stem (hES) cell cycle remains to be established. Human ES cells are characterized by an abbreviated G1 phase (~2.5 h) and accelerated organization of subnuclear domains that mediate the assembly of regulatory machinery for histone gene expression [i.e., histone locus bodies (HLBs)]. We therefore examined cell cycle parameters of iPS cells in comparison to hES cells. Analysis of DNA synthesis (BrdU incorporation), cell cycle distribution (FACS analysis and Ki67 staining) and subnuclear organization of HLBs [immuno-fluorescence microscopy and fluorescence in situ hybridization (FISH)] revealed that human iPS cells have a short G1 phase (~2.5 h) and an abbreviated cell cycle (16–18 h). Furthermore, HLBs are formed and reorganized rapidly after mitosis (within0.5 to 1.5 h). Thus, reprogrammed iPS cells have cell cycle kinetics and dynamic subnuclear organization of regulatory machinery that are principal properties of pluripotent hES cells. Our findings support the concept that the abbreviated cell cycle of hES and iPS cells is functionally linked to pluripotency. PMID:20945438

  6. Characterization and physiological effect of tapioca maltodextrin colloid plasma expander in hemorrhagic shock and resuscitation model.

    PubMed

    Chatpun, Surapong; Sawanyawisuth, Kittisak; Wansuksri, Rungtiva; Piyachomkwan, Kuakoon

    2016-05-01

    Plasma expanders (PEs) are administered fluids to replace blood volume when massive blood loss has occured. Maltodextrin from tapioca starch was selected as a study candidate to prepare a colloid PE due to an uncomplicated production process. The formulations of mixture between tapioca maltodextrin and 0.9 % sodium chloride solution were prepared and then characterized. This was to investigate the effects of a dextrose equivalent (DE) and the concentration on the physical properties. Storage stability of each formulation was also determined and compared with clinically used PE [6 % hydroxyethyl starch (HES), 130/0.4]. The effects on the circulatory system in hamsters with hemorrhagic shock and resuscitation using prepared PE were also investigated. The results showed that low DE value led to high retrogradation, turbidity and viscosity but low colloid osmotic pressure and poor solubility. Among the prepared solutions, tapioca maltodextrin with DE6 at 10 % w/v concentration had comparable properties with 6 % HES 130/0.4. Animals resuscitated with 10 % DE6 PE had improved mean arterial blood pressure similar to those resuscitated with 6 % HES 130/0.4. However, several parameters in animals resuscitated with 10 % DE6 PE were lower than those resuscitated with 6 % HES 130/0.4, i.e., heart rate, functional capillary density. Therefore, if using tapioca maltodextrin for PE, some properties have to be considered and efficiently optimized.

  7. DEVELOPMENT OF VIBRATION RESISTANT PROPELLANTS FOR THE M91 PAD CARTRIDGE. INTEGRATED MOLDED CHARGE

    DTIC Science & Technology

    A case bonded, integrated, molded propellant charge (consisting of RDX- cellulose acetate ) was developed which met the ballistic requirements for the...containing the nitrate ester single base propellant previously used and similar to the ammonium perchlorate- cellulose acetate (HES 5808.7) propellant

  8. Physicochemical properties and responses in microcirculation of native tapioca starch-based plasma expander.

    PubMed

    Chatpun, Surapong; Meesane, Jirut; Rujirojindakul, Pairaya

    2016-02-01

    Plasma expanders (PEs) such as hydroxyethyl strach are widely used for volume replacement. The plantation and production of tapioca in Thailand is abundant which may provide a new source for PEs starch with novel properties. This work investigated the properties and circulatory effects of native tapioca starch-based PE (TPE). Various formulations of mixture between native tapioca starch and 0.9% sodium chloride solution were prepared and characterized in order to obtain the proper physicochemical and rheological properties. About 1% concentration by weight per volume of TPE was compared with 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride (HES130/0.4) using an acute hemodilution by 40% of blood volume in an animal protocol. TPE had higher turbidity and viscosity but lower colloid osmotic pressure compared with HES 130/0.4. The in vivo study demonstrated that Golden Syrian hamsters hemodiluted with TPE maintained a mean arterial blood pressure and no significant difference compared to HES 130/0.4. The arterial vasodilation and functional capillary density in the animals hemodiluted with TPE had higher values than in the animals hemodiluted with HES 130/0.4. Although the in vivo study reported positive results using this native tapioca starch-based PE, the product needs work to improve some of its physiochemical properties.

  9. [Hydroxyethyl starch--an interim report].

    PubMed

    Weidhase, R; Faude, K; Weidhase, R

    1998-01-01

    Since the beginning of this century, a few biopolymers have been used as basic materials for volume substitution. Aside from gelatin and dextran, modified starch (hydroxyethyl starch, HES) is currently the first-choice means. Due to special manufacturing processes, different hydroxyethyl starches are now available. They have several different characteristics and produce different clinical effects. These clinical properties depend on the average molecular weight and the distribution of molecular weight as well as on the degree and pattern of substitution. The duration of volume effect, one of the most important parameters for the effectiveness of a volume substitute, depends to a large degree on the substitution. Elimination of HES from serum is delayed by a high degree of substitution and a high C2/C6 ratio of the substitution pattern. The molecular parameters of HES also influence other effects, such as cumulation in various organs and hemostasis. Critical reading of current HES literature shows that many questions still have to be answered. At the same time ways and means of optimizing differential volume substitution therapy and hemodilution therapy are emerging.

  10. Conjugates of degraded and oxidized hydroxyethyl starch and sulfonylureas: synthesis, characterization, and in vivo antidiabetic activity.

    PubMed

    Abbas, Muhammad Azhar; Hameed, Shahid; Farman, Muhammad; Kressler, Jörg; Mahmood, Nasir

    2015-01-21

    Orally administered drugs usually face the problem of low water solubility, low permeability, and less retention in bloodstream leading to unsatisfactory pharmacokinetic profile of drugs. Polymer conjugation has attracted increasing interest in the pharmaceutical industry for delivering such low molecular weight (Mw) drugs as well as some complex compounds. In the present work, degraded and oxidized hydroxyethyl starch (HES), a highly biocompatible semisynthetic biopolymer, was used as a drug carrier to overcome the solubility and permeability problems. The HES was coupled with synthesized N-arylsulfonylbenzimidazolones, a class of sulfonylurea derivatives, by creating an amide linkage between the two species. The coupled products were characterized using GPC, FT-IR, (1)H NMR, and (13)C NMR spectroscopy. The experiments established the viability of covalent coupling between the biopolymer and N-arylsulfonylbenzimidazolones. The coupled products were screened for their in vivo antidiabetic potential on male albino rats. The coupling of sulfonylurea derivatives with HES resulted in a marked increase of the hypoglycemic activity of all the compounds. 2,3-Dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1H-benzimidazole coupled to HES10100 was found most potent with a 67% reduction in blood glucose level of the rats as compared to 41% reduction produced by tolbutamide and 38% by metformin.

  11. Effect of fluid loading with normal saline and 6% hydroxyethyl starch on stroke volume variability and left ventricular volume

    PubMed Central

    Kanda, Hirotsugu; Hirasaki, Yuji; Iida, Takafumi; Kanao, Megumi; Toyama, Yuki; Kunisawa, Takayuki; Iwasaki, Hiroshi

    2015-01-01

    Purpose The aim of this clinical trial was to investigate changes in stroke volume variability (SVV) and left ventricular end-diastolic volume (LVEDV) after a fluid bolus of crystalloid or colloid using real-time three-dimensional transesophageal echocardiography (3D-TEE) and the Vigileo-FloTrac™ system. Materials and methods After obtaining Institutional Review Board approval, and informed consent from the research participants, 22 patients undergoing scheduled peripheral vascular bypass surgery were enrolled in the study. The patients were randomly assigned to receive 500 mL of hydroxyethyl starch (HES; HES group, n=11) or normal saline (Saline group, n=11) for fluid replacement therapy. SVV was measured using the Vigileo-FloTrac system. LVEDV, stroke volume, and cardiac output were measured by 3D-TEE. The measurements were performed over 30 minutes before and after the fluid bolus in both groups. Results SVV significantly decreased after fluid bolus in both groups (HES group, 14.7%±2.6% to 6.9%±2.7%, P<0.001; Saline group, 14.3%±3.9% to 8.8%±3.1%, P<0.001). LVEDV significantly increased after fluid loading in the HES group (87.1±24.0 mL to 99.9±27.2 mL, P<0.001), whereas no significant change was detected in the Saline group (88.8±17.3 mL to 91.4±17.6 mL, P>0.05). Stroke volume significantly increased after infusion in the HES group (50.6±12.5 mL to 61.6±19.1 mL, P<0.01) but not in the Saline group (51.6±13.4 mL to 54.1±12.8 mL, P>0.05). Cardiac output measured by 3D-TEE significantly increased in the HES group (3.5±1.1 L/min to 3.9±1.3 L/min, P<0.05), whereas no significant change was seen in the Saline group (3.4±1.1 L/min to 3.3±1.0 L/min, P>0.05). Conclusion Administration of colloid and crystalloid induced similar responses in SVV. A higher plasma-expanding effect of HES compared to normal saline was demonstrated by the significant increase in LVEDV. PMID:26491368

  12. Distribution and differentiation of myeloid-derived suppressor cells after fluid resuscitation in mice with hemorrhagic shock*

    PubMed Central

    Jiang, Jiu-kun; Fang, Wen; Hong, Liang-jie; Lu, Yuan-qiang

    2017-01-01

    Objective: To investigate the distribution and differentiation of myeloid-derived suppressor cells (MDSCs) in hemorrhagic shock mice, which are resuscitated with normal saline (NS), hypertonic saline (HTS), and hydroxyethyl starch (HES). Methods: BALB/c mice were randomly divided into control, NS, HTS, and HES resuscitation groups. Three subgroups (n=8) in each resuscitation group were marked as 2, 24, and 72 h. Flow cytometry was used to detect the MDSCs, monocytic MDSCs (M-MDSCs), and granulocytic/neutrophilic MDSCs (G-MDSCs) in peripheral blood nucleated cells (PBNCs), spleen single-cell suspension, and bone marrow nucleated cells (BMNCs). Results: The MDSCs in BMNCs among three resuscitation groups were lower 2 h after shock, in PBNCs of the HTS group were higher, and in spleen of the NS group were lower (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios in PBNCs of the HTS and HES groups were lower (both P<0.05 vs. control). At 24 h, the MDSCs in PBNCs of the NS and HTS groups were higher, while the spleen MDSCs in the HTS group were higher (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios were all less in PBNCs, spleen, and BMNCs of the NS and HTS groups, and were lower in BMNCs of the HES group (all P<0.05 vs. control). At 72 h, the elevated MDSCs in PBNCs were presented in the HTS and HES groups, and in spleen the augment turned up in three resuscitation groups (all P<0.05 vs. control). The inclined ratios to M-MDSC were exhibited in spleen of the NS and HTS groups, and in PBNCs of the NS group; the inclination to G-MDSC in BMNCs was shown in the HES group (all P<0.05 vs. control). Conclusions: HTS induces the earlier elevation of MDSCs in peripheral blood and spleen, and influences its distribution and differentiation, while HES has a less effect on the distribution but a stronger impact on the differentiation of MDSCs, especially in bone marrow. PMID:28070996

  13. Computational enzyme design

    NASA Astrophysics Data System (ADS)

    Bolon, Daniel N.

    2002-08-01

    The long-term objective of computational enzyme design is the ability to generate efficient protein catalysts for any chemical reaction. This thesis develops and experimentally validates a general computational approach for the design of enzymes with novel function. In order to include catalytic mechanism in protein design, a high-energy state (HES) rotamer (side chain representation) was constructed. In this rotamer, substrate atoms are in a HES. In addition, at least one amino acid side chain is positioned to interact favorably with substrate atoms in their HES and facilitate the reaction. Including an amino acid side chain in the HES rotamer automatically positions substrate relative to a protein scaffold and allows protein design algorithms to search for sequences capable of interacting favorably with the substrate. Because chemical similarity exists between the transition state and the high-energy state, optimizing the protein sequence to interact favorably with the HES rotamer should lead to transition state stabilization. In addition, the HES rotamer model focuses the subsequent computational active site design on a relevant phase space where an amino acid is capable of interacting in a catalytically active geometry with substrate. Using a HES rotamer model of the histidine mediated nucleophilic hydrolysis of p-nitrophenyl acetate, the catalytically inert 108 residue E. coli thioredoxin as a scaffold, and the ORBIT protein design software to compute sequences, an active site scan identified two promising active site designs. Experimentally, both candidate ?protozymes? demonstrated catalytic activity significantly above background. In addition, the rate enhancement of one of these ?protozymes? was the same order of magnitude as the first catalytic antibodies. Because polar groups are frequently buried at enzyme-substrate interfaces, improved modeling of buried polar interactions may benefit enzyme design. By studying native protein structures, rules have been

  14. Significance of Dynamic and Transient Analysis in the Design and Operation of Hybrid Energy Systems

    SciTech Connect

    Panwar, Mayank; Mohanpurkar, Manish; Hovsapian, Rob; Osorio, Julian D.

    2015-02-01

    Energy systems were historically designed and operated with a specific energy conversion objective, while managing loads and resources. In the recent years, the increased utilization of non-dispatchable renewable sources such as wind and solar has played a role in power quality and the reliability of power systems. In order to mitigate the risk associated with the non-dispatchable resources an integrated approach, such as Hybrid Energy Systems (HES), has to be taken, integrating the loads and resource management between the traditional thermal power plants and the non-dispatchable resources. As our electric energy becomes more diverse in its generation resources, the HES with its operational control system, its real-time view and its dynamic decisions making will become an essential part of the integrated energy systems and improve the overall grid reliability. The operational constraints of the energy sources on both the thermal power plants and the non-dispatchable resources in HES, plays a vital role in the planning and design stage. It is an established fact that the choice of energy source depends on the available natural resources and possible infrastructure. A critical component of decision-making depends on the complementary nature and controllability of the energy sources to supply the load demands with high reliability. Controllability of complex HES to achieve desired performance and flexibility is implemented via coordinated control systems while simultaneously generating electricity and other useful products such as useful heat or hydrogen. These systems are based on instrumentation, signal processing, control theory, and engineering system design. The entire HES along with the control systems are characterized by widely varying time constants. Hence, for a well-coordinated control and operation, we propose physics based modeling of the subsystems to assist in a dynamic and transient analysis. Dynamic and transient analysis in real and non-real time

  15. Hypereosinophilic syndrome, Churg-Strauss syndrome and parasitic diseases: possible links between eosinophilia and thrombosis.

    PubMed

    Maino, Alberto; Rossio, Raffaella; Cugno, Massimo; Marzano, Angelo V; Tedeschi, Alberto

    2012-09-01

    Throughout the past decade, a possible role of eosinophils in blood coagulation and thrombosis has been suggested. We conducted a Pubmed (MEDLINE) search of case and series referring to any kind of thrombotic events described in three conditions characterised by persistent blood eosinophilia, i.e. the hypereosinophilic syndrome (HES), the Churg Strauss syndrome (CSS), and parasitic infestations from 1966 to date. One hundred and ninety-two articles were found regarding thrombotic events in HES and CSS, and 209 cases of thrombosis were extracted. One hundred and seventy- seven articles dealing with parasitic diseases and thrombosis were found, but only 15 manuscripts reporting thrombosis of unknown origin in 22 patients were selected. In HES, arterial thromboses were more frequent than in CSS (p=0.006), representing almost half of the cases (45%), while venous and mixed artero-venous thrombosis were respectively 28% and 27%. In contrast, in CSS there was a predominance of venous thrombosis (56%, p=0.006), with arterial thrombosis representing 38% of total thrombotic events, and mixed thrombosis being the least frequent (4%). The higher incidence of arterial thrombosis in HES patients can be explained by the common cardiac involvement (64% of patients). In the 22 patients with parasitoses and thrombosis, 15 had arterial thrombosis (68%) and 7 had venous thrombosis (32 %). Literature analysis shows that there are numerous reports of thrombotic events in patients with eosinophil-related disorders supporting a role for eosinophils in thrombosis. This observation raises the problem of prevention and treatment of thromboembolism particularly in HES and CSS patients.

  16. Identification of the key genes implicated in the transformation of OLP to OSCC using RNA-sequencing.

    PubMed

    Yang, Qiaozhen; Guo, Bin; Sun, Hongying; Zhang, Jie; Liu, Shangfeng; Hexige, Saiyin; Yu, Xuedi; Wang, Xiaxia

    2017-04-01

    Oral lichen planus (OLP) is a chronic inflammatory disease that may transform to oral squamous cell carcinoma (OSCC), while its carcinogenesis mechanisms are not entirely clear. This study was designed to identify the important genes involved in the malignant transformation of OLP to OSCC. After RNA-sequencing, the differently expressed genes (DEGs) in OLP vs. normal and OSCC vs. normal groups, respectively, were identified by limma package in R language, and then clustering analysis were conducted by Pheatmap package in R language. Weighed gene co-expression network analysis (WGCNA) was performed for the DEGs to screen disease-associated modules. Using Cytoscape software, co-expression networks were constructed for the genes involved in the modules. Enrichment analysis was conducted for the genes involved in the co-expression networks using GOstat package in R language. Finally, quantitative real-time PCR (qRT-PCR) experiments were conducted to validate the key genes. There were, respectively, 223 and 548 DEGs in OLP vs. normal and OSCC vs. normal groups. WGCNA identified the blue modules for the DEGs in the two groups as disease-associated modules. Moreover, 19 common DEGs (including upregulated BCL9L, PER2 and TSPAN33, and downregulated GMPS and HES1) associated with both OLP and OSCC were identified. In the co-expression networks, BCL9L, HES1, PER2 and TSPAN33 might function in OLP via interactions (such as BCL9L-TSPAN33 and HES1-PER2). qRT-PCR analysis showed that BCL9L, PER2 and TSPAN33 were significantly upregulated, and GMP and HES1 were downregulated. These findings indicated that BCL9L, GMPS, HES1, PER2 and TSPAN33 affected the transformation of OLP to OSCC.

  17. Self-renewal and pluripotency is maintained in human embryonic stem cells by co-culture with human fetal liver stromal cells expressing hypoxia inducible factor 1alpha.

    PubMed

    Ji, Lei; Liu, Yu-xiao; Yang, Chao; Yue, Wen; Shi, Shuang-shuang; Bai, Ci-xian; Xi, Jia-fei; Nan, Xue; Pei, Xue-Tao

    2009-10-01

    Human embryonic stem (hES) cells are typically maintained on mouse embryonic fibroblast (MEF) feeders or with MEF-conditioned medium. However, these xenosupport systems greatly limit the therapeutic applications of hES cells because of the risk of cross-transfer of animal pathogens. The stem cell niche is a unique tissue microenvironment that regulates the self-renewal and differentiation of stem cells. Recent evidence suggests that stem cells are localized in the microenvironment of low oxygen. We hypothesized that hypoxia could maintain the undifferentiated phenotype of embryonic stem cells. We have co-cultured a human embryonic cell line with human fetal liver stromal cells (hFLSCs) feeder cells stably expressing hypoxia-inducible factor-1 alpha (HIF-1alpha), which is known as the key transcription factor in hypoxia. The results suggested HIF-1alpha was critical for preventing differentiation of hES cells in culture. Consistent with this observation, hypoxia upregulated the expression of Nanog and Oct-4, the key factors expressed in undifferentiated stem cells. We further demonstrated that HIF-1alpha could upregulate the expression of some soluble factors including bFGF and SDF-1alpha, which are released into the microenvironment to maintain the undifferentiated status of hES cells. This suggests that the targets of HIF-1alpha are secreted soluble factors rather than a cell-cell contact mechanism, and defines an important mechanism for the inhibition of hESCs differentiation by hypoxia. Our findings developed a transgene feeder co-culture system and will provide a more reliable alternative for future therapeutic applications of hES cells.

  18. Effect of Culture Condition Variables on Human Endostatin Gene Expression in Escherichia coli Using Response Surface Methodology

    PubMed Central

    Mohajeri, Abbas; Pilehvar-Soltanahmadi, Yones; Abdolalizadeh, Jalal; Karimi, Pouran; Zarghami, Nosratollah

    2016-01-01

    Background Recombinant human endostatin (rhES) is an angiogenesis inhibitor used as a specific drug for the treatment of non-small-cell lung cancer. As mRNA concentration affects the recombinant protein expression level, any factor affecting mRNA concentration can alter the protein expression level. Response surface methodology (RSM) based on the Box-Behnken design (BBD) is a statistical tool for experimental design and for optimizing biotechnological processes. Objectives This investigation aimed to predict and develop the optimal culture conditions for mRNA expression of the synthetic human endostatin (hES) gene in Escherichia coli BL21 (DE3). Materials and Methods The hES gene was amplified, cloned, and expressed in the E. coli expression system. Three factors, including isopropyl β-D-1-thiogalactopyranoside (IPTG) concentration, post-induction time, and cell density before induction, were selected as important factors. The mRNA expression level was determined using real-time PCR. The expression levels of hES mRNA under the different growth conditions were analyzed. SDS-PAGE and western blot analyses were carried out for further confirmation of interest-gene expression. Results A maximum rhES mRNA level of 376.16% was obtained under the following conditions: 0.6 mM IPTG, 7 hours post-induction time, and 0.9 cell density before induction. The level of rhES mRNA was significantly correlated with post-induction time, IPTG concentration, and cell density before induction (P < 0.05). The expression of the hES gene was confirmed by western blot. Conclusions The obtained results indicate that RSM is an effective method for the optimization of culture conditions for hES gene expression in E. coli. PMID:27800134

  19. Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients - a multidisciplinary statement

    PubMed Central

    2013-01-01

    Introduction Hydroxyethyl starch (HES) is a commonly used colloid in critically ill patients. However, its safety has been questioned in recent studies and meta-analyses. Methods We re-evaluated prospective randomised controlled trials (RCT) from four meta-analyses published in 2013 that compared the effect of HES with crystalloids in critically ill patients, focusing on the adherence to 'presumably correct indication'. Regarding the definition of 'presumably correct indication', studies were checked for the following six criteria (maximum six points): short time interval from shock to randomisation (<6 h), restricted use for initial volume resuscitation, use of any consistent algorithm for haemodynamic stabilisation, reproducible indicators of hypovolaemia, maximum dose of HES, and exclusion of patients with pre-existing renal failure or renal replacement therapy. Results Duration of fluid administration ranged from 90 min up to a maximum of 90 days. Four studies considered follow-up until 90-day mortality, three studies 28-/30-day mortality, whereas four studies reported only early mortality. Included studies showed a large heterogeneity of the indication score ranging between 1 and 4 points with a median (25%; 75% quartile) of 4 (2; 4). Conclusions The most important question, whether or not HES may be harmful when it is limited to immediate haemodynamic stabilisation, cannot be answered yet in the absence of any study sufficiently addressing this question. In order to overcome the limitations of most of the previous studies, we now suggest an algorithm emphasising the strict indication of HES. Additionally, we give a list of suggestions that should be adequately considered in any prospective RCT in the field of acute volume resuscitation in critically ill patients. PMID:23890518

  20. Systematically profiling and annotating long intergenic non-coding RNAs in human embryonic stem cell

    PubMed Central

    2013-01-01

    Background While more and more long intergenic non-coding RNAs (lincRNAs) were identified to take important roles in both maintaining pluripotency and regulating differentiation, how these lincRNAs may define and drive cell fate decisions on a global scale are still mostly elusive. Systematical profiling and comprehensive annotation of embryonic stem cells lincRNAs may not only bring a clearer big picture of these novel regulators but also shed light on their functionalities. Results Based on multiple RNA-Seq datasets, we systematically identified 300 human embryonic stem cell lincRNAs (hES lincRNAs). Of which, one forth (78 out of 300) hES lincRNAs were further identified to be biasedly expressed in human ES cells. Functional analysis showed that they were preferentially involved in several early-development related biological processes. Comparative genomics analysis further suggested that around half of the identified hES lincRNAs were conserved in mouse. To facilitate further investigation of these hES lincRNAs, we constructed an online portal for biologists to access all their sequences and annotations interactively. In addition to navigation through a genome browse interface, users can also locate lincRNAs through an advanced query interface based on both keywords and expression profiles, and analyze results through multiple tools. Conclusions By integrating multiple RNA-Seq datasets, we systematically characterized and annotated 300 hES lincRNAs. A full functional web portal is available freely at http://scbrowse.cbi.pku.edu.cn. As the first global profiling and annotating of human embryonic stem cell lincRNAs, this work aims to provide a valuable resource for both experimental biologists and bioinformaticians. PMID:24564552

  1. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes

    PubMed Central

    Roufosse, Florence E; Kahn, Jean-Emmanuel; Gleich, Gerald J; Schwartz, Lawrence B; Singh, Anish D; Rosenwasser, Lanny J; Denburg, Judah A; Ring, Johannes; Rothenberg, Marc E; Sheikh, Javed; Haig, Ann E; Mallett, Stephen A; Templeton, Deborah N; Ortega, Hector G; Klion, Amy D

    2012-01-01

    Background Hypereosinophilic syndromes (HES) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid-refractory or develop corticosteroid toxicity. Mepolizumab, a humanised monoclonal anti-interleukin-5 antibody, demonstrated corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HES. Objective To evaluate long-term safety and efficacy of mepolizumab (750 mg) in HES. Methods MHE100901 is an open-label extension study. The primary endpoint was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of anti-mepolizumab antibodies were also explored. Results Seventy-eight subjects received 1–66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range 4–302). The most common dosing interval was 9–12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including one death, were reported by the investigator as possibly due to mepolizumab in three subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone-free without other HES medications for ≥12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew prior to study completion for death (n=4), lack of efficacy (n=6), or other reasons. Conclusion Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES. PMID:23040887

  2. Contribution of osmotic changes to disintegrative globulization of single cortical fibers isolated from rat lens.

    PubMed

    Wang, L F; Dhir, P; Bhatnagar, A; Srivastava, S K

    1997-08-01

    In this study the contribution of osmotic changes to disintegrative globulization of lens cortical fibers was examined. Single fiber cells were isolated by trypsinization of adult rat lens cortex, and morphological changes elicited by exposure to different external solutions were monitored optically. The survival of the fiber-shaped cells was analysed in accordance with the Weibull distribution. Changes in [Ca2+]i were measured using the fluorescent calcium-sensitive dye-Fluo-3. Exposure of isolated fiber cells to Ringer's solution (containing 2 mm Ca2+) led to an exponential increase in [Ca2+]i with a time constant of 10.2+/-0.8 min, and caused disintegrative globulization in 25+/-4 min (=Tg). The process of globulization as well as the rate of increase in [Ca2+]i was delayed by removing Cl- ions from the external media. Globulization was also delayed by adding 20% bovine serum albumin (Tg=107+/-3 min) or chloride channel inhibitors 5, nitro-2-(3-phenylpropylamino) benzoate (NPPB), dideoxyforskolin, niflumic acid, and tamoxifen. When the fiber cells were suspended in isotonic (280 mm sucrose) HEPES-sucrose (HS) or HEPES-EDTA-sucrose (HES) solution, no globulization was observed for an observation time of 120 min. However, exposure to hypotonic (180 mm) HES solution led to disintegration of fiber cells in 75+/-7 min. Disintegration of the fiber induced by hypotonic HES solution could be delayed by either 0. 05 mm leupeptin (Tg=97+/-6 min) or by pre-loading the fibers with BAPTA (Tg=100+/-4 min). Inhibition of membrane calcium transport by 0.5 mm La3+ had no effect on Tg in hypotonic HES. Addition of 2 mm Ca2+ to HES solution accelerated globulization, and Tg was 57+/-4, 69+/-5 and 102+/-6 min for hypo-, iso- and hyper- tonic solutions, respectively. Transient exposure to calcium also accelerated disintegrative globulization of fiber cells exposed subsequently to HES solution. These results suggest that in ionic media, part of the calcium influx in isolated fiber

  3. Derivation of three clones from human embryonic stem cell lines by FACS sorting and their characterization.

    PubMed

    Sidhu, Kuldip S; Tuch, Bernard E

    2006-02-01

    Here we describe the first report of three human embryonic stem cell (hESC) clones, hES 3.1, 3.2, and 3.3, derived from the parent line hES3 by sorting of single-cell preparations by flow cytometry. The viability of single-cell preparations before and after cell sorting remained >98%. The hESC were selected by size gating and forward-angle light scatter and were dispersed directly as single cell/ well into 96-well plates containing human fetal fibroblasts as feeder layers. Single stem cell dispersion into 96-well plates was confirmed by using cells from a hES3 line that constitutively expressed green fluorescence protein (eGFP) under similar conditions of flow cytometry. Three clones were obtained from the parent line hES3 -- hES3.1, 3.2, and 3.3 -- and they have been in continuous culture for more than 1 year. The cloning efficiency was less than <0.5%. These hESC clones show normal stem cell characteristics, such as undifferentiated growth, high nucleocytoplasmic ratio, the same karyotype as that of the parent line (46 XX), stem cell surface markers (i.e., SSEA3, SSEA4, OCT4, TRA-1-60, and TRA-1-81), and gene expression for pluripotency (Oct-4 and nanog). They all formed embryoid bodies in suspension cultures, and after seeding in culture plates they showed pluripotency in vitro by forming cell lineages derived from all three germ layers as indicated by expression of the ectodermal marker nestin, the mesodermal marker renin, and the endodermal markers alpha-fetoprotein and GATA6. All clones showed normal expression of alkaline phosphatase activity, a marker of in vitro pluripotency. When hESC clones (1-2 x 10(6) total) were injected into nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice under the kidney capsule, all formed teratomas within 6-8 weeks. Analysis of the stem cell surface marker TRA-1-160 by flow cytometry showed nonsignificant (p < 0.05) differences between the clones and the parent line. The clones also differed in their expression

  4. Evaluating Radioprotective Effect of Hesperidin on Acute Radiation Damage in the Lung Tissue of Rats

    PubMed Central

    Rezaeyan, A.; Fardid, R.; Haddadi, G.H.; Takhshid, M.A.; Hosseinzadeh, M.; Najafi, M.; Salajegheh, A.

    2016-01-01

    Background: Oxidative stress plays an important role in the pathogenesis and progression of γ-irradiation-induced cellular damage, Lung is a radiosensitive organ and its damage is a dose-limiting factor in radiotherapy. The administration of dietary antioxidants has been suggested to protect against the succeeding tissue damage. The present study aimed to evaluate the radioprotective efficacy of Hesperidin (HES) against γ-irradiation-induced tissue damage in the lung of male rats. Materials and Methods: Thirty two rats were divided into four groups. Rats in Group 1 received PBS and underwent sham irradiation. Rats in Group 2 received HES and underwent sham irradiation. Rats in Group 3 received PBS and underwent γ-irradiation. Rats in Group 4 received HES and underwent γ-irradiation. These rats were exposed to γ-radiation 18 Gy using a single fraction cobalt-60 unit, and were administered HES (100 mg/kg/d, b.w, orally) for 7 days prior to irradiation. Rats in each group were sacrificed 24 hours after radiotherapy (RT) for the determination of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and histopathological evaluations. Results: Compared to group 1, the level of SOD and GSH significantly decreased and MDA level significantly increased in group 3 at 24 h following irradiation, (p=0.001, p<0.001, p=0.001), respectively. A statistically significant difference in all parameters was observed for rats in group 4 as compared to group 3 (p<0.05). Histopathological results 24 hours after RT showed that radiation has increased inflammation, lymphocyte, macrophage and neutrophil compared to group 1 ( p<0.0125). Oral administration of HES before RT significantly decreased macrophage and neutrophil when compared to group 3 (p<0.0125), but partly there was inflammation and lymphocyte that indicated there was no significant difference when compared to group 3 (p>0.0125). Conclusion: Oral administration of HES was found to offer protection against

  5. Hydroxyethyl starch - the importance of being earnest

    PubMed Central

    2013-01-01

    Despite ongoing controversial expert discussions the European Medicines Agency (EMA) recently recommended to suspend marketing authorisations for hydroxyethyl starch. This comment critically evaluates the line of arguments. Basically, the only indication for a colloid is intravascular hypovolemia. Crystalloid use appears reasonable to compensate ongoing extracellular losses beyond. In the hemodynamically instable patient this leads to the distinction between an initial resuscitation phase where colloids might be indicated and a crystalloidal maintenance phase thereafter. It is important to bear this in mind when reevaluating the studies the EMA referred to in the context of its recent decision: i) VISEP compared ringer’s lactate to 10% HES 200/0.5 in septic patients and found an increased incidence of renal failure in HES receivers. Unfortunately, study treatment was started only after initial stabilization with HES, randomizing hemodynamically stable patients into a rational (crystalloids) and an irrational (high dose starch until ICU discharge) maintenance treatment. ii) 6S compared ringer’s acetate to 6% HES 130/0.42 for fluid resuscitation in septic patients and found an increased need of renal replacement therapy and a higher mortality in the HES group. However, patients of both groups were again randomized only after initial stabilization with colloids, the actual comparison was, therefore, again rational vs. irrational. Beyond that, the documentation is partly fragmentary, leaving many important questions around the fate of the patients unanswered. iii) CHEST randomized ICU patients to receive saline or 6% HES 130/0.4 for fluid resuscitation. Actually, despite partly discussed in a different way, this trial showed no relevant differences in outcome. In all, two studies showed what happens to septic patients if starches are used in a way we do not observe in daily practice. The third one actually proves their safety. The benefit of perioperative goal

  6. Recording of hospitalizations for acute exacerbations of COPD in UK electronic health care records

    PubMed Central

    Rothnie, Kieran J; Müllerová, Hana; Thomas, Sara L; Chandan, Joht S; Smeeth, Liam; Hurst, John R; Davis, Kourtney; Quint, Jennifer K

    2016-01-01

    Background Accurate identification of hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) within electronic health care records is important for research, public health, and to inform health care utilization and service provision. We aimed to develop a strategy to identify hospitalizations for AECOPD in secondary care data and to investigate the validity of strategies to identify hospitalizations for AECOPD in primary care data. Methods We identified patients with chronic obstructive pulmonary disease (COPD) in the Clinical Practice Research Datalink (CPRD) with linked Hospital Episodes Statistics (HES) data. We used discharge summaries for recent hospitalizations for AECOPD to develop a strategy to identify the recording of hospitalizations for AECOPD in HES. We then used the HES strategy as a reference standard to investigate the positive predictive value (PPV) and sensitivity of strategies for identifying AECOPD using general practice CPRD data. We tested two strategies: 1) codes for hospitalization for AECOPD and 2) a code for AECOPD other than hospitalization on the same day as a code for hospitalization due to unspecified reason. Results In total, 27,182 patients with COPD were included. Our strategy to identify hospitalizations for AECOPD in HES had a sensitivity of 87.5%. When compared with HES, using a code suggesting hospitalization for AECOPD in CPRD resulted in a PPV of 50.2% (95% confidence interval [CI] 48.5%–51.8%) and a sensitivity of 4.1% (95% CI 3.9%–4.3%). Using a code for AECOPD and a code for hospitalization due to unspecified reason resulted in a PPV of 43.3% (95% CI 42.3%–44.2%) and a sensitivity of 5.4% (95% CI 5.1%–5.7%). Conclusion Hospitalization for AECOPD can be identified with high sensitivity in the HES database. The PPV and sensitivity of strategies to identify hospitalizations for AECOPD in primary care data alone are very poor. Primary care data alone should not be used to identify

  7. Hybrid expert system for decision supporting in the medical area: complexity and cognitive computing.

    PubMed

    Brasil, L M; de Azevedo, F M; Barreto, J M

    2001-09-01

    This paper proposes a hybrid expert system (HES) to minimise some complexity problems pervasive to the artificial intelligence such as: the knowledge elicitation process, known as the bottleneck of expert systems; the model choice for knowledge representation to code human reasoning; the number of neurons in the hidden layer and the topology used in the connectionist approach; the difficulty to obtain the explanation on how the network arrived to a conclusion. Two algorithms applied to developing of HES are also suggested. One of them is used to train the fuzzy neural network and the other to obtain explanations on how the fuzzy neural network attained a conclusion. To overcome these difficulties the cognitive computing was integrated to the developed system. A case study is presented (e.g. epileptic crisis) with the problem definition and simulations. Results are also discussed.

  8. Inhibitory effect of CT domain of CCN3/NOV on proliferation and differentiation of osteogenic mesenchymal stem cells, Kusa-A1

    SciTech Connect

    Katsuki, Yuko; Sakamoto, Kei; Minamizato, Tokutaro; Makino, Hatsune; Umezawa, Akihiro; Ikeda, Masa-aki; Perbal, Bernard; Amagasa, Teruo; Yamaguchi, Akira; Katsube, Ken-ichi

    2008-04-11

    CCN3/NOV activates the Notch signal through the carboxyl terminal cysteine-rich (CT) domain. CCN3 transfection to Kusa-A1 inhibited osteogenic differentiation and cell proliferation, which is accompanied by upregulation of Hes/Hey, Notch downstream targets, and p21, a CDK inhibitor. Upregulation of Hes/Hey and p21 was abrogated by the deletion of CT domain. Anti-proliferative activity of CCN3 was also abrogated by CT domain deletion whereas anti-osteogenic activity was not completely abrogated. We found that CT domain-deleted CCN3 still possesses antagonistic effect on BMP-2. These results suggest that CCN3 employs Notch and BMP pathways in anti-osteogenic activity while it inhibits cell proliferation uniquely by Notch/p21 pathway.

  9. U.S. hydropower resource assessment for Arizona

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-10-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Arizona.

  10. Home Energy Saver v.2.0

    SciTech Connect

    Mills, Evan; Brown, Richard; Pinckard, Maggie; Warner, Jeff

    2008-09-01

    A web-based residential energy calculator. Provides customized estimates of residential energy use, energy bills, and CO2 emissions, based on building description information provided by the user. Energy use is estimated by end-use and device, using engineering models. Space heating and cooling use is based on the DOE-2.1E building simulation model. Other end-uses (water heating, appliances, lighting, and miscellaneous equipment) are based on engineering models developed by LBNL. Users can estimate their household carbon footprint and compare it to average vaules for their neighborhood and other regions, displayed using the Google Maps API. Energy bills can be calculated using either average energy price data or actual utility tariffs (including time-of-use) contained in the LBNL Tariff Analysis Project (TAP). HES includes a link to the TAP energy bill calculator web service. The HES software also includes extensive default input data for required user inputs.

  11. US hydropower resource assessment for Texas

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Texas.

  12. U.S. hydropower resource assessment for Oregon

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1998-03-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering and Environmental Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Oregon.

  13. U.S. hydropower resource assessment for Tennessee

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-07-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Tennessee.

  14. Science with society in the anthropocene.

    PubMed

    Seidl, Roman; Brand, Fridolin Simon; Stauffacher, Michael; Krütli, Pius; Le, Quang Bao; Spörri, Andy; Meylan, Grégoire; Moser, Corinne; González, Monica Berger; Scholz, Roland Werner

    2013-02-01

    Interdisciplinary scientific knowledge is necessary but not sufficient when it comes to addressing sustainable transformations, as science increasingly has to deal with normative and value-related issues. A systems perspective on coupled human-environmental systems (HES) helps to address the inherent complexities. Additionally, a thorough interaction between science and society (i.e., transdisciplinarity = TD) is necessary, as sustainable transitions are sometimes contested and can cause conflicts. In order to navigate complexities regarding the delicate interaction of scientific research with societal decisions these processes must proceed in a structured and functional way. We thus propose HES-based TD processes to provide a basis for reorganizing science in coming decades.

  15. Hypereosinophilic syndrome accompanying gangrene of the toes with peripheral arterial occlusion--a case report.

    PubMed

    Funahashi, Satoru; Masaki, Ichiro; Furuyama, Tadashi

    2006-01-01

    The authors herein report the case of a teenage boy who presented with peripheral arterial occlusion of both upper and lower extremities associated with hypereosinophilia. During a 10-year follow-up, corticosteroid therapy was continued for the treatment of hypereosinophilia. The patient underwent bilateral lumbar sympathectomies because of severe ischemia of the bilateral lower extremities with gangrene of the toes. Based on the progress of his disease over the past 10 years, he was suspected to have idiopathic hypereosinophilic syndrome (HES) accompanied by peripheral arterial obstruction. Idiopathic HES is a disease characterized by unexpected hypereosinophilia, which may lead to organ damage. This is a very rare case of peripheral arterial occlusion associated with idiopathic HIS.

  16. U.S. hydropower resource assessment for Mississippi

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-11-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Mississippi.

  17. Homing endonucleases: from basics to therapeutic applications.

    PubMed

    Marcaida, Maria J; Muñoz, Inés G; Blanco, Francisco J; Prieto, Jesús; Montoya, Guillermo

    2010-03-01

    Homing endonucleases (HE) are double-stranded DNAses that target large recognition sites (12-40 bp). HE-encoding sequences are usually embedded in either introns or inteins. Their recognition sites are extremely rare, with none or only a few of these sites present in a mammalian-sized genome. However, these enzymes, unlike standard restriction endonucleases, tolerate some sequence degeneracy within their recognition sequence. Several members of this enzyme family have been used as templates to engineer tools to cleave DNA sequences that differ from their original wild-type targets. These custom HEs can be used to stimulate double-strand break homologous recombination in cells, to induce the repair of defective genes with very low toxicity levels. The use of tailored HEs opens up new possibilities for gene therapy in patients with monogenic diseases that can be treated ex vivo. This review provides an overview of recent advances in this field.

  18. US hydropower resource assessment for Montana

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Montana.

  19. U.S. hydropower resource assessment for Alabama

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1998-02-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Alabama.

  20. A Non-Destructive Culturing and Cell Sorting Method for Cardiomyocytes and Neurons Using a Double Alginate Layer

    PubMed Central

    Terazono, Hideyuki; Kim, Hyonchol; Hayashi, Masahito; Hattori, Akihiro; Nomura, Fumimasa; Kaneko, Tomoyuki; Yasuda, Kenji

    2012-01-01

    A non-destructive method of collecting cultured cells after identifying their in situ functional characteristics is proposed. In this method, cells are cultivated on an alginate layer in a culture dish and released by spot application of a calcium chelate buffer that locally melts the alginate layer and enables the collection of cultured cells at the single-cell level. Primary hippocampal neurons, beating human embryonic stem (hES) cell-derived cardiomyocytes, and beating hES cell-derived cardiomyocyte clusters cultivated on an alginate layer were successfully released and collected with a micropipette. The collected cells were recultured while maintaining their physiological function, including beating, and elongated neurites. These results suggest that the proposed method may eventually facilitate the transplantation of ES- or iPS-derived cardiomyocytes and neurons differentiated in culture. PMID:22870332

  1. US hydropower resource assessment for Arkansas

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Arkansas.

  2. U.S. hydropower resource assessment for Alaska

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-11-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Alaska.

  3. US hydropower resource assessment for Utah

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Utah.

  4. Formation and properties of silicon/fluorite heterostructures. Final report, June 1, 1994--May 31, 1997

    SciTech Connect

    Olmstead, M.A.

    1997-10-01

    Our primary goal during the previous support periods was to determine the interrelationship among the structure of the CaF{sub 2}/Si interface, the growth kinetics, the structure and morphology of the overlying film, and the intrinsic dielectric properties of the interface itself. The experiments were designed (i) to determine the CaF{sub 2} overlayer structure and morphology as a function of kinetic conditions [Den93a, Den93b, Won93, Den95, Hes95], (ii) to develop and test models explaining the observed structures [Den95, Hes95], (iii) to investigate the stability of the interface structure [Les97] and (iv) to determine and interpret the photoelectron kinetic energy distributions as a function of the emitting atom location [Rot93, Rot94, Rot96]. As summarized below, we were successful in accomplishing these experiments and in largely fulfilling our original goal.

  5. Salinomycin Suppresses PDGFRβ, MYC, and Notch Signaling in Human Medulloblastoma.

    PubMed

    Zhou, Shuang; Wang, Fengfei; Zhang, Ying; Johnson, Max R; Qian, Steven; Wu, Min; Wu, Erxi

    2014-01-01

    Medulloblastoma (MB) is the most common childhood brain tumor. Despite improved therapy and management, approximately 30% of patients die of the disease. To search for a more effective therapeutic strategy, the effects of salinomycin were tested on cell proliferation, cell death, and cell cycle progression in human MB cell lines. The results demonstrated that salinomycin inhibits cell proliferation, induces cell death , and disrupts cell cycle progression in MB cells. Salinomycin was also tested on the expression levels of key genes involved in proliferation and survival signaling and revealed that salinomycin down-regulates the expression of PDGFRβ, MYC, p21 and Bcl-2 as well as up-regulates the expression of cyclin A. In addition, the results reveal that salinomycin suppresses the expression of Hes1 and Hes5 in MB cells. Our data shed light on the potential of using salinomycin as a novel therapeutic agent for patients with MB.

  6. Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis.

    PubMed

    Musto, Pellegrino; Falcone, Antonietta; Sanpaolo, Grazia; Bodenizza, Carlo; Perla, Gianni; Minervini, Maria Marta; Cascavilla, Nicola; Dell'Olio, Matteo; La Sala, Antonio; Mantuano, Saverio; Melillo, Lorella; Nobile, Michele; Scalzulli, Potito Rosario; Bisceglia, Michele; Carella, Angelo Michele

    2004-06-01

    Four cases of hypereosinophilic syndrome (HES) treated with the tyrosine-kinase inhibitor imatinib-mesylate are reported. The drug was effective in three patients, but a prolonged clinical and hematological remission was obtained only in one patient, due to appearance of resistance or poor tolerability in the other cases. The dose of imatinib necessary to achieve a response ranged from 100 to 600 mg/d. One patient with evidence of a clonal T-cell population did not respond at all. We confirm the efficacy of imatinib in HES, but we also underline that type and duration of response may be variable. This could be due to different pathogenetic mechanisms of the disease in single patients.

  7. US hydropower resource assessment for Kansas

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Kansas.

  8. Properties of jet engine combustion particles during the PartEmis experiment: Particle size spectra (d > 15 nm) and volatility

    NASA Astrophysics Data System (ADS)

    Nyeki, S.; Gysel, M.; Weingartner, E.; Baltensperger, U.; Hitzenberger, R.; Petzold, A.; Wilson, C. W.

    2004-09-01

    Size distributions (d > 15 nm) and volatile properties of combustion particles were measured during test-rig experiments on a jet engine, consisting of a combustor and three simulated turbine stages (HES). The combustor was operated to simulate legacy (inlet temperature 300°C) and contemporary (500°C) cruise conditions, using kerosene with three different fuel sulfur contents (FSC; 50, 400 and 1300 μg g-1). Measurements found that contemporary cruise conditions resulted in lower number emission indices (EIN15) and higher geometric mean particle diameter (dG) than for legacy conditions. Increasing FSC resulted in an overall increase in EIN15 and decrease in dG. The HES stages or fuel additive (APA101) had little influence on EIN15 or dG, however, this is uncertain due to the measurement variability. EIN15 for non-volatile particles was largely independent of all examined conditions.

  9. U.S. hydropower resource assessment for Maryland

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-11-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Maryland.

  10. An introduction to induced pluripotent stem cells.

    PubMed

    Hanley, Joanna; Rastegarlari, Ghasem; Nathwani, Amit C

    2010-10-01

    Recent landmark studies show that it is now possible to convert somatic cells, such as skin fibroblasts and B lymphocytes, into pluripotent stem cells that closely resemble embryonic stem cells. These induced pluripotent stem (iPS) cells can be generated without using human embryos or oocytes, thus bypassing some of the ethical issues that have limited the use of human embryonic stems (hES) cells. Additionally, they can be derived from the patient to be treated, thereby overcoming problems of immunological rejection associated with the use of allogeneic hES cell derived progenitors. Whilst these patient-specific iPS cells have great clinical potential, their immediate utility is likely to be in drug screening and for understanding the disease process. This review discusses the promise of iPS cells as well as the challenges to their use in the clinic.

  11. US hydropower resource assessment for North Dakota

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of North Dakota.

  12. A flux-splitting method for hyperbolic-equation system of magnetized electron fluids in quasi-neutral plasmas

    SciTech Connect

    Kawashima, Rei Komurasaki, Kimiya Schönherr, Tony

    2016-04-01

    A flux-splitting method is proposed for the hyperbolic-equation system (HES) of magnetized electron fluids in quasi-neutral plasmas. The numerical fluxes are split into four categories, which are computed by using an upwind method which incorporates a flux-vector splitting (FVS) and advection upstream splitting method (AUSM). The method is applied to a test calculation condition of uniformly distributed and angled magnetic lines of force. All of the pseudo-time advancement terms converge monotonically and the conservation laws are strictly satisfied in the steady state. The calculation results are compared with those computed by using the elliptic–parabolic-equation system (EPES) approach using a magnetic-field-aligned mesh (MFAM). Both qualitative and quantitative comparisons yield good agreements of results, indicating that the HES approach with the flux-splitting method attains a high computational accuracy.

  13. U.S. hydropower resource assessment for Minnesota

    SciTech Connect

    Francfort, J.E.

    1996-07-01

    The U.S. Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Minnesota.

  14. U.S. Hydropower Resource Assessment - Georgia

    SciTech Connect

    A. M. Conner; B. N. Rinehart; J. E. Francfort

    1998-10-01

    The U.S. Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. For this purpose, the Idaho National Engineering and Environmental Laboratory developed a computer model called Hydropower Evaluation Software (HES). HES measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Georgia.

  15. PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors.

    PubMed

    Schrenk-Siemens, Katrin; Wende, Hagen; Prato, Vincenzo; Song, Kun; Rostock, Charlotte; Loewer, Alexander; Utikal, Jochen; Lewin, Gary R; Lechner, Stefan G; Siemens, Jan

    2015-01-01

    Human sensory neurons are inaccessible for functional examination, and thus little is known about the mechanisms mediating touch sensation in humans. Here we demonstrate that the mechanosensitivity of human embryonic stem (hES) cell-derived touch receptors depends on PIEZO2. To recapitulate sensory neuron development in vitro, we established a multistep differentiation protocol and generated sensory neurons via the intermediate production of neural crest cells derived from hES cells or human induced pluripotent stem (hiPS) cells. The generated neurons express a distinct set of touch receptor-specific genes and convert mechanical stimuli into electrical signals, their most salient characteristic in vivo. Strikingly, mechanosensitivity is lost after CRISPR/Cas9-mediated PIEZO2 gene deletion. Our work establishes a model system that resembles human touch receptors, which may facilitate mechanistic analysis of other sensory subtypes and provide insight into developmental programs underlying sensory neuron diversity.

  16. US hydropower resource assessment for Wyoming

    SciTech Connect

    Francfort, J.E.

    1993-12-01

    The Department of Energy is developing an estimate of the hydropower development potential in this country. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The HES measures the potential hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a dBASE menu-driven software application that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the state of Wyoming.

  17. The Economic Potential of Three Nuclear-Renewable Hybrid Energy Systems Providing Thermal Energy to Industry

    SciTech Connect

    Ruth, Mark; Cutler, Dylan; Flores-Espino, Francisco; Stark, Greg; Jenkin, Thomas

    2016-12-01

    This report is one of a series of reports that Idaho National Laboratory and National Renewable Energy Laboratory are producing to investigate the technical and economic aspects of nuclear-renewable hybrid energy systems (N-R HESs). Previous reports provided results of an analysis of two N-R HES scenarios. This report builds that analysis with a Texas-synthetic gasoline scenario providing the basis in which the N-R HES sells heat directly to an industrial customer. Subsystems were included that convert electricity to heat thus allowing the renewable energy subsystem to generate heat and benefit from that revenue stream. Nuclear and renewable energy sources are important to consider in the energy sector's evolution because both are considered to be clean and non-carbon emitting energy sources.

  18. Hawaii Energy Strategy program. Annual report 1993

    SciTech Connect

    Not Available

    1993-12-31

    This is the second annual report on the Hawaii Energy Strategy (HES) program which began on March 2, 1992, under a Cooperative Agreement (FCO3-92F19l68) with the United States Department of Energy (USDOE). The HES program is scheduled for completion by December 31, 1994. As outlined in the Statement of Joint Objectives. The purpose of the study is to develop an integrated State of Hawaii energy strategy, including an assessment of the State`s fossil fuel reserve requirements and the most effective way to meet those needs, the availability and practicality of increasing the use of native energy resources, potential alternative fossil energy technologies such as coal gasification and potential energy efficiency measures which could lead to demand reduction. This work contributes to the (US)DOE mission, will reduce the State`s vulnerability to energy supply disruptions and contributes to the public good.

  19. US hydropower resource assessment for Washington

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-07-01

    The U.S. Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Washington.

  20. U.S. Hydropower Resource Assessment - California

    SciTech Connect

    A. M. Conner; B. N. Rinehart; J. E. Francfort

    1998-10-01

    The U.S. Department of Energy is developing an estimate of the underdeveloped hydropower potential in the United States. For this purpose, the Idaho National Engineering and Environmental Laboratory developed a computer model called Hydropower Evaluation Software (HES). HES measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of California.

  1. U.S. hydropower resource assessment for Nevada

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-10-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Nevada.

  2. U.S. hydropower resource assessment for Idaho

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1998-08-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering and Environmental Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Idaho.

  3. U.S. hydropower resource assessment for Kentucky

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1998-07-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering and Environmental Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of Kentucky.

  4. U.S. hydropower resource assessment for New York

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1998-08-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering and Environmental Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of New York.

  5. U.S. hydropower resource assessment for West Virginia

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1998-02-01

    The US Department of Energy is developing an estimate of the undeveloped hydropower potential in the US. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. HES measures the undeveloped hydropower resources available in the US, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report describes the resource assessment results for the State of West Virginia.

  6. Eosinophilic Myeloproliferative Disorders

    PubMed Central

    Klion, Amy D.

    2014-01-01

    Despite recent attempts to define and classify patients with marked eosinophilia and features consistent with myeloproliferative disease, areas of controversy remain. These are particularly apparent in situations in which multiple lineages are involved in a clonal process and clinical manifestations are overlapping. Although the introduction of new molecular diagnostics and targeted therapies has begun to clarify the boundaries between some of these disorders, several questions remain with respect to the classification of patients with myeloproliferative hypereosinophilic syndrome (HES) of unknown etiology. PMID:22160043

  7. Taylor-Laplace Expansions of the Yukawa and Related Potential Energy Functions.

    DTIC Science & Technology

    1981-08-01

    thle ’Yukawa po tenilt iaI i tseIf. Inl thle I iiit a,, thle 20 continued e xponei’i t 3 van is hes , t he Yu kawa pot en t i a I trains f’ rms i l the...analyses of nuclear models . The Woods-Saxon potential has a simple form: _-VO 1 l ’Ws 1+ exp[(r-rO)/p]. This function does not easily admit a Fourier

  8. Summary of Research 1993

    DTIC Science & Technology

    1993-12-31

    summarizing into written and visual classroom current knowledge, 25 October 1993. materials for use at KPS. The syllabus of the course was completely...to designing real-time DOD EY = TIEWMOGY AURa: Software. systems depend on the assumption that the system structure is static. Our DETWORDS: Computer...guidelines beyond Barnes, P. and Hul-hes, G.e conventional compiler technology. UPrototyping Hard Real-Time Ada Systems in a Classroom Enviroamnt,8

  9. Comparison of Melatonin, Hypertonic Saline, and Hydroxyethyl Starch for Resuscitation of Secondary Intra-Abdominal Hypertension in an Animal Model

    PubMed Central

    Liu, Dong; Li, Yang; Zhang, Lianyang

    2016-01-01

    A variety of agents may have a beneficial effect in reducing injury-induced intestinal edema of fluid, but studies confirming the efficacy and mechanisms of these agents in secondary intra-abdominal hypertension (IAH) are lacking. This study was to compare the effectiveness of melatonin, 7.5% hypertonic saline (HS), and hydroxyethyl starch 130/0.4 (HES) on the resuscitation of secondary IAH in a rat model. Female SD rats were divided into: sham group, shock group, lactated Ringer solution (LR) group, melatonin group, HS group, and HES group. Except for the sham group, all rats underwent a combination of inducing portal hypertension, hemorrhaging to a MAP of 40 mmHg for 2 hr, and using an abdominal restraint device. The collected blood was reinfused and the rats were treated with LR (30ml/h), melatonin (50 mg/kg) + LR, HS (6 ml/kg) + LR, and HES (30 ml/kg) + LR, respectively. The shock group received no fluids. LR was continuously infused for 6hr. The intestinal permeability, immunofluorescence of tight junction proteins, transmission electron microscopy, level of inflammatory mediators (TNF-a, IL-1β, IL-6) and of biochemical markers of oxidative stress (malondialdehyde, myeloperoxidase activity, and glutathione peroxidase) were assessed. Expressions of the protein kinase B (Akt) and of tight junction proteins were detected by Western blot. Compared with LR, HS, and HES, melatonin was associated with less inflammatory and oxidative injury, less intestinal permeability and injury, and lower incidence of secondary IAH in this model. The salutary effect of melatonin in this model was associated with the upregulation of intestinal Akt phosphorylation. PMID:27560478

  10. An Analysis of Selected Army Promotion Board Results.

    DTIC Science & Technology

    1979-03-01

    isIs This t hes i s presents a review of recent Army o f f i c e r pro- f e s s i o n a l deve lopment and an a n a l y s i s of se lec ted p...Alternate Hypothesis). In order to perform the test of this hypothesis a norma l statistic must be calculated . The test statistic , , is given by the

  11. Hypereosinophilic syndrome causing acute hemiplegia in childhood.

    PubMed

    Noureen, Nuzhat; Rana, Muhammad Tariq

    2008-06-01

    Hypereosinophilic syndrome (HES) is a rare heterogeneous group of disorders, characterized by marked peripheral blood and tissue eosinophilia resulting in end organ damage. This case describes a six-year-old girl child who presented with sudden weakness of right half of body and fever. Computed tomogram of brain showed infarction of left internal capsule and basal ganglia. She had peripheral and bone marrow eosinophilia. No other cause was found for infarction.

  12. NOTCH SIGNALLING MODULATES HYPOXIA-INDUCED NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CANCER CELLS

    PubMed Central

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca

    2012-01-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation has been associated with tumor progression, poor prognosis and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavourable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells, in vitro. Results exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent down regulation of Notch-mediated signalling, as demonstrated by reduced levels of the Notch target genes, Hes1 and Hey1. Neuroendocrine differentiation was promoted by attenuation of Hes1 transcription, as cells expressing a dominant negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia down regulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen independent cell lines, PC3 and Du145, it did not change the extent of NE differentiation in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Conclusions hypoxia induces neuroendocrine differentiation of LNCaP cells in vitro, which appears to be driven by the inhibition of Notch signalling with subsequent down-regulation of Hes1 transcription. PMID:22172337

  13. Separation of SSEA-4 and TRA-1-60 labelled undifferentiated human embryonic stem cells from a heterogeneous cell population using magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS).

    PubMed

    Fong, Chui Yee; Peh, Gary S L; Gauthaman, Kalamegam; Bongso, Ariff

    2009-03-01

    A major concern in human embryonic stem cell (hESC)-derived cell replacement therapy is the risk of tumorigenesis from undifferentiated hESCs residing in the population of hESC-derived cells. Separation of these undifferentiated hESCs from the differentiated derivatives using cell sorting methods may be a plausible approach in overcoming this problem. We therefore explored magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) to separate labelled undifferentiated hESCs from a heterogeneous population of hESCs and hepatocellular carcinoma cells (HepG2) deliberately mixed respectively at different ratios (10:90, 20:80, 30:70, 40:60 and 50:50) to mimic a standard in vitro differentiation protocol, instead of using a hESC-differentiated cell population, so that we could be sure of the actual number of cells separated. HES-3 and HES-4 cells were labelled in separate experiments for the stem cell markers SSEA-4 and TRA-1-60 using primary antibodies. Anti-PE magnetic microbeads that recognize the PE-conjugated SSEA-4 labelled hESCs was added to the heterogeneous cell mixture and passed through the MACS column. The cells that passed through the column ('flow-through' fraction) and those retained ('labelled' fraction') were subsequently analysed using FACS. The maximum efficacy of hESCs retention using MACS was 81.0 +/- 2.9% (HES-3) and 83.6 +/- 4.2% (HES-4). Using FACS, all the undifferentiated hESCs labelled with the two cell-surface markers could be removed by selective gating. Both hESCs and HepG2 cells in the 'flow-through' fraction following MACS separation were viable in culture whereas by FACS separation only the HepG2 cells were viable. FACS efficiently helps to eliminate the undifferentiated hESCs based on their cell-surface antigens expressed.

  14. Presence of factors chemotactic for granulocytes in hypereosinophilic syndrome sera: relation with alterations in eosinophil migration.

    PubMed Central

    Gosset, P; Prin, L; Capron, M; Auriault, C; Tonnel, A B; Capron, A

    1986-01-01

    Recent work has underlined a structural and metabolic heterogeneity amongst blood eosinophils in various hypereosinophilic diseases. Little is known about the factors responsible for this variability. We have identified granulocyte chemotactic factors, termed GCFs in the sera of five patients with hypereosinophilic syndrome (HES). Sera from normal controls or from 20 patients with blood hypereosinophilia of various causes, but with little or no hypodense blood eosinophils, did not demonstrate any chemotactic activity. Two distinct GCFs were characterized, either by gel filtration or isoelectric focusing (molecular weights of 600 kD and 240 kD; pIs of approximately 5 and 7). These fractions are sensitive to proteolytic enzymes and to heating to 100 degrees C but not to 56 degrees C. The activity of GCFs has been tested towards neutrophils and eosinophils. The fractions of 240 kD and pI 7 appear more selective for the eosinophil lineage. Checkerboard analysis shows that such fractions are primarily chemotactic. In addition, hypodense eosinophils appear defective in random motility and chemotaxis towards chemotactic agents which are effective on normodense eosinophils. Moreover, preincubation of normodense eosinophils with HES sera rendered these cells unresponsive to very efficient chemotactic agents such as leukotriene B4 (LTB4) (decrease in migration of 91%; P less than 10(-3), formyl methionyl leucyl phenylalanyl (Fmlp) (decrease of 95%; P less than 10(-2)), HES sera (decrease of 91 to 93%). These findings suggest a process of deactivation of blood eosinophils with the possible retention within the circulation of activated hypodense eosinophils in HES. PMID:3780047

  15. Feeder-free and xeno-free culture of human pluripotent stem cells using UCBS matrix.

    PubMed

    Ding, Yan; Yang, Hua; Yu, Li; Xu, Chang Long; Zeng, Yi; Qiu, Ying; Li, Dong Sheng

    2015-10-01

    The ideal medium for human pluripotent stem cells (hPSCs) culture should be feeder-free, xeno-free, and completely defined. The present study aims to establish a new feeder-free and xeno-free system for culturing hPSCs. The system consists of the matrix, which was prepared from human umbilical cord blood serum (UCBS) and used to coat the culture plates, and the xeno-free medium, which was conventional serum-free hES medium supplemented with high concentrations of bFGF and Fibronectin. Compared with matrigel and mouse embryonic fibroblasts (MEFs), the UCBS matrix was proved to be equally suitable for the growth of hPSCs. After a series of experiments with different media and cytokins, the UCBS matrix was found worked the best with the basic medium (BM) supplemented with 20 ng/mL bFGF, 10 ug/mL fibronectin and Y-27632 for culture of hES cells. The hPSCs maintained normal karyotype, high proliferation rate and self-renewal ability after continuous culture more than 10 passages in this feeder-free and xeno-free system. Furthermore, a new human embryonic stem (hES) cell line was derived from discarded day 3 embryos in this newly developed culture system. In conclusion, this feeder-free and xeno-free system could not only be used to the culture hPSCs, but could also be used to derive new hES cell lines.

  16. The American Experience with Pacification in Vietnam. Volume 2: Elements of Pacification

    DTIC Science & Technology

    1972-03-01

    Evaluation System HqEl Hamlet Evaluation Worksheet ICEX Intelligence, Coordination and Exploitation I4G Information and Reports Working Group (MACV...subjective system involving ratings that were both subjective and multi - dimensional , HES/70, designed to provide a more objective and uni- dimensional ...development; reporting and evaluation systems ; and the US and GVN organization for pacification. In addition, some problem areas (e.g., land reform

  17. Role of microRNA-21 in the formation of insulin-producing cells from pancreatic progenitor cells.

    PubMed

    Bai, Chunyu; Li, Xiangchen; Gao, Yuhua; Wang, Kunfu; Fan, Yanan; Zhang, Shuang; Ma, Yuehui; Guan, Weijun

    2016-02-01

    MicroRNAs (miRNAs) regulate insulin secretion, pancreas development, and beta cell differentiation. In this study, to screen for miRNAs and their targets that function during insulin-producing cells (IPCs) formation, we examined the messenger RNA and microRNA expression profiles of pancreatic progenitor cells (PPCs) and IPCs using microarray and deep sequencing approaches, respectively. Combining our data with that from previous reports, we found that miR-21 and its targets play an important role in the formation of IPCs. However, the function of miR-21 in the formation of IPCs from PPCs is poorly understood. Therefore, we over-expressed or inhibited miR-21 and expressed small interfering RNAs of miR-21 targets in PPCs to investigate their functions in IPCs formation. We found that miR-21 acts as a bidirectional switch in the formation of IPCs by regulating the expression of target and downstream genes (SOX6, RPBJ and HES1). Small interfering RNAs were used to knock down these genes in PPCs to investigate their effects on IPCs formation. Single expression of si-RBPJ, si-SOX6 and si-HES1 in PPCs showed that si-RBPJ was an inhibitor, and that si-SOX6 and si-HES1 were promoters of IPCs formation, although si-HES1 induced formation of IPCs at higher rates than si-SOX6. These results suggest that endogenous miRNAs involved in the formation of IPCs from PPCs should be considered in the development of an effective cell transplant therapy for diabetes.

  18. Influence of laser induced hot electrons on the threshold for shock ignition of fusion reactions

    NASA Astrophysics Data System (ADS)

    Colaïtis, A.; Ribeyre, X.; Le Bel, E.; Duchateau, G.; Nicolaï, Ph.; Tikhonchuk, V.

    2016-07-01

    The effects of Hot Electrons (HEs) generated by the nonlinear Laser-Plasma Interaction (LPI) on the dynamics of Shock Ignition Inertial Confinement Fusion targets are investigated. The coupling between the laser beam, plasma dynamics and hot electron generation and propagation is described with a radiative hydrodynamics code using an inline model based on Paraxial Complex Geometrical Optics [Colaïtis et al., Phys. Rev. E 92, 041101 (2015)]. Two targets are considered: the pure-DT HiPER target and a CH-DT design with baseline spike powers of the order of 200-300 TW. In both cases, accounting for the LPI-generated HEs leads to non-igniting targets when using the baseline spike powers. While HEs are found to increase the ignitor shock pressure, they also preheat the bulk of the imploding shell, notably causing its expansion and contamination of the hotspot with the dense shell material before the time of shock convergence. The associated increase in hotspot mass (i) increases the ignitor shock pressure required to ignite the fusion reactions and (ii) significantly increases the power losses through Bremsstrahlung X-ray radiation, thus rapidly cooling the hotspot. These effects are less prominent for the CH-DT target where the plastic ablator shields the lower energy LPI-HE spectrum. Simulations using higher laser spike powers of 500 TW suggest that the CH-DT capsule marginally ignites, with an ignition window width significantly smaller than without LPI-HEs, and with three quarters of the baseline target yield. The latter effect arises from the relation between the shock launching time and the shell areal density, which becomes relevant in presence of a LPI-HE preheating.

  19. Purification and Characterization of Methyl Phthalyl Ethyl Glycolate (MPEG)

    DTIC Science & Technology

    2014-11-21

    plasticizer, HES 5808 propellant, purification, 1H NMR, 13C NMR, IR, UV- Vis, bp, HRMS, GC, GC-MS, EA, KF, flash column chromatography , dimethylformamide...We report the purification of methyl phthalyl ethyl glycolate (MPEG) by flash column chromatography (ca. grams), allowing us to establish an...analysis Et3N Triethylamine Et2O Diethyl ether IR Infrared spectroscopy GC Capillary gas chromatography GC-MS Capillary gas chromatography mass

  20. A SEARCH FOR UNRECOGNIZED CARBON-ENHANCED METAL-POOR STARS IN THE GALAXY

    SciTech Connect

    Placco, Vinicius M.; Rossi, Silvia; Kennedy, Catherine R.; Beers, Timothy C.; Lee, Young Sun; Christlieb, Norbert; Sivarani, Thirupathi; Reimers, Dieter; Wisotzki, Lutz

    2010-03-15

    We have developed a new procedure to search for carbon-enhanced metal-poor (CEMP) stars from the Hamburg/ESO (HES) prism-survey plates. This method employs an extended line index for the CH G band, which we demonstrate to have superior performance when compared to the narrower G-band index formerly employed to estimate G-band strengths for these spectra. Although CEMP stars have been found previously among candidate metal-poor stars selected from the HES, the selection on metallicity undersamples the population of intermediate-metallicity CEMP stars (-2.5 {<=} [Fe/H] {<=} -1.0); such stars are of importance for constraining the onset of the s-process in metal-deficient asymptotic giant branch stars (thought to be associated with the origin of carbon for roughly 80% of CEMP stars). The new candidates also include substantial numbers of warmer carbon-enhanced stars, which were missed in previous HES searches for carbon stars due to selection criteria that emphasized cooler stars. A first subsample, biased toward brighter stars (B< 15.5), has been extracted from the scanned HES plates. After visual inspection (to eliminate spectra compromised by plate defects, overlapping spectra, etc., and to carry out rough spectral classifications), a list of 669 previously unidentified candidate CEMP stars was compiled. Follow-up spectroscopy for a pilot sample of 132 candidates was obtained with the Goodman spectrograph on the SOAR 4.1 m telescope. Our results show that most of the observed stars lie in the targeted metallicity range, and possess prominent carbon absorption features at 4300 A. The success rate for the identification of new CEMP stars is 43% (13 out of 30) for [Fe/H] < -2.0. For stars with [Fe/H] < -2.5, the ratio increases to 80% (four out of five objects), including one star with [Fe/H] < -3.0.

  1. Validation of suicide and self-harm records in the Clinical Practice Research Datalink

    PubMed Central

    Thomas, Kyla H; Davies, Neil; Metcalfe, Chris; Windmeijer, Frank; Martin, Richard M; Gunnell, David

    2013-01-01

    Aims The UK Clinical Practice Research Datalink (CPRD) is increasingly being used to investigate suicide-related adverse drug reactions. No studies have comprehensively validated the recording of suicide and nonfatal self-harm in the CPRD. We validated general practitioners' recording of these outcomes using linked Office for National Statistics (ONS) mortality and Hospital Episode Statistics (HES) admission data. Methods We identified cases of suicide and self-harm recorded using appropriate Read codes in the CPRD between 1998 and 2010 in patients aged ≥15 years. Suicides were defined as patients with Read codes for suicide recorded within 95 days of their death. International Classification of Diseases codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES data sets. We compared CPRD-derived cases/incidence of suicide and self-harm with those identified from linked ONS mortality and HES data, national suicide incidence rates and published self-harm incidence data. Results Only 26.1% (n = 590) of the ‘true’ (ONS-confirmed) suicides were identified using Read codes. Furthermore, only 55.5% of Read code-identified suicides were confirmed as suicide by the ONS data. Of the HES-identified cases of self-harm, 68.4% were identified in the CPRD using Read codes. The CPRD self-harm rates based on Read codes had similar age and sex distributions to rates observed in self-harm hospital registers, although rates were underestimated in all age groups. Conclusions The CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over- and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked. PMID:23216533

  2. DoD Modeling and Simulation (M&S) Glossary

    DTIC Science & Technology

    1998-01-01

    Processing Standard (FIPS) Publication (PUB) 184 "Integration Language for Information Modeling ( IDEFIX ), Undated (o) "Military Handbook for Joint...Interface Guided Weapons Evaluation Facility < 4 4 30 January 1998 DoD 5000.59-M H I H/W HAMPS HAP HBR HBTWG HBV HCI HD HDF HDL...HDLC HDR HDS HDTV HDU HEFS HELIPAC HERO HES HET HF-ATSS HFE HFEA HITL HLA HMD HMI HMMRSS HMS HMS/DS HMU HOL HOM HOTMAC HPC

  3. Exploring unintended consequences of policy initiatives in mental health: the example of Child and Adolescent Mental Health Services (CAMHS) in England

    PubMed Central

    Foreman, David M

    2016-01-01

    Objectives The impact of policy and funding on Child and Adolescent Mental Health Service (CAMHS) activity and capacity, from 2003 to 2012, was assessed. The focus was on preschool children (aged 0–4 years), as current and 2003 policy initiatives stressed the importance of ‘early intervention’. Settings National service capacity from English CAMHS mapping was obtained from 2003 to 2008 inclusive. English Hospital Episode Statistics (HES) for English CAMHS was obtained from 2003 to 2012. The Child and Adolescent Faculty of the Royal College of Psychiatrists surveyed its members about comparative 0–4-year service activity and attitudes in 2012. Participants CAMHS services in England provided HES and CAMHS mapping data. The Child and Adolescent Faculty of the Royal College of Psychiatrists are child psychiatrists, including trainees. Outcome measures CAMHS mapping data provided national estimates of total numbers of CAMHS patients, whereas HES data counted appointments or episodes of inpatient care. The survey reported on Child Psychiatrists' informal estimates of service activity and attitudes towards children aged 0–4 years. Results The association between service capacity and service activity was moderated by an interaction between specified funding and age, the youngest children benefiting least from specified funding and suffering most when it was withdrawn (Pr=0.005). Policy review and significant differences between age-specific HES trends (Pr<0.001) suggested this reflected prioritisation of older children. Clinicians were unaware of this effect at local level, though it significantly influenced their attitudes to prioritising this group (Pr=0.02). Conclusions If the new policy initiative for CAMHS is to succeed, it will need to have time-limited priorities attached to sustained, specified funding, with planning for limits as well as expansion. Data collection for policy evaluation should include measures of capacity and activity. PMID:27496228

  4. Surface chemistry at Swiss Universities of Applied Sciences.

    PubMed

    Brodard, Pierre; Pfeifer, Marc E; Adlhart, Christian D; Pieles, Uwe; Shahgaldian, Patrick

    2014-01-01

    In the Swiss Universities of Applied Sciences, a number of research groups are involved in surface science, with different methodological approaches and a broad range of sophisticated characterization techniques. A snapshot of the current research going on in different groups from the University of Applied Sciences and Arts Western Switzerland (HES-SO), the Zurich University of Applied Sciences (ZHAW) and the University of Applied Sciences and Arts Northwestern Switzerland (FHNW) is given.

  5. Haemostasis monitored in stored red blood cells, plasma and platelet concentrates in the proportion of 4 :  4 :  1 diluted with crystalloids and colloids.

    PubMed

    Ågren, Anna; Edgren, Gustaf; Ambrosio, Daniela; Gryfelt, Gunilla; Östlund, Anders; Wikman, Agneta

    2016-04-01

    The aim of this in-vitro study was to evaluate haemostasis analysed with thromboelastometry and blood gas and blood count variables, in stored blood components and the effects after dilution with Ringer[Combining Acute Accent]s acetate, albumin and hydroxyethyl starch (HES). Aliquots from stored red blood cells, plasma and platelet concentrates were mixed in the proportion of 4 : 4 : 1 and analysed with rotational thromboelastometry (ROTEM), blood count [haemoglobin (Hb), haematocrit, platelet count] and blood gas (pH, calcium, sodium, potassium, glucose levels). The blood mix was thereafter diluted 20 and 33% with Ringer's acetate, albumin or HES. The stored blood component mix in a ratio of 4 : 4 : 1 had a low pH (7.11 ± 0.03, mean ± standard deviation), nonmeasurable calcium level, and high concentrations of sodium, potassium and glucose but ROTEM curves within normal range after recalcification. With Ringer's acetate dilution, the ROTEM variables changed almost linearly with increasing dilution volume. When albumin was used in the 33% dilution, the clot firmness of the fibrin clot (FibTEM) was further reduced, and with HES dilution, there was a pronounced impairment. The stored blood mix had a low pH and calcium level, both of which might have a significant influence on the coagulation process but normal ROTEM curves after recalcification. Dilution with Ringer's acetate and albumin resulted in moderate deterioration, while dilution with HES showed severely impaired haemostasis.

  6. Fibrinogen Concentrate in Dilutional Coagulopathy: a Dose Study in Pigs

    DTIC Science & Technology

    2014-01-01

    measurements, animals underwent a 60% normovolemic hemodilution (HD) with 6% hydroxyethyl starch (HES) 130/0.4 (Voluven, Fresenius Co., Bad Homburg...improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo...clinically relevant overestimation of fibrinogen concentration in plasma diluted with hydroxyethyl starch . Clin Appl Thromb Hemost 2010;16:461-71. 28

  7. Locus of Control, Attribution Theory, and the "Five Deadly Sins" of Aviation

    DTIC Science & Technology

    2006-05-01

    negative correlation between internality and self -reported involvement in hazardous events, as indicated by the Hazardous Events Scale (HES; Hunter...one’s self esteem ; it can lead to a cavalier attitude toward safety and consequent laxity in following safety precautions. The concept of... Testing . Chapin, J. (2001). Self -protective pessimism: Optimistic bias in reverse. North American Journal of Psychology, 3, 253-262. Cravens, R. W

  8. NOTCH1 is required for regeneration of Clara cells during repair of airway injury.

    PubMed

    Xing, Yiming; Li, Aimin; Borok, Zea; Li, Changgong; Minoo, Parviz

    2012-05-01

    The airways of the mammalian lung are lined with highly specialized epithelial cell types that are the targets of airborne toxicants and injury. Notch signaling plays an important role in the ontogeny of airway epithelial cells, but its contributions to recruitment, expansion or differentiation of resident progenitor/stem cells, and repair and re-establishment of the normal composition of airway epithelium following injury have not been addressed. In this study, the role of a specific Notch receptor, Notch1, was investigated by targeted inactivation in the embryonic lung epithelium using the epithelial-specific Gata5-Cre driver line. Notch1-deficient mice are viable without discernible defects in pulmonary epithelial cell-fate determination and differentiation. However, in an experimental model of airway injury, activity of Notch1 is found to be required for normal repair of the airway epithelium. Absence of Notch1 reduced the ability of a population of cells distinguished by expression of PGP9.5, otherwise a marker of pulmonary neuroendocrine cells, which appears to serve as a reservoir for regeneration of Clara cells. Hairy/enhancer of split-5 (Hes5) and paired-box-containing gene 6 (Pax6) were found to be downstream targets of Notch1. Both Hes5 and Pax6 expressions were significantly increased in association with Clara cell regeneration in wild-type lungs. Ablation of Notch1 reduced Hes5 and Pax6 and inhibited airway epithelial repair. Thus, although dispensable in developmental ontogeny of airway epithelial cells, normal activity of Notch1 is required for repair of the airway epithelium. The signaling pathway by which Notch1 regulates the repair process includes stimulation of Hes5 and Pax6 gene expression.

  9. Effects of goal-directed fluid therapy with different lactated Ringer's: hydroxyethyl starch ratios in hemorrhagic shock dogs.

    PubMed

    Tao, J P; Huang, Q Q; Huang, H Q; Yang, J J; Shi, M; Zhou, Y; Wan, L J; Zhou, C; Ou, Y J; Tong, Y Y; Yang, D G; Si, Y Y

    2015-06-18

    The effects of goal-directed fluid therapy, with lactated Ringer's (LR) and 6% hydroxyethyl starch (HES) solution, on hemorrhagic shock dogs are unknown. We aimed to determine the optimal LR: HES ratio for the resuscitation of hemorrhagic shock dogs. Hemorrhagic shock was induced in 40 ventilated dogs by drawing an estimated 60% blood volume. The animals were randomly divided into five groups (N = 8) according to the LR: HES ratio of the resuscitation fluid (3:1, 2:1, 1:1, 1:2, and 1:3), and were then resuscitated for 24 h to reach the stroke volume variation (SVV) and hemoglobin (Hb) goals by fluid infusion and autologous blood perfusion. The extravascular lung water index (EVLWI), pH, partial pressure of oxygen (PaO2), base excess (BE), sodium, chloride, Hb and creatinine clearance (Clearcrea) were checked after 24 h (R24). The EVLWI of the 3:1 group at R24 were higher than that of the 1:3 group and the baseline value (P < 0.05), whereas the PaO2 was lower (P < 0.05). In contrast to the 3:1 group at R24 and baseline, plasma chloride and sodium in the 1:3 and 1:2 groups increased; however, pH, BE, and Clearcrea decreased (P < 0.05). No significant differences were found in the 1:1 and 2:1 groups at R24 compared with baseline (P > 0.05). Resuscitation with LR and HES at 2:1 and 1:1 ratios are superior in maintaining the acid-base, electrolyte, and lung water balances as well as renal function in hemorrhagic shock dogs than at ratios of 3:l, 1:2, and1:3.

  10. Physics-Based Multi-Scale Modeling of Shear Initiated Reactions in Energetic and Reactive Materials

    DTIC Science & Technology

    2009-03-01

    Phys. 1972, 5, 1921. 7. McQuarrie , D. A., Statistical Mechanics , Harper: New York, 1976. 8. Chase, M. W.; Davies, C. A.; Downey, J. R.; Frurip, D. J...munitions due to fragment impact. Present computational capabilities in continuum mechanics codes used by Army designers do not possess the capability to...into the continuum mechanics code CTH, and perform simulations for HEs and RMs. 2 Figure 1. Schematic of multi-scale shear initiation model. As

  11. Drosophila Hey is a target of Notch in asymmetric divisions during embryonic and larval neurogenesis.

    PubMed

    Monastirioti, Maria; Giagtzoglou, Nikolaos; Koumbanakis, Konstantinos A; Zacharioudaki, Evanthia; Deligiannaki, Myrto; Wech, Irmgard; Almeida, Mara; Preiss, Anette; Bray, Sarah; Delidakis, Christos

    2010-01-01

    bHLH-O proteins are a subfamily of the basic-helix-loop-helix transcription factors characterized by an 'Orange' protein-protein interaction domain. Typical members are the Hairy/E(spl), or Hes, proteins, well studied in their ability, among others, to suppress neuronal differentiation in both invertebrates and vertebrates. Hes proteins are often effectors of Notch signalling. In vertebrates, another bHLH-O protein group, the Hey proteins, have also been shown to be Notch targets and to interact with Hes. We have studied the single Drosophila Hey orthologue. We show that it is primarily expressed in a subset of newly born neurons, which receive Notch signalling during their birth. Unlike in vertebrates, however, Hey is not expressed in precursor cells and does not block neuronal differentiation. It rather promotes one of two alternative fates that sibling neurons adopt at birth. Although in the majority of cases Hey is a Notch target, it is also expressed independently of Notch in some lineages, most notably the larval mushroom body. The availability of Hey as a Notch readout has allowed us to study Notch signalling during the genesis of secondary neurons in the larval central nervous system.

  12. Examining a home environmental strategy to reduce availability of legal products that can be misused by youth.

    PubMed

    Collins, David A; Johnson, Knowlton W; Shamblen, Stephen R

    2012-10-01

    This article presents results from a study of a home environmental strategy (HES) designed to reduce availability of harmful legal products (HLPs) in the home that can be used by youth to get high. HLPs include inhalants, prescription and nonprescription drugs, and household products that can be ingested to get high. Availability is one of the most consistent predictors of substance use among youth. Parents of 5th- to 7th-grade students in four Alaskan communities participated in telephone interviews as part of a larger study of a multicomponent community prevention model (CPM) that included a HES. The strategy was designed to encourage parents to reduce availability of HLPs by removing them from the home, and by locking up and monitoring the supplies of HLPs in the home. Data from 402 parents at Wave 1 and 371 parents at Wave 2 were analyzed using hierarchical non-Linear modeling (HNLM). Results show there was a significant decrease in HLPs in the home from Wave 1 to Wave 2, mostly inhalants and prescription and nonprescription drugs. Parents also reported a significant increase in locking up prescription and nonprescription drugs in the home. Parents' direct exposure to the HES was marginally associated with the change over time in HLP availability in the home. Indirect exposure through others and media was not associated with this change. Study lessons learned and conclusions are highlighted.

  13. Highly excited strings I: Generating function

    NASA Astrophysics Data System (ADS)

    Skliros, Dimitri P.; Copeland, Edmund J.; Saffin, Paul M.

    2017-03-01

    This is the first of a series of detailed papers on string amplitudes with highly excited strings (HES). In the present paper we construct a generating function for string amplitudes with generic HES vertex operators using a fixed-loop momentum formalism. We generalise the proof of the chiral splitting theorem of D'Hoker and Phong to string amplitudes with arbitrary HES vertex operators (with generic KK and winding charges, polarisation tensors and oscillators) in general toroidal compactifications E =R D - 1 , 1 ×T Dcr - D (with generic constant Kähler and complex structure target space moduli, background Kaluza-Klein (KK) gauge fields and torsion). We adopt a novel approach that does not rely on a ;reverse engineering; method to make explicit the loop momenta, thus avoiding a certain ambiguity pointed out in a recent paper by Sen, while also keeping the genus of the worldsheet generic. This approach will also be useful in discussions of quantum gravity and in particular in relation to black holes in string theory, non-locality and breakdown of local effective field theory, as well as in discussions of cosmic superstrings and their phenomenological relevance. We also discuss the manifestation of wave/particle (or rather wave/string) duality in string theory.

  14. Hesperidin increases intestinal β,β-carotene 15-15' mono-oxygenase 1 (BCMO1) activity in Mongolian gerbils (Meriones unguiculatus) fed with β-carotene-free diet.

    PubMed

    Poulaert, Marie; Gunata, Ziya; During, Alexandrine; Reboul, Emmanuelle; Laurent, Caroline; Gaillet, Sylvie; Dhuique-Mayer, Claudie

    2014-09-15

    β,β-Carotene 15-15' mono-oxygenase 1 (BCMO1) is a key enzyme in vitamin A (VitA) metabolism in mammals. Dietary compounds, such as carotenoids and polyphenols, were reported to influence BCMO1 activity. The aim of this study was to evaluate the effect of hesperidin (Hes), on the VitA bioefficacy of β-carotene (Bc) from orange-fleshed sweet potato, using Mongolian gerbils, focussing on BCMO1 activity. Gerbils (n=50) depleted in VitA were divided into five groups fed with basal diet containing 3% white- or orange-fleshed sweet potatoes supplemented or not with Hes. Liver BCMO1 activity was low, with no significant differences between groups. Interestingly, intestinal mucosal BCMO1 activity was significantly higher in the gerbils fed without Bc or VitA than those fed with a VitA/Bc-supplemented diet. Finally, our results show that, under a low VitA status, Hes dramatically stimulated intestinal BCMO1 activity, an effect that could possibly be related to its action as an agonist of PPARγ.

  15. How to achieve the 2020 and 2030 emissions targets of China: Evidence from high, mid and low energy-consumption industrial sub-sectors

    NASA Astrophysics Data System (ADS)

    Wang, Juan; Zhao, Tao; Wang, Yanan

    2016-11-01

    Facing the challenge of meeting emissions reduction targets of China, this paper employed the logarithmic mean Divisia index (LMDI) method to study the changes of energy-related carbon emissions in high energy-consumption sectors (HES), mid energy-consumption sectors (MES) and low energy-consumption sectors (LES) from 1996 to 2012. The decomposition results revealed that the economic growth was the most significant factor to increase carbon emissions of three subgroups while the decrease in energy intensity was the dominant factor to reduce carbon emissions of MES and LES. Considering the important roles economic growth and energy intensity played in carbon emissions, three scenarios were set based on the different growth rates of these two factors to identify whether the emissions reduction targets of 40-45% in 2020 and 60-65% in 2030 can be achieved using the co-integration technique. It was indicated that the emissions targets both in 2020 and 2030 can be achieved by LES in the base scenario. In stark contrast to LES, the carbon intensity of HES reduced only 10.03% in 2020 and 14% in 2030 compared to the 2005 level. Therefore, more attentions should be focused on the economic activity and energy intensity of HES. Finally, according to the results obtained, policy implications were provided to further mitigate the carbon intensity of China's industrial sector.

  16. [Effects of infusion media on human red blood cell morphology].

    PubMed

    Burova, O O; Gusev, A A; Petrikov, S S; Gusev, S A; Basyreva, L Iu

    2006-01-01

    The effect of various infusion media on the structure of human red blood cells was evaluated in vitro and in vivo. The in vitro experiments used 10% sodium chloride (NaCl) solution, 10% glucose solution, 20% albumin solution, Rheopolyglucin, HyperHAES solution (18 g of NaCl in combination with 60 g of hydroxyethylstarch (HES), 200/0.5), Voluven (HES 130/0.4/9:1), and a combination of hypertensive NaCl solution and Rheopolyglucin. The morphofunctional response of red blood cells was studied in the clinical setting when 6% Voluven solution (HES 130/0.4/ 9:1) and hypertensive NaCl and glucose solutions were used. It was established that 10% NaCl solution caused considerable changes in the morphology of red blood cells both in the experiment and in patients with severe brain injury. The magnitude of structural changes increased as blood NaCl concentrations became higher. 10% glucose solution, Voluven, Rheopolyglucin, and albumin did not virtually affect the structure of red blood cells. Infusion of Voluven (500 ml of 6% solution for 40 minutes) induced no changes in the morphology of red blood cells in the clinical setting. Among the test solutions used to correct intracranial hypertension (HyperHAES, 10% NaCl, a combination of rheopolyglucin and 10% NaCl), HyperHAES exerted the least effect on the morphology of red blood cells.

  17. The establishment of 20 different human embryonic stem cell lines and subclones; a report on derivation, culture, characterisation and banking.

    PubMed

    Englund, Mikael C O; Caisander, Gunilla; Noaksson, Karin; Emanuelsson, Katarina; Lundin, Kersti; Bergh, Christina; Hansson, Charles; Semb, Henrik; Strehl, Raimund; Hyllner, Johan

    2010-04-01

    This report summarises our efforts in deriving, characterising and banking of 20 different human embryonic stem cell lines. We have derived a large number of human embryonic stem cell lines between 2001 and 2005. One of these cell lines was established under totally xeno-free culture conditions. In addition, several subclones have been established, including a karyoptypical normal clone from a trisomic mother line. A master cell banking system has been utilised in concert with an extensive characterisation programme, ensuring a supply of high quality pluripotent stem cells for further research and development. In this report we also present the first data on a proprietary novel antibody, hES-Cellect, that exhibits high specificity for undifferentiated hES cells. In addition to the traditional manual dissection approach of propagating hES cells, we here also report on the successful approaches of feeder-free cultures as well as single cell cultures based on enzymatic digestion. All culture systems used as reported here have maintained the hES cells in a karyotypical normal and pluripotent state. These systems also have the advantage of being the principal springboards for further scale up of cultures for industrial or clinical applications that would require vastly more cells that can be produced by mechanical means.

  18. Effects of Acute Bleeding Followed by Hydroxyethyl Starch 130/0.4 or a Crystalloid on Propofol Concentrations, Cerebral Oxygenation, and Electroencephalographic and Haemodynamic Variables in Pigs

    PubMed Central

    Venâncio, Carlos; Souza, Almir P.; Ferreira, Luísa Maria; Branco, Paula Sério; de Pinho, Paula Guedes; Amorim, Pedro; Ferreira, David A.

    2014-01-01

    Bleeding changes the haemodynamics, compromising organ perfusion. In this study, the effects of bleeding followed by replacement with hydroxyethyl starch 130/0.4 (HES) or lactated Ringer's (LR) on cerebral oxygenation and electroencephalogram-derived parameters were investigated. Twelve young pigs under propofol-remifentanil anaesthesia were bled 30 mL/kg and, after a 20-minute waiting period, volume replacement was performed with HES (GHES; N = 6) or LR (GRL; N = 6). Bleeding caused a decrease of more than 50% in mean arterial pressure (P < 0.01) and a decrease in cerebral oximetry (P = 0.039), bispectral index, and electroencephalogram total power (P = 0.04 and P < 0.01, resp.), while propofol plasma concentrations increased (P < 0.01). Both solutions restored the haemodynamics and cerebral oxygenation similarly and were accompanied by an increase in electroencephalogram total power. No differences between groups were found. However, one hour after the end of the volume replacement, the cardiac output (P = 0.03) and the cerebral oxygenation (P = 0.008) decreased in the GLR and were significantly lower than in GHES (P = 0.02). Volume replacement with HES 130/0.4 was capable of maintaining the cardiac output and cerebral oxygenation during a longer period than LR and caused a decrease in the propofol plasma concentrations. PMID:24971192

  19. A comparison study on the binding of hesperetin and luteolin to bovine serum albumin by spectroscopy

    NASA Astrophysics Data System (ADS)

    Tang, Lin; Jia, Wanteng

    2013-02-01

    Binding mechanism of luteolin (LUT) and hesperetin (HES) to bovine serum albumin (BSA) was investigated at 288,298,310 K and pH = 7.40 by UV absorption spectroscopy, fluorescence quenching and synchronous fluorescence spectroscopy. Under simulated physiological conditions, the fluorescence data indicated that hesperetin binding to BSA mainly occurs through a static mechanism. In contrast, binding of luteolin to BSA is a combined quenching process while static quenching is prevailing. Linear interval of the Stern-Volmer plot of LUT-BSA for the concentration ratio of LUT to BSA ranged from 0.5 to 1.25 was obtained. The thermodynamic parameters obtained from the Van't Hoff equation indicated that electrostatic force was the predominant force in the LUT-BSA and HES-BSA complex. The inner filter effect was eliminated to get accurate data. The conformational changes of BSA caused by LUT and HES were observed in the UV absorption. Results of fluorescence quenching and synchronous fluorescence showed that degree of luteolin-BSA quenching was higher than hesperetin-BSA quenching, which indicated that the 4'-hydroxide radical was more helpful to the ligand binding to proteins than 4'-methoxyl group for flavones.

  20. Hawaii Energy Strategy Project 2: Fossil Energy Review. Task IV. Scenario development and analysis

    SciTech Connect

    Yamaguchi, N.D.; Breazeale, K.

    1993-12-01

    The Hawaii Energy Strategy (HES) Program is a seven-project effort led by the State of Hawaii Department of Business, Economic Development & Tourism (DBEDT) to investigate a wide spectrum of Hawaii energy issues. The East-West Center`s Program on Resources: Energy and Minerals, has been assigned HES Project 2, Fossil Energy Review, which focuses on fossil energy use in Hawaii and the greater regional and global markets. HES Project 2 has four parts: Task I (World and Regional Fossil Energy Dynamics) covers petroleum, natural gas, and coal in global and regional contexts, along with a discussion of energy and the environment. Task II (Fossil Energy in Hawaii) focuses more closely on fossil energy use in Hawaii: current utilization and trends, the structure of imports, possible future sources of supply, fuel substitutability, and energy security. Task III`s emphasis is Greenfield Options; that is, fossil energy sources not yet used in Hawaii. This task is divided into two sections: first, an in-depth {open_quotes}Assessment of Coal Technology Options and Implications for the State of Hawaii,{close_quotes} along with a spreadsheet analysis model, which was subcontracted to the Environmental Assessment and Information Sciences Division of Argonne National Laboratory; and second, a chapter on liquefied natural gas (LNG) in the Asia-Pacific market and the issues surrounding possible introduction of LNG into the Hawaii market.

  1. KyoT2 downregulates airway remodeling in asthma.

    PubMed

    Hu, Mei; Ou-Yang, Hai-Feng; Han, Xing-Peng; Ti, Xin-Yu; Wu, Chang-Gui

    2015-01-01

    The typical pathological features of asthma are airway remodeling and airway hyperresponsiveness (AHR). KyoT2, a negative modulator of Notch signaling, has been linked to asthma in several previous studies. However, whether KyoT2 is involved in the regulation of airway remodeling or the modulation of airway resistance in asthma is unclear. In this study, we aimed to evaluate the therapeutic potential of KyoT2 in preventing asthma-associated airway remodeling and AHR. BALB/c mice were used to generate a mouse model of asthma. Additionally, the expression of Hes1 and Notch1 in airway was analyzed using Immunofluorescence examination. The asthmatic mice were intranasally administered adenovirus expressing KyoT2 and were compared to control groups. Furthermore, subepithelial fibrosis and other airway remodeling features were analyzed using hematoxylin and eosin staining, Van Gieson's staining and Masson's trichrome staining. AHR was also evaluated. This study revealed that KyoT2 downregulated the expression of Hes1, repressed airway remodeling, and alleviated AHR in asthmatic mice. It is reasonable to assume that KyoT2 downregulates airway remodeling and resistance in asthmatic mice through a Hes1-dependent mechanism. Therefore, KyoT2 is a potential clinical treatment strategy for asthma.

  2. Granulosa cells and retinoic acid co-treatment enrich potential germ cells from manually selected Oct4-EGFP expressing human embryonic stem cells.

    PubMed

    Chen, Hsin-Fu; Jan, Pey-Shynan; Kuo, Hung-Chih; Wu, Fang-Chun; Lan, Chen-Wei; Huang, Mei-Chi; Chien, Chung-Liang; Ho, Hong-Nerng

    2014-09-01

    Differentiation of human embryonic stem (HES) cells to germ cells may become clinically useful in overcoming diseases related to germ-cell development. Niches were used to differentiate HES cell lines, NTU1 and H9 Oct4-enhanced green fluorescence protein (EGFP), including laminin, granulosa cell co-culture or conditioned medium, ovarian stromal cell co-culture or conditioned medium, retinoic acid, stem cell factor (SCF) and BMP4-BMP7-BMP8b treatment. Flow cytometry showed that granulosa cell co-culture (P < 0.001) or conditioned medium (P = 0.007) treatment for 14 days significantly increased the percentages of differentiated H9 Oct4-EGFP cells expressing early germ cell marker stage-specific embryonic antigen 1(SSEA1); sorted SSEA1[+] cells did not express higher levels of germ cell gene VASA and GDF9. Manually collected H9 Oct4-EGFP[+] cells expressed significantly higher levels of VASA (P = 0.005) and GDF9 (P = 0.001). H9 Oct4-EGFP[+] cells developed to ovarian follicle-like structures after culture for 28 days but with low efficiency. Unlike SCF and BMP4, retinoic acid co-treatment enhanced VASA, GDF9 and SCP3 expression. A protocol is recommended to enrich differentiated HES cells with germ-cell potential by culture with granulosa cells, conditioned medium or retinoic acid, manual selection of Oct4-EGFP[+] cells, and analysis of VASA, GDF9 expression, or both.

  3. A comparative study on the antioxidant effects of hesperidin and ellagic acid against skeletal muscle ischemia/reperfusion injury.

    PubMed

    Ekinci Akdemir, Fazile Nur; Gülçin, İlhami; Karagöz, Berna; Soslu, Recep; Alwasel, Saleh H

    2016-01-01

    The antioxidant effects of ellagic acid (EA) and hesperidin (HES) against skeletal muscle ischemia/reperfusion injury (I/R) were performed. Hindlimb ischemia has been induced by tourniquet occlusion for 2 h on left hindlimb. At the end of ischemia, the tourniquate has been removed and initiated reperfusion for 2 h. EA (100 mg/kg) has been applied orally before ischemia/reperfusion in the EA + I/R group. HES (100 mg/kg) has been given orally in the HES + I/R group. The left gastrocnemius muscle has been harvested and stored immediately at -80 °C until assessed for the levels of MDA and antioxidant enzymes activities. MDA level has statistically increased in I/R group (p < 0.05) compared to other groups. The muscle tissue antioxidant enzymes activities were lower than the other groups in the I/R group (p < 0.05). EA and HES treatments significantly reversed the damage level in I/R, also activity of tissue SOD increased in the EA + I/R and HES + I/R groups.

  4. Effect of ROCK inhibitor Y-27632 on normal and variant human embryonic stem cells (hESCs) in vitro: its benefits in hESC expansion.

    PubMed

    Gauthaman, Kalamegam; Fong, Chui-Yee; Bongso, Ariff

    2010-03-01

    The Rho associated coiled coil protein kinase (ROCK) dependent signaling pathway plays an important role in numerous physiological functions such as cell proliferation, adhesion, migration and inflammation. Human embryonic stem cells (hESCs) undergo differentiation and poor survival after single cell dissociation in culture thus limiting their expansion for cell based therapies. We evaluated the role of the selective ROCK inhibitor Y-27632 on hESC colonies and disassociated single hESCs from two different hESC lines. Karyotypically normal hESCs (HES3) and variant hESCs (BG01V) were treated with Y-27632 at 5, 10 and 20 muM concentrations for 72 h and its effects on hESC self renewal, colony morphology, cell cycle and pluripotency were evaluated. Increased cell proliferation of both HES3 and BG01V were observed for all three concentrations compared to untreated controls following passaging of cell clusters or dissociated single cells and some of these increases were statistically significant. Cell cycle assay demonstrated normal cell cycle progression with no peaks evident of apoptosis. No morphological differentiation was evident following treatment with the highest concentration of Y-27632 (20 muM) and the stemness related genes continued to be highly expressed in both HES3 and BG01V cells compared to untreated controls. The results confirmed that Y-27632 is a useful agent that aids in the expansion of undifferentiated hESC numbers for downstream applications in regenerative medicine.

  5. Notch signaling induces retinal stem-like properties in perinatal neural retina progenitors and promotes symmetric divisions in adult retinal stem cells.

    PubMed

    Balenci, Laurent; van der Kooy, Derek

    2014-02-01

    Understanding the mechanisms regulating retinal stem cell (RSC) activity is fundamental for future stem cell-based therapeutic purposes. By combining gain and loss of function approaches, we addressed whether Notch signaling may play a selective role in retinal stem versus retinal progenitor cells in both developing and adult eyes. Inhibition of either Notch or fibroblast growth factor signaling reduced proliferation of retinal stem and retinal progenitor cells, and inhibited RSC self-renewal. Conversely, exogenous Delta-like 3 and direct intrinsic Notch activation stimulated expansionary symmetric divisions in adult RSCs with the concomitant upregulation of Hes5. Knocking down Hes5 expression specifically decreased the numbers, but not the diameters, of adult RSC primary spheres, indicating that HES5 is the downstream effector of Notch receptor in controlling adult RSC proliferation. In addition, constitutive Notch activation induced retinal stem-like asymmetric self-renewal properties, with no expansion (no symmetrical division) in perinatal neural retina progenitor cells. These findings highlight central roles of Notch signaling activity in regulating the modes of division of retinal stem and retinal progenitor cells.

  6. Cognitive influence of a 5-h ENERGY® shot: Are effects perceived or real?

    PubMed

    Buckenmeyer, Philip J; Bauer, Jeffery A; Hokanson, James F; Hendrick, Joy L

    2015-12-01

    With the gain in popularity and use of 'functional energy drinks' (FEDs), manufacturers of these beverages have been making greater claims as to their benefits on a number of performance factors including mental alertness, energy, and physical performance. Few experimental studies have been conducted on FEDs, and no study to date has examined their effects over time. This study looked at the effects of consumption of a 5-h ENERGY® shot (5-HES) on various cognitive functions across five hours on 24 college-aged students using a double-blind, cross-over, placebo-based design. Participants completed a series of five computer-based tests before ingesting the beverage (either 5-HES or placebo) and then completed the tests for each of the next five hours (morning to midday). One week later, they repeated the process with the other beverage. While 90% of participants subjectively thought that the 5-HES was effective at one-hour post-ingestion, no evidence was found to support an enhanced effect on recognition, reaction time, short-term and working memory, or attention capacity. In conclusion, the 5-h Energy Shot® did not significantly improve short- or long-term cognitive function for selected computer-based tasks despite a high level of perception that it was working effectively compared to a placebo with college-aged participants.

  7. Expression of ZNF396 in basal cell carcinoma.

    PubMed

    Bai, Juncheng; Kito, Yusuke; Okubo, Hiroshi; Nagayama, Tomoko; Takeuchi, Tamotsu

    2014-05-01

    Zfp191 represses differentiation and keeps various cells in the stem/progenitor stage. Here, we report that a Zfp191 homolog protein, ZNF396, is expressed in basal cell carcinoma (BCC) and possibly represses the expression of a Notch system effector molecule, Hes1 (hairy and enhancer of split-1), and prevents BCC cells from undergoing Notch-mediated squamous cell differentiation. ZNF396 immunoreactivity was found in the nucleus of 35 of 38 cutaneous BCC and 4 of 74 squamous cell carcinoma tissue specimens. In non-tumorous epidermal tissues, ZNF396 immunoreactivity was restricted in basal cells. siRNA-mediated silencing of ZNF396 induced the expression of Notch2, Hes1, and involucrin in cultured BCC cells. Finally, we found that siRNA-mediated silencing of ZNF396 gene inhibited the proliferation of TE354.T basal cell carcinoma cells. ZNF396 might repress Notch-Hes1 signaling axis and prevent tumor cells from undergoing squamous differentiation in BCC.

  8. Lossless data compression studies for NOAA hyperspectral environmental suite using 3D integer wavelet transforms with 3D embedded zerotree coding

    NASA Astrophysics Data System (ADS)

    Huang, Bormin; Huang, Hung-Lung; Chen, Hao; Ahuja, Alok; Baggett, Kevin; Schmit, Timothy J.; Heymann, Roger W.

    2003-09-01

    Hyperspectral sounder data is a particular class of data that requires high accuracy for useful retrieval of atmospheric temperature and moisture profiles, surface characteristics, cloud properties, and trace gas information. Therefore compression of these data sets is better to be lossless or near lossless. The next-generation NOAA/NESDIS GOES-R hyperspectral sounder, now referred to as the HES (Hyperspectral Environmental Suite), will have hyperspectral resolution (over one thousand channels with spectral widths on the order of 0.5 wavenumber) and high spatial resolution (less than 10 km). Given the large volume of three-dimensional hyperspectral sounder data that will be generated by the HES instrument, the use of robust data compression techniques will be beneficial to data transfer and archive. In this paper, we study lossless data compression for the HES using 3D integer wavelet transforms via the lifting schemes. The wavelet coefficients are then processed with the 3D embedded zerotree wavelet (EZW) algorithm followed by context-based arithmetic coding. We extend the 3D EZW scheme to take on any size of 3D satellite data, each of whose dimensions need not be divisible by 2N, where N is the levels of the wavelet decomposition being performed. The compression ratios of various kinds of wavelet transforms are presented along with a comparison with the JPEG2000 codec.

  9. SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch

    SciTech Connect

    Genethliou, Nicholas; Panayiotou, Elena; Panayi, Helen; Orford, Michael; Mean, Richard; Lapathitis, George; Gill, Herman; Raoof, Sahir; Gasperi, Rita De; Elder, Gregory; Kessaris, Nicoletta; Richardson, William D.; Malas, Stavros

    2009-12-25

    During neural development the transition from neurogenesis to gliogenesis, known as the neuron-glial ({Nu}/G) fate switch, requires the coordinated function of patterning factors, pro-glial factors and Notch signalling. How this process is coordinated in the embryonic spinal cord is poorly understood. Here, we demonstrate that during the N/G fate switch in the ventral spinal cord (vSC) SOX1 links the function of neural patterning and Notch signalling. We show that, SOX1 expression in the vSC is regulated by PAX6, NKX2.2 and Notch signalling in a domain-specific manner. We further show that SOX1 regulates the expression of Hes1 and that loss of Sox1 leads to enhanced production of oligodendrocyte precursors from the pMN. Finally, we show that Notch signalling functions upstream of SOX1 during this fate switch and is independently required for the acquisition of the glial fate perse by regulating Nuclear Factor I A expression in a PAX6/SOX1/HES1/HES5-independent manner. These data integrate functional roles of neural patterning factors, Notch signalling and SOX1 during gliogenesis.

  10. Distribution and mobility of heavy elements in floodplain agricultural soils along the Ibar River (Southern Serbia and Northern Kosovo). Chemometric investigation of pollutant sources and ecological risk assessment.

    PubMed

    Barać, Nemanja; Škrivanj, Sandra; Bukumirić, Zoran; Živojinović, Dragana; Manojlović, Dragan; Barać, Milan; Petrović, Rada; Ćorac, Aleksandar

    2016-05-01

    This work investigates the influence of a high-magnitude flood event on heavy elements (HEs) pollution and mobility in the agricultural soils along Ibar River in Southern Serbia and Northern Kosovo. The study area was one of the most important Pb/Zn industrial regions in Europe. Soil samples (n = 50) collected before and after the floods in May 2014 were subjected to the sequential extraction procedure proposed by the Community Bureau of Reference (BCR). The results indicated that the floods significantly increased not only the pseudo total concentrations of HEs in the soil but also their mobile and potentially bioavailable amounts. Moreover, higher concentrations (both pseudo total and potentially bioavailable) were found in the agricultural soils closer to the industrial hotspots. Principal component analysis and hierarchical cluster analysis successfully grouped the analyzed elements according to their anthropogenic or natural origin. The floods significantly increased the potential ecological risk of HEs associated with Pb/Zn industrial activities in the study area. The potential ecological risk of Cd after the floods was highest and should be of special concern.

  11. Suppressing unspecific cell uptake for targeted delivery using hydroxyethyl starch nanocapsules.

    PubMed

    Baier, Grit; Baumann, Daniela; Siebert, Jörg Max; Musyanovych, Anna; Mailänder, Volker; Landfester, Katharina

    2012-09-10

    Synthesizing nanocarriers with stealth properties and delivering a "payload" to the particular organ remains a big challenge but is the prime prerequisite for any in vivo application. As a nontoxic alternative to the modification by poly(ethylene glycol) PEG, we describe the synthesis of cross-linked hydroxyethyl starch (HES, M(w) 200,000 g/mol) nanocapsules with a size range of 170-300 nm, which do not show nonspecific uptake into cells. The specific uptake was shown by coupling a folic acid conjugate as a model targeting agent onto the surface of the nanocapsules, because folic acid has a high affinity to a variety of human carcinoma cell lines which overexpress the folate receptor on the cell surface. The covalent binding of the folic acid conjugate onto HES capsules was confirmed by FTIR and NMR spectroscopy. The coupling efficiency was determined using fluorescence spectroscopy. The specific cellular uptake of the HES nanocapsules after folic acid coupling into the folate-receptor presenting cells was studied by confocal laser scanning microscopy (CLSM) and flow cytometry.

  12. Nanominerals and potentially hazardous elements from coal cleaning rejects of abandoned mines: Environmental impact and risk assessment.

    PubMed

    Fdez-Ortiz de Vallejuelo, Silvia; Gredilla, Ainara; da Boit, Kátia; Teixeira, Elba C; Sampaio, Carlos H; Madariaga, Juan Manuel; Silva, Luis F O

    2017-02-01

    Soils around coal mining are important reservoir of hazardous elements (HEs), nanominerals, and ultrafine compounds. This research reports and discusses the soil concentrations of HEs (As, Cd, Cr, Cu, Ni, Pb, and Zn) in coal residues of abandoned mines. To assess differences regarding environmental impact and risk assessment between coal abandoned mines from the Santa Catarina state, eighteen coal cleaning rejects with different mineralogical and chemical composition, from eight abandoned mines were collected. Nanominerals and ultra-fine minerals from mining-contaminated areas were analyzed by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), and high-resolution transmission electron microscope (HR-TEM), providing new information on the mineralogy and nano-mineralogy of these coal residues. The total contents of 57 elements (HEs, alkali metals, and rare earth elements) were analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The calculation of NWACs (Normalized Average Weighted Concentration), together with the chemometric analysis by Principal component analysis (PCA) confirmed the variability of the samples regarding their city and their mine of origin. Moreover, the results confirmed the existence of hotspots in mines near urban areas.

  13. Nitric Oxide Receptor Soluble Guanylyl Cyclase Undergoes Splicing Regulation in Differentiating Human Embryonic Cells

    PubMed Central

    Sharin, Vladislav G.; Mujoo, Kalpana; Kots, Alexander Y.; Martin, Emil; Murad, Ferid

    2011-01-01

    Nitric oxide (NO), an important mediator molecule in mammalian physiology, initiates a number of signaling mechanisms by activating the enzyme soluble guanylyl cyclase (sGC). Recently, a new role for NO/cyclic guanosine monophosphate signaling in embryonic development and cell differentiation has emerged. The changes in expression of NO synthase isoforms and various sGC subunits has been demonstrated during human and mouse embryonic stem (ES) cells differentiation. Previously, our laboratory demonstrated that nascent α1 sGC transcript undergoes alternative splicing and that expression of α1 sGC splice forms directly affects sGC activity. Expression of sGC splice variants in the process of human ES (hES) cells differentiation has not been investigated. In this report, we demonstrate that α1 sGC undergoes alternative splicing during random hES differentiation for the first time. Our results indicate that C-α1 sGC splice form is expressed at high levels in differentiating cells and its intracellular distribution varies from canonical α1 sGC subunit. Together, our data suggest that alternative splicing of sGC subunits is associated with differentiation of hES cells. PMID:20964618

  14. Reconstruction of hydrologic responses to late-Glacial (9-33ka) abrupt climate transitions in the coastal southwest United States

    NASA Astrophysics Data System (ADS)

    Wu, M.; Feakins, S. J.; Kirby, M. E.

    2013-12-01

    A sediment core retrieved from Lake Elsinore, the largest natural freshwater lake in southern California, spans an age of 9 to 33ka BP. The period includes several late-Glacial abrupt climate transitions such as the Heinrich events (HEs) 1-3, the Bølling-Allerød (B-A), and the Younger Dryas (YD). This terrestrial site provides a unique opportunity to evaluate changes in hydrology in coastal southwest United States across these key abrupt climate transition events. Hydrogen isotopic ratios (δDwax) of the long-chain C28 alkanoic acid, a biomarker for terrestrial leaf wax, extracted from the sediments, were analyzed to reveal the δD of precipitation water in the past (δDprecip). In the modern climate, higher δDprecip values are associated with moisture sourced from the tropical Pacific, which brings a drier and warmer climate, whereas lower δDprecip values are associated with moisture sourced from north Pacific brought by polar jet stream, causing a wetter and colder climate. δDwax ranges from about -210‰ to -100‰ between late-Glacial HEs and the beginning of Holocene. The pattern generally correlates with Greenland ice core and regional speleothem records, with lower δDwax values corresponding to colder periods (HEs), and higher δDwax values corresponding to warmer periods (B-A and early Holocene). We infer cold and wet climate with north Pacific sourced moisture during the glacial, followed by gradual warming and drying into the B-A and Holocene, when the moisture sources shifted to the tropical Pacific. There is no substantive response to the YD. The fluctuations of δDwax into and out of the HEs can be as large as about 60‰, suggesting greatly variable hydrology across these late-Glacial abrupt climate transition events. The large shifts in δDwax signal during deglaciation and HEs indicate that hydrology in the coastal southwest US has responded sensitively to climate change, and therefore has important implications for water resources in this

  15. A novel acquired cryptic three-way translocation t(2;11;5)(p21.3;q13.5;q23.2) with a submicroscopic deletion at 11p14.3 in an adult with hypereosinophilic syndrome.

    PubMed

    Kjeldsen, Eigil

    2015-08-01

    Hypereosinophilic syndrome (HES) is a clinically and pathologically heterogeneous disease entity. It is characterized by persistent eosinophilia and organ damage after excluding other causes. Clonal eosinophilia is distinguished from idiopathic eosinophilia by the presence of histologic, cytogenetic, or molecular evidence of an underlying malignancy. There are two distinct subcategories of clonal eosinophilia: chronic eosinophilic leukemia, not otherwise specified and myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor α/β or fibroblast growth factor receptor 1. More than 50% of HES are without knowledge of underlying pathogenic molecular pathways. Here we examined a HES patient by oligo-based aCGH analysis and molecular cytogenetic methods. Examination for the common eosinophilia-related cytogenetic abnormalities involving the genes PDGFRA, PDGFRB, and FGFR1 together with BCR-ABL fusion gene was negative. Cytogenetic analysis and multi-color FISH analysis revealed a novel cryptic three-way translocation t(2;11;5)(p21.3;q13.5;q23.2). By oaCGH analysis we could not find any copy number changes related to the cytogenetic breakpoints but instead detected a 0.9Mb submicroscopic deletion at 11p14.3. The deleted region involved the 5'-upstream sequences and exons 1-4 of the LUZP2 gene, which encodes a leucine zipper protein. Analysis of surrogate germ-line cells revealed a normal result showing that the detected chromosomal aberrations were acquired. This is the first report on a HES patient associated with a novel complex three-way translocation t(2;11;5)(p21.3;q13.5;q23.2) and a submicroscopic deletion in chromosome band 11p14.3. The study also demonstrates the benefits of oligo-based aCGH analysis in detecting hidden disease related chromosomal abnormalities. The present findings provide additional clues to unravel important molecular pathways in HES to obtain the full spectrum of acquired chromosomal and

  16. The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study.

    PubMed

    Zhang, Jin-Feng; Chen, Yao; Qiu, Xian-Xin; Tang, Wen-Long; Zhang, Jian-Dong; Huang, Jian-Huang; Lin, Guo-Shi; Wang, Xing-Fu; Lin, Zhi-Xiong

    2016-03-01

    Delta-like ligand-4 (DLL4)-Notch signaling is known to play a pivotal role in the regulation of tumor angiogenesis. We had previously found that DLL4 was overexpressed, while Notch1 receptor, which binds to DLL4 during angiogenesis, was absent in the majority of human primary glioblastomas. Thus, DLL4-Notch signaling pathway in the regulation of tumor angiogenesis in primary glioblastoma remains unknown. Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for expression of components of DLL4-Notch signaling, vascular endothelial growth factor (VEGF), and microvessel density (MVD). Immunohistochemistry results showed that the positive staining of DLL4 and Notch4 was primarily distributed in tumor vascular endothelial cells but rarely detected in tumor cells. However, VEGF, hairy/enhancer of split-1 (HES1; a target gene of Notch signaling), and Notch1-3 expression was seen in both tumor vascular endothelial cells and tumor cells. Univariate analysis showed that the expression levels of VEGF and DLL4, HES1, and Notch4 in tumor endothelial cells were significantly associated with MVD in primary glioblastoma (P < 0.001). Binary logistic regression analysis showed that high expression levels of DLL4, HES1, and Notch4 in tumor endothelial cells were associated with a decrease of MVD in primary glioblastoma, while MVD increased with elevated VEGF expression in contrast. In addition, DLL4, Notch4, and HES1 expression were positively correlated in tumor vascular endothelial cells (P < 0.05). We conclude that the vascular DLL4-Notch4 signaling and VEGF signaling complementing each other plays an important role in the progression of tumor angiogenesis in primary glioblastoma. Graphical abstract A, positive staining of DLL4 in human kidney; B, positive staining of VEGF in human breast cancer; C, positive staining of CD34 in human lung cancer; D, positive staining of HES1 in human breast cancer; E-H, positive staining of Notch1

  17. Status on the Component Models Developed in the Modelica Framework: High-Temperature Steam Electrolysis Plant & Gas Turbine Power Plant

    SciTech Connect

    Suk Kim, Jong; McKellar, Michael; Bragg-Sitton, Shannon M.; Boardman, Richard D.

    2016-10-01

    This report has been prepared as part of an effort to design and build a modeling and simulation (M&S) framework to assess the economic viability of a nuclear-renewable hybrid energy system (N-R HES). In order to facilitate dynamic M&S of such an integrated system, research groups in multiple national laboratories have been developing various subsystems as dynamic physics-based components using the Modelica programming language. In fiscal year (FY) 2015, Idaho National Laboratory (INL) performed a dynamic analysis of two region-specific N-R HES configurations, including the gas-to-liquid (natural gas to Fischer-Tropsch synthetic fuel) and brackish water reverse osmosis desalination plants as industrial processes. In FY 2016, INL has developed two additional subsystems in the Modelica framework: a high-temperature steam electrolysis (HTSE) plant and a gas turbine power plant (GTPP). HTSE has been proposed as a high priority industrial process to be integrated with a light water reactor (LWR) in an N-R HES. This integrated energy system would be capable of dynamically apportioning thermal and electrical energy (1) to provide responsive generation to the power grid and (2) to produce alternative industrial products (i.e., hydrogen and oxygen) without generating any greenhouse gases. A dynamic performance analysis of the LWR/HTSE integration case was carried out to evaluate the technical feasibility (load-following capability) and safety of such a system operating under highly variable conditions requiring flexible output. To support the dynamic analysis, the detailed dynamic model and control design of the HTSE process, which employs solid oxide electrolysis cells, have been developed to predict the process behavior over a large range of operating conditions. As first-generation N-R HES technology will be based on LWRs, which provide thermal energy at a relatively low temperature, complementary temperature-boosting technology was suggested for integration with the

  18. TSG attenuates LPC-induced endothelial cells inflammatory damage through notch signaling inhibition.

    PubMed

    Zhao, Jing; Liang, Yuan; Song, Fan; Xu, Shouzhu; Nian, Lun; Zhou, Xuanxuan; Wang, Siwang

    2016-01-01

    Lysophosphatidylcholine (LPC) induces inflammation in endothelial cells (ECs) but the mechanism is not fully understood. The Notch signaling pathway is involved in chronic EC inflammation, but its functions in LPC-induced endothelial inflammatory damage and 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside's (TSG) protective effect during LPC-induced inflammatory damage in human umbilical vein endothelial cells (HUVECs) is largely unknown. We report that Notch signaling activation contributed to LPC-induced injury in HUVECs, and that TSG protected HUVECs from LPC-induced injury by antagonizing Notch signaling activation by LPC. γ-secretase inhibitor (DAPT), a specific inhibitor of the Notch signaling pathway, and Notch1 siRNA were used to inhibit Notch activity. HUVECs were exposed to LPC in the presence or absence of TSG, DAPT, and Notch1 siRNA. LPC treatment of HUVECs resulted in reduced cell viability, and Notch1 and Hes1 upregulation. Either silencing of Notch1 by siRNA or pharmacological inhibition of Notch signaling by DAPT prevented the loss of cell viability, and induction of apoptosis, and enhanced expression Notch1, Hes1 and MCP-1 by LPC in HUVECs. Similarly, TSG reduced LPC stimulation of Notch1, Hes1, and MCP-1 expression, prevented the release of IL-6 and CRP and rescued HUVECs from LPC-induced cell damage. Our data indicate that the Notch signaling pathway is a crucial mediator of endothelial inflammatory damage and that TSG protects against endothelial inflammatory damage by inhibiting the Notch signaling pathway. Our findings suggest that targeting Notch signaling by natural products such as TSG is a promising strategy for the prevention and treatment of chronic inflammation associated diseases, including atherosclerosis. © 2015 IUBMB Life, 68(1):37-50, 2016.

  19. Hydroxyethyl Starch Could Save a Patient With Acute Aluminum Phosphide Poisoning.

    PubMed

    Marashi, Sayed Mahdi; Nasri Nasrabadi, Zeynab; Jafarzadeh, Mostafa; Mohammadi, Sogand

    2016-07-01

    A 40-year-old male patient with suicidal ingestion of one tablet of aluminium phosphide was referred to the department of toxicology emergency of Baharloo Hospital, Tehran, Iran. The garlic odor was smelled from the patient and abdominal pain and continuous vomiting as well as agitation and heartburn were the first signs and symptoms. Systolic and diastolic blood pressures at the arrival time were 95 and 67 mmHg, respectively. Gastric lavage with potassium permanganate (1:10,000), and 2 vials of sodium bicarbonate through a nasogastric tube was started for the patient and the management was continued with free intravenous infusion of 1 liter of NaCl 0.9% serum plus NaHCO3, hydrocortisone acetate (200 mg), calcium gluconate (1 g) and magnesium sulfate (1 g). Regarding the large intravenous fluid therapy and vasoconstrictor administering (norepinephrine started by 5 µg/min and continued till 15 µg/min), there were no signs of response and the systolic blood pressure was 49 mmHg. At this time, hydroxyethyl starch (HES) (6% hetastarch 600/0.75 in 0.9% sodium chloride) with a dose of 600 cc in 6 hours was started for the patient. At the end of therapy with HES, the patient was stable with systolic and diastolic blood pressure of 110 and 77 mmHg, respectively. He was discharged on the 6th day after the psychological consultation, with normal clinical and paraclinical examinations. This is the first report of using HES in the management of AlP poisoning and its benefit to survive the patient.

  20. Programmed hyperphagia in offspring of obese dams: Altered expression of hypothalamic nutrient sensors, neurogenic factors and epigenetic modulators.

    PubMed

    Desai, Mina; Han, Guang; Ross, Michael G

    2016-04-01

    Maternal overnutrition results in programmed offspring obesity, mediated in part, by hyperphagia. This is remarkably similar to the effects of maternal undernutrition on offspring hyperphagia and obesity. In view of the marked differences in the energy environment of the over and under-nutrition exposures, we studied the expression of select epigenetic modifiers associated with energy imbalance including neurogenic factors and appetite/satiety neuropeptides which are indicative of neurogenic differentiation. HF offspring were exposed to maternal overnutrition (high fat diet; HF) during pregnancy and lactation. We determined the protein expression of energy sensors (mTOR, pAMPK), epigenetic factors (DNA methylase, DNMT1; histone deacetylase, SIRT1/HDAC1), neurogenic factors (Hes1, Mash1, Ngn3) and appetite/satiety neuropeptides (AgRP/POMC) in newborn hypothalamus and adult arcuate nucleus (ARC). Despite maternal obesity, male offspring born to obese dams had similar body weight at birth as Controls. However, when nursed by the same dams, male offspring of obese dams exhibited marked adiposity. At 1 day of age, HF newborn males had significantly decreased energy sensors, DNMT1 including Hes1 and Mash1, which may impact neuroprogenitor cell proliferation and differentiation. This is consistent with increased AgRP in HF newborns. At 6 months of age, HF adult males had significantly increased energy sensors and decreased histone deactylases. In addition, the persistent decreased Hes1, Mash1 as well as Ngn3 are consistent with increased AgRP and decreased POMC. Thus, altered energy sensors and epigenetic responses which modulate gene expression and adult neuronal differentiation may contribute to hyperphagia and obesity in HF male offspring.

  1. Colocalization of β-catenin with Notch intracellular domain in colon cancer: a possible role of Notch1 signaling in activation of CyclinD1-mediated cell proliferation.

    PubMed

    Gopalakrishnan, Natarajan; Saravanakumar, Marimuthu; Madankumar, Perumal; Thiyagu, Mani; Devaraj, Halagowder

    2014-11-01

    The Wnt and Notch1 signaling pathways play major roles in intestinal development and tumorigenesis. Sub-cellular localization of β-catenin has been implicated in colorectal carcinogenesis. However, the β-catenin and Notch intracellular domain (NICD) interaction has to be addressed. Immunohistochemistries of β-catenin, NICD, and dual immunofluorescence of β-catenin and NICD were analyzed in colorectal tissues and HT29 cell line. Moreover, real-time PCR analysis of CyclinD1, Hes1 and MUC2 was done in HT29 cells upon N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) treatment. Dual staining emphasized the strong interaction of β-catenin and NICD in adenoma and adenocarcinoma than in normal tissues. Hes1 transcript levels were decreased 1.5- and 7.1-fold in 12.5 and 25 µM DAPT-treated HT29 cells. CyclinD1 transcript levels decreased 1.2- and 1.6-fold, and MUC2 transcript level increased 4.3- and 7.5-fold in 12.5 and 25 µM DAPT-treated HT29 cells. The results of this study showed that the sub-cellular localization of β-catenin converges with NICD inducing proliferation through the activation of CyclinD1 and Hes1. Moreover, the inhibition of Notch1 signaling by DAPT leads to the arrest of cell proliferation and induces apoptosis leading to the upregulation of MUC2, a secretory cell lineage marker.

  2. Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors.

    PubMed

    Dumont, Amaury G; Yang, Yanwen; Reynoso, David; Katz, Daniela; Trent, Jonathan C; Hughes, Dennis P

    2012-09-01

    Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs. Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may

  3. Characterization of HIFU ablation using DNA fragmentation labeling as apoptosis stain

    NASA Astrophysics Data System (ADS)

    Anquez, Jeremie; Corréas, Jean-Michel; Pau, Bernard; Lacoste, François; Yon, Sylvain

    2012-11-01

    The goal of this work was to compare modalities to precisely quantify the extent of thermally induced lesions: gross pathology vs. histopathology vs. devascularization. Liver areas of 14 rabbits were targeted with HIFU and RF ablations in an acute study. Contrast enhanced computorized tomography (CE-CT) scan images were acquired two hours after HIFU and RF treatment to obtain the devascularized volumes of the livers. The animals were then euthanized and deep frozen. The livers were sliced and each slice was photographed and stacked yielding a volume of gross pathology. The volume VGP of the HIFU lesions were derived. The area AGP of the lesions were computed on a particular slice. The lesions were segmented as hypo intense (devascularized) regions on CE-CT images and their volumes VC were computed. The ratios VC/VGP were computed for all the HIFU lesions on all the 14 subjects with a mean value of 1.2. Histology was performed on the livers using Hematoxyline Eosine Staining (HES) and DNA Fragmentation labeling (TUNEL® technology) which characterizes apoptosis. Apoptotic regions of area AT were segmented on the images stained by TUNEL®. No necrosis was identified on the HES data. While TUNEL® did not mark the cores of the RF lesions as apoptotic, the periphery of HIFU and RF lesions was always recognized with TUNEL® as apoptotic. The ratio AGP/AT was computed. The mean value was 0.95 and 0.25 for HIFU and RF lesions respectively. These findings show that the devascularized territory seen on CE-CT scan coincide with the coagulated territories seen with gross pathology. Those actually correspond to cells in apoptosis. It is confirmed that HES stain does not show necrosis 2 hours after thermal ablation. TUNEL® technology for DNA fragmentation labeling appears as a useful marker for thermally induced acute lesions in the liver.

  4. Sporadic E layer at mid-latitudes: average properties and influence of atmospheric tides

    NASA Astrophysics Data System (ADS)

    Pignalberi, A.; Pezzopane, M.; Zuccheretti, E.

    2014-11-01

    This paper describes a study of the daily variability shown by the main characteristics of the sporadic E (Es) layer, that is the top frequency (ftEs) and the lowest virtual height (h'Es). The study is based on ionograms recorded by the Advanced Ionospheric Sounder by the Istituto Nazionale di Geofisica e Vulcanologia (AIS-INGV) ionosondes installed in the ionospheric stations at Rome (41.8° N, 12.5° E) and Gibilmanna (37.9° N, 14.0° E), Italy, during the summer (June, July, August and September) of 2013, a year falling in the ascending phase of solar cycle 24. The ftEs presents a diurnal variation characterized by two maxima, the first around noon is very well defined and the second in the evening/night is much less defined; the amplitude of both maxima decreases from June to September accompanied by a general decrease of the ftEs values which is more pronounced in the daytime than in the nighttime. h'Es also presents a diurnal variation characterized by two maxima but, unlike ftEs, these present the same amplitude which is independent from the considered month. Assuming that both ftEs and h'Es trends are influenced by the atmospheric tides, the height-time-intensity (HTI) technique was applied to deeply investigate how these waves control the Es dynamics. The HTI study, along with a fast Fourier transform analysis, show that a well-defined semidiurnal periodicity characterizes the Es layer dynamics most accurately in June and July, while in August and September the daytime semidiurnal periodicity becomes weaker and the role of the diurnal periodicity is consequently highlighted.

  5. MiRNA182 regulates percentage of myeloid and erythroid cells in chronic myeloid leukemia.

    PubMed

    Arya, Deepak; Sachithanandan, Sasikala P; Ross, Cecil; Palakodeti, Dasaradhi; Li, Shang; Krishna, Sudhir

    2017-01-12

    The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients. Earlier, miRNA182-5p upregulation was reported in several solid tumours and haematological malignancies. We undertook a strategy involving transient modulation and CRISPR/Cas9 (clustered regularly interspersed short palindromic repeats)-mediated knockout of the MIR182 locus in CML cells. The lineage contribution was assessed by methylcellulose colony formation assay. The transient modulation of miRNA182-5p revealed a biased phenotype. Strikingly, Δ182 cells (homozygous deletion of MIR182 locus) produced a marked shift in lineage distribution. The phenotype was rescued by ectopic expression of miRNA182-5p in Δ182 cells. A bioinformatic analysis and Hes1 modulation data suggested that Hes1 could be a putative target of miRNA182-5p. A reciprocal relationship between miRNA182-5p and Hes1 was seen in the context of TK inhibition. In conclusion, we reveal a key role for miRNA182-5p in restricting the myeloid development of leukemic cells. We propose that the Δ182 cell line will be valuable in designing experiments for next-generation pharmacological interventions.

  6. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    SciTech Connect

    Kleinstreuer, N.C.; Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R.; Weir-Hauptman, A.M.; Palmer, J.A.; Knudsen, T.B.; Dix, D.J.; Donley, E.L.R.; Cezar, G.G.

    2011-11-15

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal development and

  7. Time to achieve target mean arterial pressure during resuscitation from experimental anaphylactic shock in an animal model. A comparison of adrenaline alone or in combination with different volume expanders.

    PubMed

    Tajima, K; Zheng, F; Collange, O; Barthel, G; Thornton, S N; Longrois, D; Levy, B; Audibert, G; Malinovsky, J M; Mertes, P M

    2013-11-01

    Anaphylactic shock is a rare, but potentially lethal complication, combining life-threatening circulatory failure and massive fluid shifts. Treatment guidelines rely on adrenaline and volume expansion by intravenous fluids, but there is no solid evidence for the choice of one specific type of fluid over another. Our purpose was to compare the time to achieve target mean arterial pressure upon resuscitation using adrenaline alone versus adrenaline with different resuscitation fluids in an animal model and to compare the tissue oxygen pressures (PtiO2) with the various strategies. Twenty-five ovalbumin-sensitised Brown Norway rats were allocated to five groups after anaphylactic shock induction: vehicle (CON), adrenaline alone (AD), or adrenaline with isotonic saline (AD+IS), hydroxyethyl starch (AD+HES) or hypertonic saline (AD+HS). Time to reach a target mean arterial pressure value of 75 mmHg, cardiac output, skeletal muscle PtiO2, lactate/pyruvate ratio and cumulative doses of adrenaline were recorded. Non-treated rats died within 15 minutes. The target mean arterial pressure value was reached faster with AD+HES (median: 10 minutes, range: 7.5 to 12.5 minutes) and AD+IS (median: 17.5 minutes, range: 5 to 25 minutes) versus adrenaline alone (median: 25 minutes, range: 20-30 minutes). There were also reduced adrenaline requirements in these groups. The skeletal muscle PtiO2 was restored only in the AD+HES group. Although direct extrapolation to humans should be made with caution, our results support the combined use of adrenaline and volume expansion for resuscitation from anaphylactic shock. When used with adrenaline the most effective fluid was hydroxyethyl starch, whereas hypertonic saline was the least effective.

  8. Advanced uncertainty modelling for container port risk analysis.

    PubMed

    Alyami, Hani; Yang, Zaili; Riahi, Ramin; Bonsall, Stephen; Wang, Jin

    2016-08-13

    Globalization has led to a rapid increase of container movements in seaports. Risks in seaports need to be appropriately addressed to ensure economic wealth, operational efficiency, and personnel safety. As a result, the safety performance of a Container Terminal Operational System (CTOS) plays a growing role in improving the efficiency of international trade. This paper proposes a novel method to facilitate the application of Failure Mode and Effects Analysis (FMEA) in assessing the safety performance of CTOS. The new approach is developed through incorporating a Fuzzy Rule-Based Bayesian Network (FRBN) with Evidential Reasoning (ER) in a complementary manner. The former provides a realistic and flexible method to describe input failure information for risk estimates of individual hazardous events (HEs) at the bottom level of a risk analysis hierarchy. The latter is used to aggregate HEs safety estimates collectively, allowing dynamic risk-based decision support in CTOS from a systematic perspective. The novel feature of the proposed method, compared to those in traditional port risk analysis lies in a dynamic model capable of dealing with continually changing operational conditions in ports. More importantly, a new sensitivity analysis method is developed and carried out to rank the HEs by taking into account their specific risk estimations (locally) and their Risk Influence (RI) to a port's safety system (globally). Due to its generality, the new approach can be tailored for a wide range of applications in different safety and reliability engineering and management systems, particularly when real time risk ranking is required to measure, predict, and improve the associated system safety performance.

  9. Mutations of NOTCH3 in childhood pulmonary arterial hypertension

    PubMed Central

    Chida, Ayako; Shintani, Masaki; Matsushita, Yoshihisa; Sato, Hiroki; Eitoku, Takahiro; Nakayama, Tomotaka; Furutani, Yoshiyuki; Hayama, Emiko; Kawamura, Yoichi; Inai, Kei; Ohtsuki, Shinichi; Saji, Tsutomu; Nonoyama, Shigeaki; Nakanishi, Toshio

    2014-01-01

    Mutations of BMPR2 and other TGF-β superfamily genes have been reported in pulmonary arterial hypertension (PAH). However, 60–90% of idiopathic PAH cases have no mutations in these genes. Recently, the expression of NOTCH3 was shown to be increased in the pulmonary artery smooth muscle cells of PAH patients. We sought to investigate NOTCH3 and its target genes in PAH patients and clarify the role of NOTCH3 signaling. We screened for mutations in NOTCH3, HES1, and HES5 in 41 PAH patients who had no mutations in BMPR2, ALK1, endoglin, SMAD1/4/8, BMPR1B, or Caveolin-1. Two novel missense mutations (c.2519 G>A p.G840E, c.2698 A>C p.T900P) in NOTCH3 were identified in two PAH patients. We performed functional analysis using stable cell lines expressing either wild-type or mutant NOTCH3. The protein-folding chaperone GRP78/BiP was colocalized with wild-type NOTCH3 in the endoplasmic reticulum, whereas the majority of GRP78/BiP was translocated into the nuclei of cells expressing mutant NOTCH3. Cell proliferation and viability were higher for cells expressing mutant NOTCH3 than for those expressing wild-type NOTCH3. We identified novel NOTCH3 mutations in PAH patients and revealed that these mutations were involved in cell proliferation and viability. NOTCH3 mutants induced an impairment in NOTCH3-HES5 signaling. The results may contribute to the elucidation of PAH pathogenesis. PMID:24936512

  10. Coronavirus receptor switch explained from the stereochemistry of protein–carbohydrate interactions and a single mutation

    PubMed Central

    Bakkers, Mark J. G.; Zeng, Qinghong; Feitsma, Louris J.; Hulswit, Ruben J. G.; Li, Zeshi; Westerbeke, Aniek; van Kuppeveld, Frank J. M.; Boons, Geert-Jan; Langereis, Martijn A.; de Groot, Raoul J.

    2016-01-01

    Hemagglutinin-esterases (HEs) are bimodular envelope proteins of orthomyxoviruses, toroviruses, and coronaviruses with a carbohydrate-binding “lectin” domain appended to a receptor-destroying sialate-O-acetylesterase (“esterase”). In concert, these domains facilitate dynamic virion attachment to cell-surface sialoglycans. Most HEs (type I) target 9-O-acetylated sialic acids (9-O-Ac-Sias), but one group of coronaviruses switched to using 4-O-Ac-Sias instead (type II). This specificity shift required quasisynchronous adaptations in the Sia-binding sites of both lectin and esterase domains. Previously, a partially disordered crystal structure of a type II HE revealed how the shift in lectin ligand specificity was achieved. How the switch in esterase substrate specificity was realized remained unresolved, however. Here, we present a complete structure of a type II HE with a receptor analog in the catalytic site and identify the mutations underlying the 9-O- to 4-O-Ac-Sia substrate switch. We show that (i) common principles pertaining to the stereochemistry of protein–carbohydrate interactions were at the core of the transition in lectin ligand and esterase substrate specificity; (ii) in consequence, the switch in O-Ac-Sia specificity could be readily accomplished via convergent intramolecular coevolution with only modest architectural changes in lectin and esterase domains; and (iii) a single, inconspicuous Ala-to-Ser substitution in the catalytic site was key to the emergence of the type II HEs. Our findings provide fundamental insights into how proteins “see” sugars and how this affects protein and virus evolution. PMID:27185912

  11. Literature review of the lifetime of DOE materials: Aging of plastic bonded explosives and the explosives and polymers contained therein

    SciTech Connect

    Burgess, C.E.; Woodyard, J.D.; Rainwater, K.A.; Lightfoot, J.M.; Richardson, B.R.

    1998-09-01

    There are concerns about the lifetime of the nation`s stockpile of high explosives (HEs) and their components. The DOE`s Core Surveillance and Enhanced Surveillance programs specifically target degradation of HE, binders, and plastic-bonded explosives (PBXs) for determination of component lifetimes and handling procedures. The principal goal of this project is to identify the decomposition mechanisms of HEs, plasticizers, and plastic polymer binders resulting from exposure to ionizing radiation, heat, and humidity. The primary HEs of concern are 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) and 1,3,5,7-tetranitro-1,3,5,7-tetraazocyclooctane (HMX). Hexahydro-1,3,5-triazine (RDX) is closely related to these two compounds and is also included in the literature review. Both Kel-F 800 and Estane are polymers of interest. A stabilizer, Irganox 1010, and an energetic plasticizer that is a blend of acetaldehyde 2,2-dinitropropyl acetal, are also of interest, but the focus of this report will be on the explosives and polymers. This presents a literature review that provides background on the synthesis, degradation, and techniques to analyze TATB, HMX, RDX, Kel-F 800, Estane, and the PBXs of these compounds. As there are many factors that can influence degradation of materials, the degradation discussion will be divided into sections based on each factor and how it might affect the degradation mechanism. The factors reviewed that influence the degradation of these materials are exposure to heat, UV- and {gamma}-irradiation, and the chemistry of these compounds. The report presents a recently compiled accounting of the available literature. 80 refs., 7 figs.

  12. Id4, a New Candidate Gene for Senile Osteoporosis, Acts as a Molecular Switch Promoting Osteoblast Differentiation

    PubMed Central

    Yamashita, Yzumi; Nakachi, Yutaka; Nikaido, Itoshi; Bono, Hidemasa; Ninomiya, Yuichi; Kanesaki-Yatsuka, Yukiko; Akita, Masumi; Motegi, Hiromi; Wakana, Shigeharu; Noda, Tetsuo; Sablitzky, Fred; Arai, Shigeki; Kurokawa, Riki; Fukuda, Toru; Katagiri, Takenobu; Schönbach, Christian; Suda, Tatsuo; Mizuno, Yosuke; Okazaki, Yasushi

    2010-01-01

    Excessive accumulation of bone marrow adipocytes observed in senile osteoporosis or age-related osteopenia is caused by the unbalanced differentiation of MSCs into bone marrow adipocytes or osteoblasts. Several transcription factors are known to regulate the balance between adipocyte and osteoblast differentiation. However, the molecular mechanisms that regulate the balance between adipocyte and osteoblast differentiation in the bone marrow have yet to be elucidated. To identify candidate genes associated with senile osteoporosis, we performed genome-wide expression analyses of differentiating osteoblasts and adipocytes. Among transcription factors that were enriched in the early phase of differentiation, Id4 was identified as a key molecule affecting the differentiation of both cell types. Experiments using bone marrow-derived stromal cell line ST2 and Id4-deficient mice showed that lack of Id4 drastically reduces osteoblast differentiation and drives differentiation toward adipocytes. On the other hand knockdown of Id4 in adipogenic-induced ST2 cells increased the expression of Pparγ2, a master regulator of adipocyte differentiation. Similar results were observed in bone marrow cells of femur and tibia of Id4-deficient mice. However the effect of Id4 on Pparγ2 and adipocyte differentiation is unlikely to be of direct nature. The mechanism of Id4 promoting osteoblast differentiation is associated with the Id4-mediated release of Hes1 from Hes1-Hey2 complexes. Hes1 increases the stability and transcriptional activity of Runx2, a key molecule of osteoblast differentiation, which results in an enhanced osteoblast-specific gene expression. The new role of Id4 in promoting osteoblast differentiation renders it a target for preventing the onset of senile osteoporosis. PMID:20628571

  13. Changes in hip flexor passive compliance do not account for improvement in vertical jump performance after hip flexor static stretching.

    PubMed

    Wakefield, C Brent; Cottrell, G Trevor

    2015-06-01

    To date, there is limited research investigating stretching of antagonist muscles and its effects on agonist muscle function. The purpose of this research was to investigate the effects of pre-static stretching (pre-SS) of the hip flexor musculature on passive hip extension range of motion (ROM) and vertical jump height. Fifteen subjects reported to the laboratory on 4 separate days (D1, D2, D3, and D4). D1 was for familiarization, while on D2 to D4, subjects randomly completed 1 of 3 intervention conditions; no stretch (CON), hip flexor stretch (HFS), or hip extensor stretch (HES). Subject's pre- and post-intervention hip extension ROM were measured before performing 3 sets of pre- and post-maximal counter-movement vertical jumps. Vertical jump height was normalized to baseline for data analysis. A repeated-measures ANOVA with post hoc paired sample t-tests revealed a significant increase in vertical jump height in the HFS condition (1.74% ± 0.73; p ≤ 0.05) when compared with CON (-1.34% ± 0.96) or HES (-1.74% ± 0.65) conditions. There was also a significant increase in hip extension ROM after the HFS stretching protocol (6.5 ± 2.75%; p ≤ 0.05) when compared with the CON protocol (-1.73 ± 3.26); however, no significant difference when compared with the HES protocol (1.84 ± 2.79). A correlation analysis showed that the relative hip laxity of each subject had no effect on response to either condition nor did the magnitude of hip ROM change predict improvement in vertical jump. These results suggest that performing SS of the hip flexors may enhance vertical jump performance independent of changes in passive compliance of the hip flexor muscular tendon unit.

  14. [The idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia].

    PubMed

    Chrobák, L; Voglová, J

    2005-12-01

    Idiopathic hypereosinophilic syndrome is a heterogenous group of hematological disorders characterized by eosinophilia (> 1.5 x 10(9)/l) persistent for more than 6 months, exclusion of reactive eosinophilia from other causes, such as parasitic infections or allergy, and evidence of end-organ damage. According to World Health Organization the exclusion includes all neoplastic disorders in which eosinophils are part of the neoplastic clone. Excluded should be also T cell population with aberant phenotype and abnormal cytokine production, recently considert also as "lymphocytic" variants of the HES [42]. HES has to be reclassified as chronic eosinophilic leukemia (CEL) when there is evidence for clonality based on the presence of chromosomal abnormalities or inactivation of X-chromosome in female patients. The successful empiric treatment of patients with tyrosine kinase inhibitor imatinib (Glivec) suggested the presence of an imatinib-sensitive tyrosine kinase inhibitor. The identification of a specific intersticial chromosome deletion del(4)(q12;q12) creating the FIP1L1-PDGFRA fusion gene confirmed this hypothesis. Patients carrying this gene should be reclassified as CEL and detection of this gene is a positive predictor for response to imatinib therapy. Effective doses of imatinib are 100 mg/day. The side effects are minimal. The only exception is an acute left ventricular dysfunction which has been reported in three patients within the first week of treatment with imatinib. Imatinib has been successfully used also in some patients with the constitutively activated thyrosine kinase ETV6-PDGFRbeta [1] and in systemic mast cell disease associated with eosinophilia. Other therapeutical options for HES/CEL have been mentioned. The resistence to imatinib and the possibilities how to overcome it are discussed.

  15. Coronavirus receptor switch explained from the stereochemistry of protein-carbohydrate interactions and a single mutation.

    PubMed

    Bakkers, Mark J G; Zeng, Qinghong; Feitsma, Louris J; Hulswit, Ruben J G; Li, Zeshi; Westerbeke, Aniek; van Kuppeveld, Frank J M; Boons, Geert-Jan; Langereis, Martijn A; Huizinga, Eric G; de Groot, Raoul J

    2016-05-31

    Hemagglutinin-esterases (HEs) are bimodular envelope proteins of orthomyxoviruses, toroviruses, and coronaviruses with a carbohydrate-binding "lectin" domain appended to a receptor-destroying sialate-O-acetylesterase ("esterase"). In concert, these domains facilitate dynamic virion attachment to cell-surface sialoglycans. Most HEs (type I) target 9-O-acetylated sialic acids (9-O-Ac-Sias), but one group of coronaviruses switched to using 4-O-Ac-Sias instead (type II). This specificity shift required quasisynchronous adaptations in the Sia-binding sites of both lectin and esterase domains. Previously, a partially disordered crystal structure of a type II HE revealed how the shift in lectin ligand specificity was achieved. How the switch in esterase substrate specificity was realized remained unresolved, however. Here, we present a complete structure of a type II HE with a receptor analog in the catalytic site and identify the mutations underlying the 9-O- to 4-O-Ac-Sia substrate switch. We show that (i) common principles pertaining to the stereochemistry of protein-carbohydrate interactions were at the core of the transition in lectin ligand and esterase substrate specificity; (ii) in consequence, the switch in O-Ac-Sia specificity could be readily accomplished via convergent intramolecular coevolution with only modest architectural changes in lectin and esterase domains; and (iii) a single, inconspicuous Ala-to-Ser substitution in the catalytic site was key to the emergence of the type II HEs. Our findings provide fundamental insights into how proteins "see" sugars and how this affects protein and virus evolution.

  16. Precise cis-regulatory control of spatial and temporal expression of the alx-1 gene in the skeletogenic lineage of s. purpuratus.

    PubMed

    Damle, Sagar; Davidson, Eric H

    2011-09-15

    Deployment of the gene-regulatory network (GRN) responsible for skeletogenesis in the embryo of the sea urchin Strongylocentrotus purpuratus is restricted to the large micromere lineage by a double negative regulatory gate. The gate consists of a GRN subcircuit composed of the pmar1 and hesC genes, which encode repressors and are wired in tandem, plus a set of target regulatory genes under hesC control. The skeletogenic cell state is specified initially by micromere-specific expression of these regulatory genes, viz. alx1, ets1, tbrain and tel, plus the gene encoding the Notch ligand Delta. Here we use a recently developed high throughput methodology for experimental cis-regulatory analysis to elucidate the genomic regulatory system controlling alx1 expression in time and embryonic space. The results entirely confirm the double negative gate control system at the cis-regulatory level, including definition of the functional HesC target sites, and add the crucial new information that the drivers of alx1 expression are initially Ets1, and then Alx1 itself plus Ets1. Cis-regulatory analysis demonstrates that these inputs quantitatively account for the magnitude of alx1 expression. Furthermore, the Alx1 gene product not only performs an auto-regulatory role, promoting a fast rise in alx1 expression, but also, when at high levels, it behaves as an auto-repressor. A synthetic experiment indicates that this behavior is probably due to dimerization. In summary, the results we report provide the sequence level basis for control of alx1 spatial expression by the double negative gate GRN architecture, and explain the rising, then falling temporal expression profile of the alx1 gene in terms of its auto-regulatory genetic wiring.

  17. Regional Characteristics for Interpreting Inverted Echo Sounder (IES) observations

    DTIC Science & Technology

    1987-06-01

    0 11 function of r’ in Figs. 1 -6 %here quadratic regression laser. I he slope. B ,is about halt the salues found in Cur’es ha\\e been supernmpostd...ere computed as lollows I he SS data exhibits the lowest salue ofr. 1 he %an- ahilit\\ of𔃻)’ is comparable to that in NS. but the signal- 1) B 7...Correlations between /,, are the salues of’ B, and their associated error%. I hes /.and Tr(Table 3: the isopxcnals se-lected corresr nd are the regional

  18. Living carbocationic polymerization of isobutylene by epoxide/Lewis acid systems: The mechanism of initiation

    NASA Astrophysics Data System (ADS)

    Hayat Soytas, Serap

    The objective of the work presented in this dissertation was to generate a fundamental understanding of the synthesis of star-branched polyisobutylenes (PIBs) arising from hexaepoxysqualene (HES)/Lewis acid (LA) initiating systems, using BCl3 and TiCl4 as LAs. The understanding of initiation and propagation mechanisms by HES is crucial to control the number of arms and arm lengths of star PIBs expected from this initiator. The initiation by monofunctional epoxides, such as alpha-methylstyrene epoxide (MSE), 1,2-epoxy-2,4,4-trimethylpentane (TMPO-1), and 2,3-epoxy-2,4,4-trimethylpentane (TMPO-2), was investigated. In situ FTIR spectroscopy, which was highly utilized in this research, provided valuable information. Most importantly, the ability to identify the head group by in situ FTIR of growing PIB chains initiated by an epoxide, i.e. the --C--O--LA complex, contributed significantly to the understanding of initiation of IB polymerization. This technique allowed the monitoring of the rate of initiation with the multifunctional epoxy initiator. Previous research showed that TiCl4 gave 40% initiating efficiency in conjunction with the aromatic epoxy initiator MSE, whereas the aliphatic initiators TMPO-1 and TMPO-2 gave only 3 and 10% efficiency, respectively. In this research it was found that BCl3 is more efficient with the aliphatic initiator, TMPO-1, yielding an asymmetric telechelic PIB carrying an alpha-primary OH and an o-tertiary Cl functional group with 70% initiator efficiency, while MSE gave only 1--4% efficiency. The TMPO-2/BCl3 system gave 20% initiator efficiency. The various initiation mechanisms were discussed. IB polymerization was successfully initiated by HES in the presence of excess BCl3 and monitored by in situ FTIR spectroscopy. The gradual increase of the IR band assigned to the --C--O--BCl 2 group demonstrated that slow initiation was occurring. Chain extension with the HES/BCl3 initiated PIB was achieved leading to high molecular weight PIBs

  19. Preliminary studies on the heat exchanger option for S-CO{sub 2} power conversion cycle coupled to water cooled SMR

    SciTech Connect

    Ahn, Y.; Lee, J.; Lee, J. I.

    2012-07-01

    For more than a half century, the steam Rankine cycle had been the major power conversion cycle for a nuclear power plant. However, as the interest on the next generation reactors grows, a variety of alternative power conversion systems have been studied. Among them, the S-CO{sub 2} cycle (Supercritical carbon dioxide Brayton cycle) is considered as a promising candidate due to several benefits such as 1) Relatively high thermal efficiency at relatively low turbine inlet temperature, 2) High efficiency with simple lay-out 3) Compactness of turbo-machineries. 4) Compactness of total cycle combined with PCHE (Printed Circuit Heat Exchanger). According to the conventional classification of heat exchangers (HE), there are three kind of HE, 1) Tubular HEs, 2) Plate-type HEs, 3) Extended surface HEs. So far, the researcher has mostly assumed PCHE type HE for the S-CO{sub 2} cycle due to its compactness with reasonably low pressure drop. However, PCHE is currently one of the most expensive components in the cycle, which can have a negative effect on the economics of the cycle. Therefore, an alternative for the HE should be seriously investigated. By comparing the operating condition (pressure and temperature) there are three kind of HE in the S-CO{sub 2} cycle, 1) IHX (Intermediate Heat exchanger) 2) Recuperator and 3) Pre-cooler. In each heat exchanger, hot side and cold side coolants are different, i.e. reactor coolant to S-CO{sub 2} (IHX), S-CO{sub 2} to S-CO{sub 2}(Recuperator), S-CO{sub 2} to water (Pre-cooler). By considering all the attributes mentioned above, all existing types of heat exchangers are compared to find a possible alternative to PCHE. The comparing factors are 1) Size(volume), 2) Cost. Plate fin type HEs are considered to be the most competitive heat exchanger regarding the size and the cost after some improvements on the design limit are made. (authors)

  20. A Brief Report of Immunohistochemical Markers to Identify Aggressive Hepatoblastoma.

    PubMed

    Singh, Vivekanand; Manalang, Michelle; Singh, Meenal; Apte, Udayan

    2017-02-09

    Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although survival of patients has improved significantly over the last 2 decades, a significant number of patients do not respond to standard chemotherapy. We conducted a pilot study to understand if there was immunophenotypic difference between tumors that respond well to chemotherapy versus that do not. We selected 10 cases of HB from children presenting at our hospital. All patients had initial tissue diagnosis, underwent chemotherapy followed by surgical resection. The cases were divided into 2 groups: aggressive group with 5 cases (all of which had a poor response to chemotherapy); and a good clinical outcome group with 5 cases (all of which responded well to chemotherapy). We excluded the small cell variant of HB from the study because its poor clinical outcome is well known. To be placed in the aggressive group we used the following criteria: <70% necrosis following chemotherapy or recurrence/distant metastasis following chemotherapy. From tissue obtained before chemotherapy, 1 representative block of formalin-fixed, paraffin-embedded tissue was selected for immunohistochemistry. Following review of published literature, antibodies were selected to detect Survivin, PLK-1, Cytokeratin19 (CK19), N-Myc, Yap, Notch2, Hes1, Hes5, and C-Myc. Our results show that Survivin, CK19, and Yap have a diffuse (>75%) positive staining of tumor cells in the aggressive tumors compared with good outcome tumors. However, staining for Yap was weak. Interestingly, there was loss of nuclear expression of C-Myc in majority of tumor cells in aggressive tumors, whereas nuclear staining was retained in most tumor cells of good responders. The N-Myc and PLK-1 immunostains did not reveal any significant differences in the 2 groups of HB. The immunostains for Notch2, Hes1, and Hes5 showed weak to moderately strong staining in tumor cells, but there was no obvious difference in the 2 groups. Our pilot study

  1. Teratoma formation assays with human embryonic stem cells: a rationale for one type of human-animal chimera.

    PubMed

    Lensch, M William; Schlaeger, Thorsten M; Zon, Leonard I; Daley, George Q

    2007-09-13

    Despite a long and valuable history, human-animal chimera research has often been questioned. Among the moral issues raised by chimeras is the concept that integration of human cells into anatomical locations such as the brain might endow animals with "human-like" capacities including self-awareness. We present a justification for one type of human-animal chimera experiment: the evaluation of hES cell developmental potency via teratoma formation in immunodeficient mice. We argue that this experiment raises no significant moral concerns and should be the jurisdiction of animal care and use committees and exempt from formal review by the stem cell research oversight process.

  2. The Economic Potential of Two Nuclear-Renewable Hybrid Energy Systems

    SciTech Connect

    Ruth, Mark; Cutler, Dylan; Flores-Espino, Francisco; Stark, Greg; Jenkin, Thomas; Simpkins, Travis; Macknick, Jordan

    2016-08-01

    This report is one of a series of reports that investigate the technical and economic aspects of Nuclear-Renewable Hybrid Energy System. It provides the results of an analysis of two scenarios. The first is a Texas-syntheic gasoline scenario and the second is an Arizona-desalination scenario. The analysis focuses on the economics of the N-R HESs and how they compare to other options, including configurations without all the subsystems in each N-R HES and alternatives in which natural gas provides the energy.

  3. Numb/Notch signaling pathway modulation enhances human pancreatic cancer cell radiosensitivity.

    PubMed

    Bi, Yi-Liang; Min, Min; Shen, Wei; Liu, Yan

    2016-11-01

    The present study aims to evaluate whether repression of the Numb/Notch signaling pathway affects the radiosensitivity of human pancreatic cancer cell lines. Different doses of X-rays (0, 2, 3, 4, and 5 Gy) were applied to the PANC-1, SW1990, and MIA PaCa-2 human pancreatic cancer cell lines, and the Numb/Notch pathway inhibitor DAPT was added at different doses (0, 1, 3, and 5 μmol/l). MTT assay, colony formation assay, flow cytometry, scratch assay, and Transwell experiments were performed, and qRT-PCR and Western blot were conducted for the detection of Numb expression. Tumorigenicity assay in nude mice was carried out to verify the influence of blocker of the Numb/Notch signaling pathway on the radiosensitivity of xenograft tumors. The MTT assay, colony formation assay and flow cytometry experiments revealed that proliferation decreased as radiation dose increased. The viability of PANC-1 cells at 5 Gy, SW 1990 cells at 4 Gy and 5 Gy, and MIA PaCa-2 cells at 2-5 Gy was significantly lower than that of non-irradiated cells (all P < 0.05). The migration and invasion assays indicated that the PANC-1 cell line was least radiosensitive, while the MIA PaCa-2 cell line was the most radiosensitive. Numb expression significantly increased with increasing radiation dose, whereas the expression of Hes1, Notch1, and Hes5 significantly decreased compared to non-irradiated cells (P < 0.05). Compared to untreated control cells, DAPT dose dependently increased Numb expression and inhibited Notch1, Hes1, and Hes5 expressions at 2 Gy (P < 0.05). Subcutaneous tumorigenicity assay in nude mice demonstrated that DAPT increased the radiosensitivity of PANC-1, SW 1990, and MIA PaCa-2 cells. These findings suggest that Numb/Notch signaling in pancreatic cancer cells is associated with X-ray radiation and that inhibition of the Numb/Notch signaling pathway can enhance radiosensitivity, suggesting that inhibition of the Numb/Notch signaling pathway may serve as a potential

  4. Experimental Vaccines in Schistosomiasis

    DTIC Science & Technology

    1978-01-01

    nd it Will-hes kFarin in London, using irra- as s"ocintes (�) attempted -I novel wherby F y rd dite -eren appears to offer a . more hooeful...47 3 . . .... . ..... Ra’s 0 *Pe- A F und’s coimtplclc adjuvant IFCA Inompkcl Frvun-’s adiu\\-nnt ICG = Baiile Cani-cte Gu.xIIn Pre. It. Cont. Schisto...F.Miner, CAPT, MC, USN F 3 4= .... B0 : Naval Medical Researc Institute U-. U - THIS DCC1WE IS BEST QUALITY ?RACTICABL, TH.E £CPY 1LUFN!SFD TO DDO

  5. Clinical characteristics of patients with chronic eosinophilic leukaemia (CEL) harbouring FIP1L1-PDGFRA fusion transcript--results of Polish multicentre study.

    PubMed

    Helbig, Grzegorz; Moskwa, Andrzej; Hus, Marek; Piszcz, Jarosław; Swiderska, Alina; Urbanowicz, Alina; Całbecka, Małgorzata; Gajkowska, Justyna; Seferyńska, Ilona; Hałasz, Magdalena; Woszczyk, Dariusz; Markiewicz, Miroslaw; Krzemień, Sławomira

    2010-06-01

    A small subgroup of patients with hypereosinophilic syndrome (HES) demonstrates imatinib-sensitive fusion transcript-the FIP1L1-PDGFRA (F/P+). These cases are currently diagnosed as chronic eosinophilic leukaemia (CEL). In this paper, we screened 77 patients to estimate the frequency of FIP1L1-PDGFRA transcript among patients with unexplained, long-term hypereosinophilia exceeding 1.5 x 10(9)/L and to analyse the clinical and serological features in F/P+ CEL population. The FIP1L1-PDGFRA chimeric protein was detectable in 16 (14 males and 2 females) out of 77 examined HES patients (20%) by RT-PCR. Two patients suffered from cough at diagnosis. Three out of 16 (18%) patients had no organ involvements, in 5-one organ was affected and in the remaining eight cases-at least two. Eosinophilic organ damage/dysfunction identified splenomegaly in the majority of studied patients. We compared clinical and serological features between CEL F/P+ (n = 16) and HES (n = 61) patients. F/P+ cases had significantly increased WBC and absolute eosinophil count (AEC) at diagnosis (p = 0.008 and 0.02), whereas platelet count was decreased in this population (p = 0.03). Serum B12 and tryptase levels were increased (p = 0.002 and 0.004) in CEL F/P+ patients when compared to HES cases whereas serum IL-5 levels were significantly increased in the latter group (p = 0.01). Male gender and splenomegaly occurred more frequent in CEL F/P+ population (p = 0.002 and 0.0007, respectively). Additionally, patients with F/P+ CEL (n = 16) were compared with F/P- CEL (n = 8). The latter group, was significantly older, had lower AEC and higher platelet count. In conclusion, significant clinical symptoms are infrequent present and splenomegaly remains the most common organ involvement in patients with CEL expressing F/P fusion transcript. Our study confirmed the long-term remission on imatinib in this patient population.

  6. The Equation of State of PBX 9502

    NASA Astrophysics Data System (ADS)

    Aslam, Tariq

    Reactive flow modeling of high explosives (HEs) requires accurate equation of states (EOS) for both the HE's reactants and products. The Wescott-Stewart-Davis ``wide-ranging EOS'' model will be examined. A procedure for calibrating both the reactants and products for this EOS will be presented. Several thermodynamic pathways will be explored for the plastic bonded HE PBX 9502. These include: isothermal compression, isentropic compression, single and multiple shock compression, isobaric thermal expansion, adiabatic expansion of the products and the overdriven detonation state. Data from several different experimental techniques are employed to constrain model parameters. Validation tests of the model EOS will also be presented.

  7. The Mass and Angular Momentum Balance of the Zonally-Averaged Global Circulation.

    DTIC Science & Technology

    1981-01-01

    gene,.Zl circulation research dur- Ing the past three decades (e.g., Lorenz, 1967; Newell et al., 1970; Starr, 1966; Oort and Rasmusson, 1970; and...mean maes circulations will be presented through the use of a mess strem function (e.g., Oort and lasmusson, 1970). The isobaric mass 4 * stream...isobaric ass cirewlatiwi for January 19719 In Pigs?. a bet’ sall Consistent with the results of Previous investtIgtions ( Oort I hesSS,1910). The sting

  8. Comparative analysis of her genes during fish somitogenesis suggests a mouse/chick-like mode of oscillation in medaka.

    PubMed

    Gajewski, Martin; Elmasri, Harun; Girschick, Manuel; Sieger, Dirk; Winkler, Christoph

    2006-06-01

    Somitogenesis is the key developmental step, which divides the vertebrate body axis into segmentally repeated structures. It requires an intricate process of pre-patterning, which is driven by an oscillator mechanism consisting of the Delta-Notch pathway and various hairy- and Enhancer of split-related (her) genes. The subset of her genes, which are necessary to set up the segmentation clock, reveal a complex scenario of interactions. To understand which her genes are essential core players in this process, we compared the expression patterns of somitogenesis-relevant her genes in zebrafish and medaka (Oryzias latipes). Most of the respective medaka genes (Ol-her) are duplicated like what has been shown for zebrafish (Dr-her) and pufferfish genes (Fr-her). However, zebrafish genes show some additional copies and significant differences in expression patterns. For the paralogues Dr-her1 and Dr-her11, only one copy exists in the medaka (Ol-her1/11), which combines the expression patterns found for both zebrafish genes. In contrast to Dr-her5, the medaka orthologue appears to play a role in somitogenesis because it is expressed in the presomitic mesoderm (PSM). PSM expression also suggests a role for both Ol-her13 genes, homologues of mouse Hes6 (mHes6), in this process, which would be consistent with a conserved mHes6 homologue gear in the segmentation clock exclusively in lower vertebrates. Members of the mHes5 homologue group seem to be involved in somite formation in all vertebrates (e.g. Dr- and Ol-her12), although different paralogues are additionally recruited in zebrafish (e.g. Dr-her15) and medaka (e.g. Ol-her4). We found that the linkage between duplicates is strongly conserved between pufferfish and medaka and less well conserved in zebrafish. Nevertheless, linkage and orientation of several her duplicates are identical in all three species. Therefore, small-scale duplications must have happened before whole genome duplication occurred in a fish ancestor

  9. Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells

    NASA Astrophysics Data System (ADS)

    Shen, Qin; Goderie, Susan K.; Jin, Li; Karanth, Nithin; Sun, Yu; Abramova, Natalia; Vincent, Peter; Pumiglia, Kevin; Temple, Sally

    2004-05-01

    Neural stem cells are reported to lie in a vascular niche, but there is no direct evidence for a functional relationship between the stem cells and blood vessel component cells. We show that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulates neuroepithelial cell contact, activating Notch and Hes1 to promote self-renewal. These findings identify endothelial cells as a critical component of the neural stem cell niche.

  10. The Ecology of the Benthic and Endolithic Communities of a Rocky Reef in the Kelp Beds off Del Monte Beach, Monterey, California.

    DTIC Science & Technology

    1981-06-01

    RECIPIENT’S CATALOG NUMMER 4. TITLCj~ T.egj max-& ~vRC eocology of the !nthic and %Ser’S hes is,4 .1ndo RLthic ommunities of a lcky eef S EFRIGOG EOTNNE 0 t...1 . CONTRACT OR GRANT mumB90R( s ) 9. PER11FORMING ORGANIZATION NAME ANC ACORESS 10. PROGRAM EL9EMENT. PROJE01CT. TASKC AREA &WORK UNIT MBER’S Naval...COITION OF IMOV goIsSOSL6T7NLSSFE9 ~ ) 41 S /N@10014550 ISECURITY CLASSFICATION OF TNIS PAGE66 IMN Doe ete") UNCLASSIFIED 󈧘. (continued) the level of

  11. Subspace Iteration and Immersed Interface Methods: Theory, Algorithm, and Applications

    DTIC Science & Technology

    2010-08-20

    solution via alevel set fun tion. The new approa hes provide a se ond order dis retedelta fun tion for ellipti and elasti interfa e problems. The...domains [10℄with appli ation to ow past xed obsta les. In the appli ation to problems in mathemati al biology , our immersed-interfa e/level set method...applied to the biologi al problem of for es reating bran hing morphogenesis shows that ontra tility of the mes-en hyme is indeed suÆ ient to reate a

  12. Atrophin Protein RERE Positively Regulates Notch Targets in the Developing Vertebrate Spinal Cord.

    PubMed

    Wang, Hui; Gui, Hongxing; Rallo, Michael S; Xu, Zhiyan; Matise, Michael P

    2017-01-31

    The Notch signaling pathway controls cell fate decision, proliferation and other biological functions in both vertebrates and invertebrates. Precise regulation of the canonical Notch pathway ensures robustness of the signal throughout development and adult tissue homeostasis. Aberrant Notch signaling results in profound developmental defects and is linked to many human diseases. In this study, we identified the Atrophin family protein RERE (also called Atro2) as a positive regulator of Notch target Hes genes in the developing vertebrate spinal cord. Prior studies have shown that during early embryogenesis in mouse and zebrafish, deficit of RERE causes various patterning defects in multiple organs including the neural tube. Here, we detected the expression of RERE in the developing chick spinal cord, and found that normal RERE activity is needed for proper neural progenitor proliferation and neuronal differentiation possibly by affecting Notch mediated Hes expression. In mammalian cells, RERE co-immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by overexpressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. Our findings suggest that RERE stimulates Notch target gene expression by preventing degradation of NICD protein, thereby facilitating the assembly of a transcriptional activating complex containing NICD, CSL and other coactivators. This article is protected by copyright. All rights reserved.

  13. Notch signalling suppresses regulatory T-cell function in murine experimental autoimmune uveitis.

    PubMed

    Rong, Hua; Shen, Hongjie; Xu, Yueli; Yang, Hai

    2016-12-01

    Autoimmune uveitis is an intraocular inflammatory disorder in developed countries. Understanding the mechanisms underlying the development and modulation of immune reaction in uveitic eyes is critical for designing therapeutic interventions. Here we investigated the role of Notch signalling in regulatory T-cell (Treg cell) function during experimental autoimmune uveitis (EAU). Using the Foxp3-GFP reporter mouse strain, the significance of Notch signalling for the function of infiltrating Treg cells was characterized in an EAU model. We found that infiltrating Treg cells substantially expressed Notch-1, Notch-2, JAG1 and DLL1 in uveitic eyes. Activation of Notch signalling, represented by expression of HES1 and HES5, was enhanced in infiltrating Treg cells. Treatment with JAG1 and DLL1 down-regulated Foxp3 expression and immunosuppressive activity of isolated infiltrating Treg cells in vitro, whereas neutralizing antibodies against JAG1 and DLL1 diminished Notch ligand-mediated negative effects on Treg cells. To investigate the significance of Notch signalling for Treg cell function in vivo, lentivirus-derived Notch short hairpin RNAs were transduced into in vitro expanded Treg cells before adoptive transfer of Treg cells into EAU mice. Transfer of Notch-1-deficient Treg cells remarkably reduced pro-inflammatory cytokine production and inflammatory cell infiltration in uveitic eyes. Taken together, Notch signalling negatively modulates the immunosuppressive function of infiltrating Treg cells in mouse EAU.

  14. MAGP2 controls Notch via interactions with RGD binding integrins: Identification of a novel ECM-integrin-Notch signaling axis.

    PubMed

    Deford, Peter; Brown, Kasey; Richards, Rae Lee; King, Aric; Newburn, Kristin; Westover, Katherine; Albig, Allan R

    2016-02-01

    Canonical Notch signaling involves Notch receptor activation via interaction with cell surface bound Notch ligand. Recent findings also indicate that Notch signaling may be modulated by cross-talk with other signaling mechanisms. The ECM protein MAGP2 was previously shown to regulate Notch in a cell type dependent manner, although the molecular details of this interaction have not been dissected. Here, we report that MAGP2 cell type specific control of Notch is independent of individual Notch receptor-ligand combinations but dependent on interaction with RGD binding integrins. Overexpressed MAGP2 was found to suppress transcriptional activity from the Notch responsive Hes1 promoter activity in endothelial cells, while overexpression of a RGD→RGE MAGP2 mutant increased Notch signaling in the same cell type. This effect was not unique to MAGP2 since the RGD domain of the ECM protein EGFL7 was also found to be an important modulator of Hes1 promoter activity. Independently of MAGP2 or EGFL7, inhibition of RGD-binding integrins with soluble RGD peptides also increased accumulation of active N1ICD fragments and Notch responsive promoter activity independently of changes in Notch1, Jag1, or Dll4 expression. Finally, β1 or β3 integrin blocking antibodies also enhanced Notch signaling. Collectively, these results answer the question of how MAGP2 controls cell type dependent Notch signaling, but more importantly uncover a new mechanism to understand how extracellular matrices and cellular environments impact Notch signaling.

  15. Atractylenolide I-mediated Notch pathway inhibition attenuates gastric cancer stem cell traits.

    PubMed

    Ma, Li; Mao, Rurong; Shen, Ke; Zheng, Yuanhong; Li, Yueqi; Liu, Jianwen; Ni, Lei

    2014-07-18

    Atractylenolide I (AT-I), one of the main naturally occurring compounds of Rhizoma Atractylodis Macrocephalae, has remarkable anti-cancer effects on various cancers. However, its effects on the treatment of gastric cancer remain unclear. Via multiple cellular and molecular approaches, we demonstrated that AT-I could potently inhibit cancer cell proliferation and induce apoptosis through inactivating Notch pathway. AT-I treatment led to the reduction of expressions of Notch1, Jagged1, and its downstream Hes1/ Hey1. Our results showed that AT-I inhibited the self-renewal capacity of gastric stem-like cells (GCSLCs) by suppression of their sphere formation capacity and cell viability. AT-I attenuated gastric cancer stem cell (GCSC) traits partly through inactivating Notch1, leading to reducing the expressions of its downstream target Hes1, Hey1 and CD44 in vitro. Collectively, our results suggest that AT-I might develop as a potential therapeutic drug for the treatment of gastric cancer.

  16. Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development.

    PubMed

    Felli, M P; Maroder, M; Mitsiadis, T A; Campese, A F; Bellavia, D; Vacca, A; Mann, R S; Frati, L; Lendahl, U; Gulino, A; Screpanti, I

    1999-07-01

    The suggested role of Notch1 or its mutants in thymocyte differentiation and T cell tumorigenesis raises the question of how the different members of the Notch family influence distinct steps in T cell development and the role played by Notch ligands in the thymus. We report here that different Notch receptor-ligand partnerships may occur inside the thymus, as we observed differential expression of Notch1, 2 and 3 receptors, their ligands Jagged1 and 2, and downstream intracellular effectors hairy and Enhancer of Split homolog 1 (HES-1) and hairy and Enhancer of Split homolog 5 (HES-5), depending on ontogenetic stage and thymic cell populations. Indeed, while Jagged2 is expressed in both stromal cells and thymocytes, Jagged1 expression is restricted to stromal cells. Moreover, a differential distribution of Notch3, with respect to Notch1, was observed in distinct age-related thymocyte subsets. Finally, Notch3 was preferentially up-regulated in thymocytes, following the induction of their differentiation by interaction with thymic epithelial cells expressing the cognate Jagged1 and 2 ligands, suggesting that, besides Notch1, Notch3 may also be involved in distinct steps of thymocyte development. Our results suggest that the Notch signaling pathway is involved in a complex interplay of T cell developmental stages, as a consequence of the heterogeneity and specific expression of members of the Notch receptor family and their cognate ligands, in distinct thymic cell compartments.

  17. Human papillomavirus 16E6 and NFX1-123 potentiate notch signaling and differentiation without activating cellular arrest

    SciTech Connect

    Vliet-Gregg, Portia A.; Hamilton, Jennifer R.; Katzenellenbogen, Rachel A.

    2015-04-15

    High-risk human papillomavirus (HR HPV) oncoproteins bind host cell proteins to dysregulate and uncouple apoptosis, senescence, differentiation, and growth. These pathways are important for both the viral life cycle and cancer development. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and they collaboratively increase the growth and differentiation master regulator, Notch1. In 16E6 expressing keratinocytes (16E6 HFKs), the Notch canonical pathway genes Hes1 and Hes5 were increased with overexpression of NFX1-123, and their expression was directly linked to the activation or blockade of the Notch1 receptor. Keratinocyte differentiation genes Keratin 1 and Keratin 10 were also increased, but in contrast their upregulation was only indirectly associated with Notch1 receptor stimulation and was fully unlinked to growth arrest, increased p21{sup Waf1/CIP1}, or decreased proliferative factor Ki67. This leads to a model of 16E6, NFX1-123, and Notch1 differently regulating canonical and differentiation pathways and entirely uncoupling cellular arrest from increased differentiation. - Highlights: • 16E6 and NFX1-123 increased the Notch canonical pathway through Notch1. • 16E6 and NFX1-123 increased the differentiation pathway indirectly through Notch1. • 16E6 and NFX1-123 increased differentiation gene expression without growth arrest. • Increased NFX1-123 with 16E6 may create an ideal cellular phenotype for HPV.

  18. Impact of the National Institute for Health and Care Excellence (NICE) guidance on medical technology uptake: analysis of the uptake of spinal cord stimulation in England 2008–2012

    PubMed Central

    Vyawahare, Bharati; Hallas, Natalie; Brookes, Morag; Taylor, Rod S; Eldabe, Sam

    2014-01-01

    Background The National Institute for Health and Care Excellence (NICE) Technology Appraisal Guidance on spinal cord stimulation (SCS) was published in 2008 and updated in 2012 with no change. This guidance recommends SCS as a cost-effective treatment for patients with neuropathic pain. Objective To assess the impact of NICE guidance by comparing SCS uptake in England pre-NICE (2008–2009) and post-NICE (2009–2012) guidance. We also compared the English SCS uptake rate with that of Belgium, the Netherlands, France and Germany. Design SCS implant data for England was obtained from the Hospital Episode Statistics (HES) database and compared with other European countries where comparable data were available. Results The HES data showed small increases in SCS implantation and replacement/revision procedures, and a large increase in SCS trials between 2008 and 2012. The increase in the total number of SCS procedures per million of population in England is driven primarily by revision/replacements and increased trial activity. Marked variability in SCS uptake at both health regions and primary care trust level was observed. Conclusions Despite the positive NICE recommendation for the routine use of SCS, we found no evidence of a significant impact on SCS uptake in England. Rates of SCS implantation in England are lower than many other European countries. PMID:24398364

  19. Physiological levels of A-, B- and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability.

    PubMed

    Jacob, Matthias; Saller, Thomas; Chappell, Daniel; Rehm, Markus; Welsch, Ulrich; Becker, Bernhard F

    2013-05-01

    Atrial natriuretic peptide (ANP) is a peptide hormone released from the cardiac atria during hypervolemia. Though named for its well-known renal effect, ANP has been demonstrated to acutely increase vascular permeability in vivo. Experimentally, this phenomenon was associated with a marked shedding of the endothelial glycocalyx, at least for supraphysiological intravascular concentrations. This study investigates the impact and mechanism of action of physiological doses of ANP and related peptides on the vascular barrier. In isolated guinea pig hearts, prepared and perfused in a modified Langendorff mode with and without the intravascular presence of the colloid hydroxyethyl starch (HES), we measured functional changes in vascular permeability and glycocalyx shedding related to intracoronary infusion of physiological concentrations of A-, B- and C-type natriuretic peptide (ANP, BNP and CNP). Significant coronary venous washout of glycocalyx constituents (syndecan-1 and heparan sulfate) was observed. As tested for ANP, this effect was positively related to the intracoronary concentration. Intravascular shedding of the glycocalyx was morphologically confirmed by electron microscopy. Also, functional vascular barrier competence decreased, as indicated by significant increases in transudate formation and HES extravasation. Ortho-phenanthroline, a non-specific inhibitor of matrix metalloproteases, was able to reduce ANP-induced glycocalyx shedding. These findings suggest participation of natriuretic peptides in pathophysiological processes like heart failure, inflammation or sepsis. Inhibition of metalloproteases might serve as a basis for future therapeutical options.

  20. Full-field OCT for fast diagnostic of head and neck cancer

    NASA Astrophysics Data System (ADS)

    De Leeuw, Frederic; Casiraghi, Odile; Ben Lakhdar, Aïcha; Abbaci, Muriel; Laplace-Builhé, Corinne

    2015-02-01

    Full-Field OCT (FFOCT) produces optical slices of tissue using white light interferometry providing in-depth 2D images, with an isotropic resolution around 1 micrometer. These optical biopsy images are similar to those obtained with established histological procedures, but without tissue preparation and within few minutes. This technology could be useful when diagnosing a lesion or at the time of its surgical management. Here we evaluate the clinical value of FFOCT imaging in the management of patients with Head and Neck cancers by assessing the accuracy of the diagnosis done on FFOCT images from resected specimen. FFOCT images from Head and Neck samples were first compared to the gold standard (HES-conventional histology). An image atlas dedicated to the training of pathologists was built and diagnosis criteria were identified. Then, we performed a morphological correlative study: both healthy and cancerous samples from patients who undergo Head and Neck surgery of oral cavity, pharynx, and larynx were imaged. Images were interpreted in a random way by two pathologists and the FFOCT based diagnostics were compared with HES (gold standard) of the same samples. Here we present preliminary results showing that FFOCT provides a quick assessment of tissue architecture at microscopic level that could guide surgeons for tumor margin delineation during intraoperative procedure.

  1. Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands

    PubMed Central

    Cheng, Pingyan; Nefedova, Yulia; Corzo, Cesar A.; Gabrilovich, Dmitry I.

    2007-01-01

    Notch is a major factor mediating interaction between hematopoietic progenitor cells (HPCs) and bone marrow stroma (BMS). However its contribution to dendritic cell (DC) differentiation is controversial. We found that main Notch ligands Delta-1 and Jagged-1 had the opposite effect on DC differentiation. Delta-1 promoted generation of fully differentiated DCs, whereas Jagged-1 stimulated accumulation of DC precursors but prevented their transition to terminally differentiated DCs. BMS expressed a substantially higher level of Jagged-1 than Delta-1. Just the opposite expression pattern was observed in spleen stroma (SS). The BMS effect on DC differentiation was similar to that of Jagged-1, whereas the effect of SS was similar to the effect of Delta-1. Down-regulation of Jagged-1 in BMS substantially increased DC differentiation. Experiments in vivo with adoptive transfer of DC precursors further supported the different roles of BMS and SS in DC development. Jagged-1 and Delta-1 equally activated CBF-1/RBPJκ transcription factor, which is a major Notch target. However, they produced a different pattern of activation of Notch target gene Hes1. Overexpression of Hes1 resulted in increased DC differentiation from HPCs. Thus, this study not only revealed the different role of Notch ligands in DC differentiation but also may provide a new insight into regulation of DC differentiation by BMS. PMID:16973960

  2. Strong Thermal Nonequilibrium in Hypersonic CO and CH_4 Probed by Crds

    NASA Astrophysics Data System (ADS)

    Louviot, Maud; Suas-David, Nicolas; Boudon, Vincent; Georges, Robert; Rey, Michael; Kassi, Samir

    2015-06-01

    A new experimental set-up coupling a High Enthalpy Source (HES) reaching 2000~K to a cw Cavity Ring-Down Spectrometer has been developed to investigate rotationnally cold hot bands of polyatomic molecules in the [1.5,1.7]~μm region. The rotational and vibrational molecular degrees of freedom are strongly decoupled in the hypersonic expansion produced by the HES and probed by Cavity Ring-Down Spectroscopy. Carbon monoxide has been used as a first test molecule to validate the experimental approach. Its expansion in argon led to rotational and vibrational temperatures of 6.7± 0.8~K and 2006± 476~K, respectively. The Tetradecad polyad of methane (1.67~μm) was investigated under similar conditions leading to rotational and vibrational temperatures of 13± 5~K and 750± 100~K, respectively. The rotationally cold structure of the spectra reveals many hot bands involving highly excited vibrational states of methane.

  3. Strong thermal nonequilibrium in hypersonic CO and CH4 probed by CRDS

    NASA Astrophysics Data System (ADS)

    Louviot, M.; Suas-David, N.; Boudon, V.; Georges, R.; Rey, M.; Kassi, S.

    2015-06-01

    A new experimental setup coupling a High Enthalpy Source (HES) reaching 2000 K to a cw-cavity ring-down spectrometer has been developed to investigate rotationally cold hot bands of polyatomic molecules in the [1.5, 1.7] μm region. The rotational and vibrational molecular degrees of freedom are strongly decoupled in the hypersonic expansion produced by the HES and probed by cavity ring-down spectroscopy. Carbon monoxide has been used as a first test molecule to validate the experimental approach. Its expansion in argon led to rotational and vibrational temperatures of 6.7 ± 0.8 K and 2006 ± 476 K, respectively. The tetradecad polyad of methane (1.67 μm) was investigated under similar conditions leading to rotational and vibrational temperatures of 13 ± 5 K and 750 ± 100 K, respectively. The rotationally cold structure of the spectra reveals many hot bands involving highly excited vibrational states of methane.

  4. Strong thermal nonequilibrium in hypersonic CO and CH4 probed by CRDS.

    PubMed

    Louviot, M; Suas-David, N; Boudon, V; Georges, R; Rey, M; Kassi, S

    2015-06-07

    A new experimental setup coupling a High Enthalpy Source (HES) reaching 2000 K to a cw-cavity ring-down spectrometer has been developed to investigate rotationally cold hot bands of polyatomic molecules in the [1.5, 1.7] μm region. The rotational and vibrational molecular degrees of freedom are strongly decoupled in the hypersonic expansion produced by the HES and probed by cavity ring-down spectroscopy. Carbon monoxide has been used as a first test molecule to validate the experimental approach. Its expansion in argon led to rotational and vibrational temperatures of 6.7 ± 0.8 K and 2006 ± 476 K, respectively. The tetradecad polyad of methane (1.67 μm) was investigated under similar conditions leading to rotational and vibrational temperatures of 13 ± 5 K and 750 ± 100 K, respectively. The rotationally cold structure of the spectra reveals many hot bands involving highly excited vibrational states of methane.

  5. Complete mitochondrial genome of the medicinal fungus Ophiocordyceps sinensis

    PubMed Central

    Li, Yi; Hu, Xiao-Di; Yang, Rui-Heng; Hsiang, Tom; Wang, Ke; Liang, De-Quan; Liang, Fan; Cao, De-Ming; Zhou, Fan; Wen, Ge; Yao, Yi-Jian

    2015-01-01

    As part of a genome sequencing project for Ophiocordyceps sinensis, strain 1229, a complete mitochondrial (mt) genome was assembled as a single circular dsDNA of 157,510 bp, one of the largest reported for fungi. Conserved genes including the large and small rRNA subunits, 27 tRNA and 15 protein-coding genes, were identified. In addition, 58 non-conserved open reading frames (ncORFs) in the intergenic and intronic regions were also identified. Transcription analyses using RNA-Seq validated the expression of most conserved genes and ncORFs. Fifty-two introns (groups I and II) were found within conserved genes, accounting for 68.5% of the genome. Thirty-two homing endonucleases (HEs) with motif patterns LAGLIDADG (21) and GIY-YIG (11) were identified in group I introns. The ncORFs found in group II introns mostly encoded reverse transcriptases (RTs). As in other hypocrealean fungi, gene contents and order were found to be conserved in the mt genome of O. sinensis, but the genome size was enlarged by longer intergenic regions and numerous introns. Intergenic and intronic regions were composed of abundant repetitive sequences usually associated with mobile elements. It is likely that intronic ncORFs, which encode RTs and HEs, may have contributed to the enlarged mt genome of O. sinensis. PMID:26370521

  6. Biological therapy induces expression changes in Notch pathway in psoriasis.

    PubMed

    Skarmoutsou, Evangelia; Trovato, Chiara; Granata, Mariagrazia; Rossi, Giulio A; Mosca, Ambra; Longo, Valentina; Gangemi, Pietro; Pettinato, Maurizio; D'Amico, Fabio; Mazzarino, Maria Clorinda

    2015-12-01

    Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

  7. Pollination Mode and Mating System Explain Patterns in Genetic Differentiation in Neotropical Plants

    PubMed Central

    Ballesteros-Mejia, Liliana; Lima, Natácia E.; Lima-Ribeiro, Matheus S.

    2016-01-01

    We studied genetic diversity and differentiation patterns in Neotropical plants to address effects of life history traits (LHT) and ecological attributes based on an exhaustive literature survey. We used generalized linear mixed models (GLMMs) to test the effects as fixed and random factors of growth form, pollination and dispersal modes, mating and breeding systems, geographical range and habitat on patterns of genetic diversity (HS, HeS, π and h), inbreeding coefficient (FIS), allelic richness (AR) and differentiation among populations (FST) for both nuclear and chloroplast genomes. In addition, we used phylogenetic generalized least squares (pGLS) to account for phylogenetic independence on predictor variables and verify the robustness of the results from significant GLMMs. In general, GLMM revealed more significant relationships among LHTs and genetic patterns than pGLS. After accounting for phylogenetic independence (i.e., using pGLS), FST for nuclear microsatellites was significantly related to pollination mode, mating system and habitat. Plants specifically with outcrossing mating system had lower FST. Moreover, AR was significantly related to pollination mode and geographical range and HeS for nuclear dominant markers was significantly related to habitat. Our findings showed that different results might be retrieved when phylogenetic non-independence is taken into account and that LHTs and ecological attributes affect substantially the genetic pattern in Neotropical plants, hence may drive key evolutionary processes in plants. PMID:27472384

  8. Embryonic stem cells in science and medicine, part II: law, ethics, and the continuing need for dialogue.

    PubMed

    Solomon, Louis M; Brockman-Lee, Sandra A

    2008-03-01

    Just as our first article, "Embryonic Stem Cells in Science and Medicine: An Invitation for Dialogue," in the December 2007 issue of Gender Medicine went to press, two groups of researchers had just announced that adult human somatic cells had been reprogrammed to behave like pluripotent stem cells, and that the reprogrammed cells were able to differentiate into cell types of the 3 germ layers in vitro and in a mouse model. A third group has since done so. Because the reprogrammed cells were not embryonic in origin, the announcements were heralded as "stunning" and "leaps forward," because, it was argued, the ability to generate stem cells, without destroying embryos in the process, would avoid the difficult ethical questions raised by human embryonic stem (hES) cell research. This article addresses the most recent announcements and briefly retraces the relevant history so that we may consider whether the moral, ethical, and social issues do in fact disappear as a result of these new advancements. We conclude that, despite the hoopla, little has changed. If indeed there were ethical issues surrounding hES cell research, they remain-and remain as urgent to address and resolve as they had been previously. Lastly, we argue that the medical and scientific communities continue to do themselves a disservice by failing to create a cohesive governing body to address and make concrete recommendations concerning the moral, ethical, and related social issues affecting their communities.

  9. Loss of Resources and Hurricane Experience as Predictors of Postpartum Depression Among Women in Southern Louisiana

    PubMed Central

    Ehrlich, Matthew; Xiong, Xu; Buekens, Pierre; Pridjian, Gabriella; Elkind-Hirsch, Karen

    2010-01-01

    Abstract Background After a natural disaster, mental disorders often become a long-term public health concern. Previous studies under smaller-scale natural disaster conditions suggest loss of psychosocial resources is associated with psychological distress. Methods We examined the occurrence of depression 6 and 12 months postpartum among 208 women residing in New Orleans and Baton Rouge, Louisiana, who were pregnant during or immediately after Hurricane Katrina's landfall. Based on the Conservation of Resources (COR) theory, we explored the contribution of both tangible/financial and nontangible (psychosocial) loss of resources (LOR) on the outcome of depression, measured using the Edinburgh Postnatal Depression Scale (EPDS). We also investigated the influence on depression of individuals' hurricane experience through a Hurricane Experience Score (HES) that includes such factors as witnessing death, contact with flood waters, and injury to self or family members. Results Both tangible and nontangible LOR were associated with depression cross-sectionally and prospectively. Severe hurricane exposure (high HES) was also associated with depression. Regression analysis showed LOR-associated depression was explained almost entirely by nontangible rather than tangible factors. Consistent with COR theory, however, nontangible LOR explained some of the association between severe hurricane exposure and depression in our models. A similar result was seen prospectively for depression at 12 months, even controlling for depression symptoms at 6 months. Conclusions These results suggest the need for preventive measures aimed at preserving psychosocial resources to reduce the long-term effects of disasters. PMID:20438305

  10. Dissecting neural differentiation regulatory networks through epigenetic footprinting

    PubMed Central

    Yaffe, Yakey; Donaghey, Julie; Pop, Ramona; Mallard, William; Issner, Robbyn; Gifford, Casey A.; Goren, Alon; Xing, Jeff; Gu, Hongcang; Cachiarelli, Davide; Tsankov, Alexander; Epstein, Chuck; Rinn, John R.; Mikkelsen, Tarjei S.; Kohlbacher, Oliver; Gnirke, Andreas; Bernstein, Bradley E.

    2014-01-01

    Human pluripotent stem cell derived models that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signaling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells (NPCs) in the embryonic and adult nervous system1-3. This can be exploited to isolate distinct populations of human embryonic stem (ES) cell derived NPCs4. Here, we report the transcriptional and epigenomic analysis of six consecutive stages derived from a HES5-GFP reporter ES cell line5 differentiated along the neural trajectory aimed at modeling key cell fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect the regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell state transition based on the progressive remodeling of the epigenetic landscape and then validated these through a pooled shRNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and show here that they are mediated by combinations of core and stage- specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation. PMID:25533951

  11. Factors influencing wastewater management performance: case study of housing estates in suburban Bangkok, Thailand.

    PubMed

    Sujaritpong, Sarunya; Nitivattananon, Vilas

    2009-01-01

    As population densities have risen and settlements become increasingly crowded, wastewater effluent volumes have, not unexpectedly, also risen. The adverse impacts of effluent from housing estates (HEs) in suburban areas of Thailand, served by local wastewater management (WWM) systems, are of particular concern. Because of this problem, which reflects the poor performance of WWM systems, it has become increasingly important that the pivotal factors that hinder WWM improvements be identified and effective solutions be proposed and implemented. The goal of the research described in this paper was to determine the critical factors influencing WWM performance at HEs in suburban Bangkok, using multiple regression analysis. Three significant factors encompassing financial, social, institutional and general aspects were identified for each type of WWM system (community centralized and onsite). For the community centralized system, the key factors were house price, type of organization managing the HE, and the attitudes of the organization. For onsite systems, the three factors were total number of house units, direct experience with water pollution and percentage of occupied houses. These findings reflect the importance of having a WWM that employs an integrated approach rather than focusing on specific aspects in isolation from other factors. WWM performance could be improved if significant factors indicating high priority concerns were to be identified and properly applied. Addressing the priority concerns could, consequently, contribute to the development of appropriate environmental management measures, plans, and policies related to HE WWM.

  12. Three-dimensional epithelial tissues generated from human embryonic stem cells.

    PubMed

    Hewitt, Kyle J; Shamis, Yulia; Carlson, Mark W; Aberdam, Edith; Aberdam, Daniel; Garlick, Jonathan A

    2009-11-01

    The use of pluripotent human embryonic stem (hES) cells for tissue engineering may provide advantages over traditional sources of progenitor cells because of their ability to give rise to multiple cell types and their unlimited expansion potential. We derived cell populations with properties of ectodermal and mesenchymal cells in two-dimensional culture and incorporated these divergent cell populations into three-dimensional (3D) epithelial tissues. When grown in specific media and substrate conditions, two-dimensional cultures were enriched in cells (EDK1) with mesenchymal morphology and surface markers. Cells with a distinct epithelial morphology (HDE1) that expressed cytokeratin 12 and beta-catenin at cell junctions became the predominant cell type when EDK1 were grown on surfaces enriched in keratinocyte-derived extracellular matrix proteins. When these cells were incorporated into the stromal and epithelial tissue compartments of 3D tissues, they generated multilayer epithelia similar to those generated with foreskin-derived epithelium and fibroblasts. Three-dimensional tissues demonstrated stromal cells with morphologic features of mature fibroblasts, type IV collagen deposition in the basement membrane, and a stratified epithelium that expressed cytokeratin 12. By deriving two distinct cell lineages from a common hES cell source to fabricate complex tissues, it is possible to explore environmental cues that will direct hES-derived cells toward optimal tissue form and function.

  13. Involvement of Notch1 signaling in neurogenesis in the subventricular zone of normal and ischemic rat brain in vivo.

    PubMed

    Wang, Xiaomei; Mao, Xiaoou; Xie, Lin; Greenberg, David A; Jin, Kunlin

    2009-10-01

    The Notch1 signaling pathway is regarded as one of the main regulators of neural stem cell behavior during development, but its role in the adult brain is less well understood. We found that Notch1 was mainly expressed in doublecortin (DCX)-positive cells corresponding to newborn neurons, whereas the Notch1 ligand, Jagged1, was predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytic cells in the subventricular zone (SVZ) of the normal adult brain. These findings were confirmed by conditional depletion of DCX-positive cells in transgenic mice carrying herpes simplex virus thymidine kinase (HSV-TK) under the control of the DCX promoter. In addition, the activated form of Notch1 (Notch intracellular domain, NICD) and its downstream transcriptional targets, Hes1 and sonic hedgehog (Shh), were also expressed in SVZ cells. Increased activation of Notch1 signaling increased SVZ cell proliferation, whereas inhibiting Notch1 signaling resulted in a reduction of proliferating cells in the SVZ. Levels of NICD, Hes1, and Shh were increased in the SVZ at 4 and 24 h after focal cerebral ischemia. Finally, ischemia-induced cell proliferation in the SVZ was blocked by inhibition of the Notch1 signaling pathway, suggesting that Notch1 signaling may have a key role in normal adult and ischemia-induced neurogenesis.

  14. Activation of the NOTCH pathway in Head and Neck Cancer

    PubMed Central

    Sun, Wenyue; Gaykalova, Daria A.; Ochs, Michael F.; Mambo, Elizabeth; Arnaoutakis, Demetri; Liu, Yan; Loyo, Myriam; Agrawal, Nishant; Howard, Jason; Li, Ryan; Ahn, Sun; Fertig, Elana; Sidransky, David; Houghton, Jeffery; Buddavarapu, Kalyan; Sanford, Tiffany; Choudhary, Ashish; Darden, Will; Adai, Alex; Latham, Gary; Bishop, Justin; Sharma, Rajni; Westra, William H.; Hennessey, Patrick; Chung, Christine H.; Califano, Joseph A.

    2014-01-01

    NOTCH1 mutations have been reported to occur in 10 to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation and mutation analyses. Copy number increases were identified in NOTCH pathway genes including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4/37 of the tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptors mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently. PMID:24351288

  15. Identification of oscillatory genes in somitogenesis from functional genomic analysis of a human mesenchymal stem cell model.

    PubMed

    William, Dilusha A; Saitta, Biagio; Gibson, Joshua D; Traas, Jeremy; Markov, Vladimir; Gonzalez, Dorian M; Sewell, William; Anderson, Douglas M; Pratt, Stephen C; Rappaport, Eric F; Kusumi, Kenro

    2007-05-01

    During somitogenesis, oscillatory expression of genes in the notch and wnt signaling pathways plays a key role in regulating segmentation. These oscillations in expression levels are elements of a species-specific developmental mechanism. To date, the periodicity and components of the human clock remain unstudied. Here we show that a human mesenchymal stem/stromal cell (MSC) model can be induced to display oscillatory gene expression. We observed that the known cycling gene HES1 oscillated with a 5 h period consistent with available data on the rate of somitogenesis in humans. We also observed cycling of Hes1 expression in mouse C2C12 myoblasts with a period of 2 h, consistent with previous in vitro and embryonic studies. Furthermore, we used microarray and quantitative PCR (Q-PCR) analysis to identify additional genes that display oscillatory expression both in vitro and in mouse embryos. We confirmed oscillatory expression of the notch pathway gene Maml3 and the wnt pathway gene Nkd2 by whole mount in situ hybridization analysis and Q-PCR. Expression patterns of these genes were disrupted in Wnt3a(tm1Amc) mutants but not in Dll3(pu) mutants. Our results demonstrate that human and mouse in vitro models can recapitulate oscillatory expression observed in embryo and that a number of genes in multiple developmental pathways display dynamic expression in vitro.

  16. Hypogammaglobulinaemia in nephrotic rats is attributable to hypercatabolism of IgG.

    PubMed Central

    Beaman, M; Oldfield, S; MacLennan, I C; Michael, J; Adu, D

    1988-01-01

    The effect of the nephrotic syndrome induced by puromycin aminonucleoside (PA) in rats on specific antibody responses to 2,4 dinitrophenyl (DNP) conjugated to either spider crab haemocyanin (MSH), a T cell-dependent antigen, or hydroxyethyl starch (HES), a T cell-independent type 2 antigen were studied. The serum IgG anti-DNP levels following immunization with both antigens were reduced in nephrotic animals compared with controls while IgM anti-DNP antibody titres were higher. The half-life of IgG anti-DNP antibodies passively transferred into non-immunized nephrotic rats was markedly reduced while the half-life of anti-DNP antibodies of the IgM class was comparable to that in controls. Low serum IgG and elevated IgM levels were seen in nephrotic animals compared to controls. Antibody-forming cells specific for DNP were demonstrated by immunohistology on rat spleens and the numbers of both IgG and IgM-producing cells were found to be significantly increased (P less than 0.05) in nephrotic animals in response to both DNP-HES and DNP-MSH. These data indicate that in nephrotic rats the alteration seen in the serum immunoglobulin levels is not attributable to reduced antibody production but increased catabolism of serum IgG antibodies. PMID:3233791

  17. Protein HESylation for half-life extension: synthesis, characterization and pharmacokinetics of HESylated anakinra.

    PubMed

    Liebner, Robert; Mathaes, Roman; Meyer, Martin; Hey, Thomas; Winter, Gerhard; Besheer, Ahmed

    2014-07-01

    Half-life extension (HLE) is becoming an essential component of the industrial development of small-sized therapeutic peptides and proteins. HESylation(®) is a HLE technology based on coupling drug molecules to the biodegradable hydroxyethyl starch (HES). In this study, we report on the synthesis, characterization and pharmacokinetics of HESylated anakinra, where anakinra was conjugated to propionaldehyde-HES using reductive amination, leading to a monoHESylated protein. Characterization using size exclusion chromatography and dynamic light scattering confirmed conjugation and the increase in molecular size, while Fourier transform infrared spectroscopy showed that the secondary structure of the conjugate was not affected by coupling. Meanwhile, microcalorimetry and aggregation studies showed a significant increase in protein stability. Surface plasmon resonance and microscale thermophoresis showed that the conjugate retained its nanomolar affinity, and finally, the pharmacokinetics of the HESylated protein exhibited a 6.5-fold increase in the half-life, and a 45-fold increase in the AUC. These results indicate that HESylation(®) is a promising HLE technology.

  18. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos.

    PubMed

    Tefferi, Ayalew; Thiele, Juergen; Vardiman, James W

    2009-09-01

    The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of "myeloproliferative disorders (MPD)" by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and "CMPD, unclassifiable." The revised 2008 WHO classification system featured the following changes: 1) the term "CMPD" was replaced by "myeloproliferative neoplasm (MPN)," 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into "CEL not otherwise specified (CEL-NOS)" and "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1"; CEL-NOS remained a subcategory of "MPN," whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies.

  19. The segmentation clock in mice: interaction between the Wnt and Notch signalling pathways.

    PubMed

    Rodríguez-González, J G; Santillán, M; Fowler, A C; Mackey, Michael C

    2007-09-07

    In the last few years, the efforts to elucidate the mechanisms underlying the segmentation clock in various vertebrate species have multiplied. Early evidence suggested that oscillations are caused by one of the genes under the Notch signalling pathway (like those of the her or Hes families). Recently, Aulehla et al. [Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4, 395-406] discovered that Axin2 (a gene under the Wnt3a signalling pathway) also oscillates in the presomitic mesoderm (PSM) of mice embryos and proposed some mechanisms through which the Notch and Wnt3a pathways may interact. They further suggested that a decreasing concentration of Wnt3a along the PSM may be the gradient the segmentation clock interacts with to form somites. These results were reviewed by Rida et al. [A notch feeling of somite segmentation and beyond. Dev. Biol. 265, 2-22], who introduced a complex clockwork comprising genes Hes1, Lfng (under the Notch pathway), and Axin2, as well as their multiple interactions. In the present work we develop a mathematical model based on the Rida et al. review and use it to tackle some of the questions raided by the Aulehla et al. paper: can the Axin2 feedback loop constitute a clock? Could a decreasing Wnt3a signaling constitute the wavefront, where phase is recorded and the spatial pattern laid down? What is the master oscillator?

  20. Evidence for increasing severity of community-onset boils and abscesses in UK General Practice.

    PubMed

    Shallcross, L J; Hayward, A C; Johnson, A M; Petersen, I

    2015-08-01

    In England, hospital admissions for severe staphylococcal boils and abscesses trebled between 1989 and 2004. We investigated this trend using routine data from primary and secondary care. We used The Health Improvement Network (THIN), a large primary-care database and national data on hospital admissions from Hospital Episode Statistics (HES). Time trends in the incidence of primary-care consultations for boils and abscesses were estimated for 1995-2010. HES data were used to calculate age-standardized hospital admission rates for boils, abscesses and cellulitis. The incidence of boil or abscess was 450 [95% confidence interval (CI) 447-452] per 100 000 person-years and increased slightly over the study period (incidence rate ratio 1·005, 95% CI 1·004-1·007). The rate of repeat consultation for a boil or abscess increased from 66 (95% CI 59-73) per 100 000 person-years in 1995 to peak at 97 (95% CI 94-101) per 100 000 person-years in 2006, remaining stable thereafter. Hospital admissions for abscesses, carbuncles, furuncles and cellulitis almost doubled, from 123 admissions per 100 000 in 1998/1999 to 236 admissions per 100 000 in 2010/2011. Rising hospitalization and recurrence rates set against a background of stable community incidence suggests increased disease severity. Patients may be experiencing more severe and recurrent staphylococcal skin disease with limited treatment options.

  1. Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes

    SciTech Connect

    Arnett, Kelly L.; Hass, Matthew; McArthur, Debbie G.; Ilagan, Ma Xenia G.; Aster, Jon C.; Kopan, Raphael; Blacklow, Stephen C.

    2010-11-12

    Ligand-induced proteolysis of Notch produces an intracellular effector domain that transduces essential signals by regulating the transcription of target genes. This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA. These complexes form higher-order assemblies on paired, head-to-head CSL recognition sites. Here we report the X-ray structure of a dimeric human Notch1 transcription complex loaded on the paired site from the human HES1 promoter. The small interface between the Notch ankyrin domains could accommodate DNA bending and untwisting to allow a range of spacer lengths between the two sites. Cooperative dimerization occurred on the human and mouse Hes5 promoters at a sequence that diverged from the CSL-binding consensus at one of the sites. These studies reveal how promoter organizational features control cooperativity and, thus, the responsiveness of different promoters to Notch signaling.

  2. Predicting human developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics

    SciTech Connect

    West, Paul R.; Weir, April M.; Smith, Alan M.; Donley, Elizabeth L.R.; Cezar, Gabriela G.

    2010-08-15

    Teratogens, substances that may cause fetal abnormalities during development, are responsible for a significant number of birth defects. Animal models used to predict teratogenicity often do not faithfully correlate to human response. Here, we seek to develop a more predictive developmental toxicity model based on an in vitro method that utilizes both human embryonic stem (hES) cells and metabolomics to discover biomarkers of developmental toxicity. We developed a method where hES cells were dosed with several drugs of known teratogenicity then LC-MS analysis was performed to measure changes in abundance levels of small molecules in response to drug dosing. Statistical analysis was employed to select for specific mass features that can provide a prediction of the developmental toxicity of a substance. These molecules can serve as biomarkers of developmental toxicity, leading to better prediction of teratogenicity. In particular, our work shows a correlation between teratogenicity and changes of greater than 10% in the ratio of arginine to asymmetric dimethylarginine levels. In addition, this study resulted in the establishment of a predictive model based on the most informative mass features. This model was subsequently tested for its predictive accuracy in two blinded studies using eight drugs of known teratogenicity, where it correctly predicted the teratogenicity for seven of the eight drugs. Thus, our initial data shows that this platform is a robust alternative to animal and other in vitro models for the prediction of the developmental toxicity of chemicals that may also provide invaluable information about the underlying biochemical pathways.

  3. Chronic rapamycin treatment on the nutrient utilization and metabolism of juvenile turbot (Psetta maxima)

    PubMed Central

    Wang, Qingchao; He, Gen; Mai, Kangsen; Xu, Wei; Zhou, Huihui; Wang, Xuan; Mei, Lin

    2016-01-01

    High dietary protein inclusion is necessary in fish feeds and also represents a major cost in the aquaculture industry, which demands improved dietary conversion into body proteins in fish. In mammals, the target of rapamycin (TOR) is a key nutritionally responsive molecule governing postprandial anabolism. However, its physiological significance in teleosts has not been fully examined. In the present study, we examined the nutritional physiology of turbot after chronic rapamycin inhibition. Our results showed that a 6-week inhibition of TOR using dietary rapamycin inclusion (30 mg/kg diet) reduced growth performance and feed utilization. The rapamycin treatment inhibited TOR signaling and reduced expression of key enzymes in glycolysis, lipogenesis, cholesterol biosynthesis, while increasing the expression of enzymes involved in gluconeogenesis. Furthermore, rapamycin treatment increased intestinal goblet cell number in turbot, while the expressions of Notch and Hes1 were down regulated. It was possible that stimulated goblet cell differentiation by rapamycin was mediated through Notch-Hes1 pathway. Therefore, our results demonstrate the important role of TOR signaling in fish nutritional physiology. PMID:27305975

  4. The REF-1 family of bHLH transcription factors pattern C. elegans embryos through Notch-dependent and Notch-independent pathways.

    PubMed

    Neves, Alexandre; Priess, James R

    2005-06-01

    Much of the patterning of early C. elegans embryos involves a series of Notch interactions that occur in rapid succession and have distinct outcomes; however, none of the targets for these interactions have been identified. We show that the REF-1 family of bHLH transcription factors is a major target of Notch signaling in all these interactions and that most examples of Notch-mediated transcriptional repression can be attributed to REF-1 activities. The REF-1 family is expressed and has similar functions in both Notch-dependent and Notch-independent pathways, and this dual mode of deployment is used repeatedly to pattern the embryo. REF-1 proteins are unusual in that they contain two different bHLH domains and lack the distinguishing characteristics of Hairy/Enhancer of Split (HES) bHLH proteins that are Notch targets in other systems. Our results show that the highly divergent REF-1 proteins are nonetheless HES-like bHLH effectors of Notch signaling.

  5. Atractylenolide I-mediated Notch pathway inhibition attenuates gastric cancer stem cell traits

    SciTech Connect

    Ma, Li; Mao, Rurong; Shen, Ke; Zheng, Yuanhong; Li, Yueqi; Liu, Jianwen; Ni, Lei

    2014-07-18

    Highlights: • This paper supports the anti-tumor effects of AT-I on gastric cancer in vitro. • AT-I attenuates gastric cancer stem cell traits. • It is the systematic study regarding AT-I suppression of Notch pathway in GC and GCSLCs. - Abstract: Atractylenolide I (AT-I), one of the main naturally occurring compounds of Rhizoma Atractylodis Macrocephalae, has remarkable anti-cancer effects on various cancers. However, its effects on the treatment of gastric cancer remain unclear. Via multiple cellular and molecular approaches, we demonstrated that AT-I could potently inhibit cancer cell proliferation and induce apoptosis through inactivating Notch pathway. AT-I treatment led to the reduction of expressions of Notch1, Jagged1, and its downstream Hes1/ Hey1. Our results showed that AT-I inhibited the self-renewal capacity of gastric stem-like cells (GCSLCs) by suppression of their sphere formation capacity and cell viability. AT-I attenuated gastric cancer stem cell (GCSC) traits partly through inactivating Notch1, leading to reducing the expressions of its downstream target Hes1, Hey1 and CD44 in vitro. Collectively, our results suggest that AT-I might develop as a potential therapeutic drug for the treatment of gastric cancer.

  6. Acute Lymphoblastic Leukemia Cells Inhibit the Differentiation of Bone Mesenchymal Stem Cells into Osteoblasts In Vitro by Activating Notch Signaling

    PubMed Central

    Yang, Gui-Cun; Xu, You-Hua; Chen, Hong-Xia; Wang, Xiao-Jing

    2015-01-01

    The disruption of normal hematopoiesis has been observed in leukemia, but the mechanism is unclear. Osteoblasts originate from bone mesenchymal stem cells (BMSCs) and can maintain normal hematopoiesis. To investigate how leukemic cells inhibit the osteogenic differentiation of BMSCs and the role of Notch signaling in this process, we cocultured BMSCs with acute lymphoblastic leukemia (ALL) cells in osteogenic induction medium. The expression levels of Notch1, Hes1, and the osteogenic markers Runx2, Osteopontin (OPN), and Osteocalcin (OCN) were assessed by real-time RT-PCR and western blotting on day 3. Alkaline phosphatase (ALP) activity was analyzed using an ALP kit, and mineralization deposits were detected by Alizarin red S staining on day 14. And then we treated BMSCs with Jagged1 and anti-Jagged1 neutralizing Ab. The expression of Notch1, Hes1, and the abovementioned osteogenic differentiation markers was measured. Inhibition of the expression of Runx2, OPN, and OCN and reduction of ALP activity and mineralization deposits were observed in BMSCs cocultured with ALL cells, while Notch signal inhibiting rescued these effects. All these results indicated that ALL cells could inhibit the osteogenic differentiation of BMSCs by activating Notch signaling, resulting in a decreased number of osteoblastic cells, which may impair normal hematopoiesis. PMID:26339248

  7. Mouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signaling.

    PubMed

    Ishikawa, Aki; Kitajima, Satoshi; Takahashi, Yu; Kokubo, Hiroki; Kanno, Jun; Inoue, Tohru; Saga, Yumiko

    2004-12-01

    During vertebrate embryogenesis, the formation of reiterated structures along the body axis is dependent upon the generation of the somite by segmentation of the presomitic mesoderm (PSM). Notch signaling plays a crucial role in both the generation and regulation of the molecular clock that provides the spatial information for PSM cells to form somites. In a screen for novel genes involved in somitogenesis, we identified a gene encoding a Wnt antagonist, Nkd1, which is transcribed in an oscillatory manner, and may represent a new member of the molecular clock constituents. The transcription of nkd1 is extremely downregulated in the PSM of vestigial tail (vt/vt), a hypomorphic mutant of Wnt3a, whereas nkd1 oscillations have a similar phase to lunatic fringe (L-fng) transcription and they are arrested in Hes7 (a negative regulator of Notch signaling) deficient embryos. These results suggest that the transcription of nkd1 requires Wnt3a, and that its oscillation patterns depend upon the function of Hes7. Wnt signaling has been postulated to be upstream of Notch signaling but we demonstrate in this study that a Wnt-signal-related gene may also be regulated by Notch signaling. Collectively, our data suggest that the reciprocal interaction of Notch and Wnt signals, and of their respective negative feedback loops, function to organize the segmentation clock required for somitogenesis.

  8. PEDF & stem cells: niche vs. nurture.

    PubMed

    Fitchev, Philip; Chung, Chuhan; Plunkett, Beth A; Brendler, Charles B; Crawford, Susan E

    2014-01-01

    Anti-angiogenic pigment epithelium-derived factor (PEDF) is a multifunctional 50kD secreted glycoprotein emerging as a key factor in stem cell renewal. Characteristics of the stem cell niche can be highly dependent on location, access to the vasculature, oxygen tension and neighboring cells. In the neural stem cell (NSC) niche, specifically the subventricular zone, PEDF actively participates in the self renewal process and promotes stemness by upregulating Notch signaling effectors Hes1 and Hes5. The local vascular endothelial cells and ependymal cells are the likely sources of PEDF for the NSC while mesenchymal and retinal stem cells can actually produce PEDF. The opposing actions of PEDF and VEGF on various cells are recapitulated in the NSC niche. Intraventricular injection of PEDF promotes stem cell renewal, while injection of VEGF prompts differentiation and neurogenesis in the subventricular zone. Enhancing the expression of PEDF in stem cells has promising therapeutic implications. Bone marrow mesenchymal stem cells overexpressing PEDF effectively inhibited pathologic angiogenesis in the murine eye and these same cells suppressed hepatocellular carcinoma growth. As a protein with bioactivities in nearly all normal organ systems, it is likely that PEDF will continue to gain visibility as an essential component in the development and delivery of novel stem cell-based therapies to combat disease.

  9. Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche

    PubMed Central

    Bulfamante, Gaetano; Falleni, Monica; Tosi, Delfina; Todoerti, Katia; Lazzari, Elisa; Crews, Leslie A.; Jamieson, Catriona H.M.; Ravaioli, Sara; Baccianti, Francesco; Garavelli, Silvia; Platonova, Natalia; Neri, Antonino; Chiaramonte, Raffaella

    2016-01-01

    Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche. We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands. PMID:27463014

  10. Dissecting neural differentiation regulatory networks through epigenetic footprinting.

    PubMed

    Ziller, Michael J; Edri, Reuven; Yaffe, Yakey; Donaghey, Julie; Pop, Ramona; Mallard, William; Issner, Robbyn; Gifford, Casey A; Goren, Alon; Xing, Jeffrey; Gu, Hongcang; Cacchiarelli, Davide; Tsankov, Alexander M; Epstein, Charles; Rinn, John L; Mikkelsen, Tarjei S; Kohlbacher, Oliver; Gnirke, Andreas; Bernstein, Bradley E; Elkabetz, Yechiel; Meissner, Alexander

    2015-02-19

    Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system. Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line. Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.

  11. Scaling and memory in volatility return intervals in financial markets

    NASA Astrophysics Data System (ADS)

    Yamasaki, Kazuko; Muchnik, Lev; Havlin, Shlomo; Bunde, Armin; Stanley, H. Eugene

    2005-06-01

    For both stock and currency markets, we study the return intervals τ between the daily volatilities of the price changes that are above a certain threshold q. We find that the distribution function Pq(τ) scales with the mean return interval [Formula] as [Formula]. The scaling function f(x) is similar in form for all seven stocks and for all seven currency databases analyzed, and f(x) is consistent with a power-law form, f(x) ˜ x-γ with γ ≈ 2. We also quantify how the conditional distribution Pq(τ|τ0) depends on the previous return interval τ0 and find that small (or large) return intervals are more likely to be followed by small (or large) return intervals. This “clustering” of the volatility return intervals is a previously unrecognized phenomenon that we relate to the long-term correlations known to be present in the volatility. Author contributions: S.H. and H.E.S. designed research; K.Y., L.M., S.H., and H.E.S. performed research; A.B. contributed new reagents/analytic tools; A.B. analyzed data; and S.H. wrote the paper.Abbreviations: pdf, probability density function; S&P 500, Standard and Poor's 500 Index; USD, U.S. dollar; JPY, Japanese yen; SEK, Swedish krona.

  12. Transcriptional regulation of the 5-HT1A receptor: implications for mental illness.

    PubMed

    Albert, Paul R

    2012-09-05

    The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5-HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression.

  13. Curcumin attenuates endothelial cell oxidative stress injury through Notch signaling inhibition.

    PubMed

    Yang, Yang; Duan, Weixun; Liang, Zhenxin; Yi, Wei; Yan, Juanjuan; Wang, Ning; Li, Yue; Chen, Wensheng; Yu, Shiqiang; Jin, Zhenxiao; Yi, Dinghua

    2013-03-01

    Previous studies have demonstrated that Notch signaling pathway plays a regulatory role in cellular oxidative stress injury (OSI). In this study, our aim was to explore the role of the Notch signaling pathway in hydrogen peroxide (H(2)O(2))-induced OSI and the protective effect of curcumin during (H(2)O(2))-induced injury in human umbilical vein endothelial cells (HUVECs). DAPT, a specific inhibitor of the Notch signaling pathway, and Notch1 siRNA were used to study Notch activity. Further, HUVECs were exposed to H(2)O(2) in the absence or presence of curcumin. DAPT and Notch1 siRNA significantly inhibited OSI and the expression of Notch1 and Hes1. Curcumin conferred a protective effect on the HUVECs against H(2)O(2), which was evidenced by improved cell viability, adhesive ability and migratory ability and a decreased apoptotic index, decreased production of reactive oxygen species (ROS) and a reduction in several biochemical parameters. Immunofluorescence and Western blotting analyses demonstrated that H(2)O(2) treatment upregulated the expression of Notch1, Hes1, Caspase3, Bax and cytochrome c downregulated the expression of Bcl2, and treatment with curcumin reversed these effects. We demonstrated for the first time that the inhibition of Notch signaling pathway imparts a protective effect against endothelial OSI. The protective effects of curcumin against OSI are at least in part dependent on Notch1 inhibition.

  14. Pollination Mode and Mating System Explain Patterns in Genetic Differentiation in Neotropical Plants.

    PubMed

    Ballesteros-Mejia, Liliana; Lima, Natácia E; Lima-Ribeiro, Matheus S; Collevatti, Rosane G

    2016-01-01

    We studied genetic diversity and differentiation patterns in Neotropical plants to address effects of life history traits (LHT) and ecological attributes based on an exhaustive literature survey. We used generalized linear mixed models (GLMMs) to test the effects as fixed and random factors of growth form, pollination and dispersal modes, mating and breeding systems, geographical range and habitat on patterns of genetic diversity (HS, HeS, π and h), inbreeding coefficient (FIS), allelic richness (AR) and differentiation among populations (FST) for both nuclear and chloroplast genomes. In addition, we used phylogenetic generalized least squares (pGLS) to account for phylogenetic independence on predictor variables and verify the robustness of the results from significant GLMMs. In general, GLMM revealed more significant relationships among LHTs and genetic patterns than pGLS. After accounting for phylogenetic independence (i.e., using pGLS), FST for nuclear microsatellites was significantly related to pollination mode, mating system and habitat. Plants specifically with outcrossing mating system had lower FST. Moreover, AR was significantly related to pollination mode and geographical range and HeS for nuclear dominant markers was significantly related to habitat. Our findings showed that different results might be retrieved when phylogenetic non-independence is taken into account and that LHTs and ecological attributes affect substantially the genetic pattern in Neotropical plants, hence may drive key evolutionary processes in plants.

  15. Role of p63 and the Notch pathway in cochlea development and sensorineural deafness.

    PubMed

    Terrinoni, Alessandro; Serra, Valeria; Bruno, Ernesto; Strasser, Andreas; Valente, Elizabeth; Flores, Elsa R; van Bokhoven, Hans; Lu, Xin; Knight, Richard A; Melino, Gerry

    2013-04-30

    The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis--Puma, Noxa, or both--are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.

  16. Human health risks from TNT, RDX, and HMX in environmental media and consideration of the US Regulatory Environment

    SciTech Connect

    Daniels, J.I.; Knezovich, J.P.

    1994-12-01

    Although the most economical method for disposing of unwanted energetic high explosives [HEs; e.g., 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-triazine (RDX, also known as Cyclonite), and octahydro-1,3,5,7-tetrazocine (HMX, also known as Octogen)] involves open burning and open or underground detonation [OB/O(U)D]; federal, state, and even local government agencies in the United States (U.S.) are implementing stricter environmental regulations that eventually may prevent such activities. These stricter regulations will promote alternative technologies that are designed to be environmentally benign. However, past HE-waste disposal practices at manufacturing and fabrication facilities in the U.S. have included uncontrolled OB/O(U)D, as well as direct surface discharge of HE-contaminated waste water, resulting in contaminated environmental media (e.g., ground water, soil, and perhaps even edible vegetation) near residential areas. Using TNT, RDX, and HMX as examples, this paper describes how risk-based standards for HEs can be derived that account for potential multimedia exposures (associated with contaminated air, water, food, and soil) by individuals near a contaminated site, and used to (1) protect public health and safety; (2)prevent limited resources from being dedicated to unnecessary cleanup activities; and (3) identify the most cost-effective, practical, and environmentally benign technologies suitable for integrating with the handling of the large quantity of high explosives scheduled for demilitarization.

  17. Numerical simulation of long-duration blast wave evolution in confined facilities

    NASA Astrophysics Data System (ADS)

    Togashi, F.; Baum, J. D.; Mestreau, E.; Löhner, R.; Sunshine, D.

    2010-10-01

    The objective of this research effort was to investigate the quasi-steady flow field produced by explosives in confined facilities. In this effort we modeled tests in which a high explosive (HE) cylindrical charge was hung in the center of a room and detonated. The HEs used for the tests were C-4 and AFX 757. While C-4 is just slightly under-oxidized and is typically modeled as an ideal explosive, AFX 757 includes a significant percentage of aluminum particles, so long-time afterburning and energy release must be considered. The Lawrence Livermore National Laboratory (LLNL)-produced thermo-chemical equilibrium algorithm, “Cheetah”, was used to estimate the remaining burnable detonation products. From these remaining species, the afterburning energy was computed and added to the flow field. Computations of the detonation and afterburn of two HEs in the confined multi-room facility were performed. The results demonstrate excellent agreement with available experimental data in terms of blast wave time of arrival, peak shock amplitude, reverberation, and total impulse (and hence, total energy release, via either the detonation or afterburn processes.

  18. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm.

    PubMed

    Dunwoodie, Sally L; Clements, Melanie; Sparrow, Duncan B; Sa, Xin; Conlon, Ronald A; Beddington, Rosa S P

    2002-04-01

    A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following gene targeting, and results in severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae and costal defects, are similar to those associated with the Dll3-dependent pudgy mutant in mouse and with spondylocostal dysplasia (MIM 277300) in humans. This study demonstrates that Dll3(neo) and Dll3(pu) are functionally equivalent alleles with respect to the skeletal dysplasia, and we suggest that the three human DLL3 mutations associated with spondylocostal dysplasia are also functionally equivalent to the Dll3(neo) null allele. Our phenotypic analysis of Dll3(neo)/Dll3(neo) mutants shows that the developmental origins of the skeletal defects lie in delayed and irregular somite formation, which results in the perturbation of anteroposterior somite polarity. As the expression of Lfng, Hes1, Hes5 and Hey1 is disrupted in the presomitic mesoderm, we suggest that the somitic aberrations are founded in the disruption of the segmentation clock that intrinsically oscillates within presomitic mesoderm.

  19. RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53–Fbxw7 pathway

    SciTech Connect

    Wang, Haihe; Yang, Zhanchun; Liu, Chunbo; Huang, Shishun; Wang, Hongzhi; Chen, Yingli; Chen, Guofu

    2014-11-07

    Highlights: • RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. • RITA can significantly inhibit the in vitro growth of SMMC7721 and HepG2 cells. • RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC. - Abstract: Aberrant Notch signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell growth. However, the role of Notch signaling in HCC and its underlying mechanism remain elusive. RBP-J-interacting and tubulin-associated (RITA) mediates the nuclear export of RBP-J to tubulin fibers and downregulates Notch-mediated transcription. In this study, we found that RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Our findings indicate that RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC.

  20. Cobalt chloride pretreatment promotes cardiac differentiation of human embryonic stem cells under atmospheric oxygen level.

    PubMed

    Ng, Kwong-Man; Chan, Yau-Chi; Lee, Yee-Ki; Lai, Wing-Hon; Au, Ka-Wing; Fung, Man-Lung; Siu, Chung-Wah; Li, Ronald A; Tse, Hung-Fat

    2011-12-01

    Our previous study demonstrated the direct involvement of the HIF-1α subunit in the promotion of cardiac differentiation of murine embryonic stem cells (ESCs). We report the use of cobalt chloride to induce HIF-1α stabilization in human ESCs to promote cardiac differentiation. Treatment of undifferentiated hES2 human ESCs with 50 μM cobalt chloride markedly increased protein levels of the HIF-1α subunit, and was associated with increased expression of early cardiac specific transcription factors and cardiotrophic factors including NK2.5, vascular endothelial growth factor, and cardiotrophin-1. When pretreated cells were subjected to cardiac differentiation, a notable increase in the occurrence of beating embryoid bodies and sarcomeric actinin-positive cells was observed, along with increased expression of the cardiac-specific markers, MHC-A, MHC-B, and MLC2V. Electrophysiological study revealed increased atrial- and nodal-like cells in the cobalt chloride-pretreated group. Confocal calcium imaging analysis indicated that the maximum upstroke and decay velocities were significantly increased in both noncaffeine and caffeine-induced calcium transient in cardiomyocytes derived from the cobalt chloride-pretreated cells, suggesting these cells were functionally more mature. In conclusion, our study demonstrated that cobalt chloride pretreatment of hES2 human ESCs promotes cardiac differentiation and the maturation of calcium homeostasis of cardiomyocytes derived from ESCs.

  1. Progress and prospects of engineered sequence-specific DNA modulating technologies for the management of liver diseases

    PubMed Central

    Nicholson, Samantha A; Moyo, Buhle; Arbuthnot, Patrick B

    2015-01-01

    Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viral hepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins (ZFPs), transcription activator-like effectors (TALEs), homing endonucleases (HEs) and clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR associated (Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases. PMID:25937863

  2. Construction of bone marrow mesenchymal cells-derived engineered hepatic tissue and its therapeutic effect in rats with 90% subtotal hepatectomy.

    PubMed

    Yu, J; Yuan, J; Xu, R

    2014-09-16

    Engineered hepatic tissue (EHT) is considered as a promising strategy for healing acute liver failure (ALF), therefore, in the present study we evaluated the therapeutic potential of the EHT which engaged with bone marrow mesenchymal cells (BMSCs) derived hepatocytes (BMSCs—Hepas) in ALF rats. After characterization of isolated BMSCs, we seeded passage 3 BMSCs which have being cultured in medium containing 20 ng/ml hepatocyte growth factor (HGF) and 10 ng/ml epidermal growth factor (EGF) for 14 days on three scaffolds individually in Transwell system, and then cultured for more than 3 days to construct three kinds of EHT named EHT1, EHT2, and EHT3. Based on morphology and urea production assays, we chose an optimal one and transplanted it into ALF rat with 90% subtotal hepatectomy and assessed its therapeutic potential by survival time, hepatic encephalopathy score (HES) and related liver function test. The remnant liver was acquired, sectioned and identified by con-focal scanning microscopy. The isolated cells possessed basic properties of BMSCs, when cultured in hepatogenic medium for 2 weeks, BMSCs would restore to the functional properties of primary rats' hepatocytes, expressing albumin (ALB) and alpha fetoprotein (AFP) simultaneously. Transplantation of EHT3 significantly prolonged the survival time, increased HES, and ameliorated the liver function. BMSC will be a newly cell source for the construction of EHT. Importantly, the EHT transplantation may be an effective strategy to treat ALF in clinic.

  3. Cloning and Expression of Recombinant Human Endostatin in Periplasm of Escherichia coli Expression System

    PubMed Central

    Mohajeri, Abbas; Pilehvar-Soltanahmadi, Yones; Pourhassan-Moghaddam, Mohammad; Abdolalizadeh, Jalal; Karimi, Pouran; Zarghami, Nosratollah

    2016-01-01

    Purpose: Recombinant human endostatin (rhEs) is an angiogenesis inhibitor which is used as a specific drug in the treatment of non-small-cell lung cancer. In the current research, we developed an efficient method for expressing soluble form of the rhEs protein in the periplasmic space of Escherichia coli via fusing with pelB signal peptide. Methods: The human endostatin (hEs) gene was amplified using synthetic (hEs) gene as a template; then, cloned and expressed under T7 lac promoter. IPTG was used as an inducer for rhEs expression. Next, the osmotic shock was used to extraction of protein from the periplasmic space. The presence of rhEs in the periplasmic space was approved by SDS-PAGE and Western blotting. Results: The results show the applicability of pelB fusion protein system usage for secreting rhEs in the periplasm of E. coli in the laboratory scale. The rhEs represents approximately 35 % (0.83mg/l) of the total cell protein. Conclusion: The present study apparently is the first report of codon-optimized rhEs expression as a fusion with pelB signal peptide. The results presented the successful secretion of soluble rhEs to the periplasmic space. PMID:27478780

  4. Common profiles of Notch signaling differentiate disease-free survival in luminal type A and triple negative breast cancer

    PubMed Central

    Orzechowska, Magdalena; Jędroszka, Dorota; Bednarek, Andrzej K

    2017-01-01

    Breast cancer (BC) is characterized by high heterogeneity regarding its biology and clinical characteristics. The Notch pathway regulates such processes as organ modeling and epithelial-to-mesenchymal transition (EMT). The aim of the study was to determine the effect of differential expression of Notch members on disease-free survival (DFS) in luminal type A (lumA) and triple negative (TN) BC. The differential expression of 19 Notch members was examined in a TCGA BC cohort. DFS analysis was performed using the log-rank test (p<0.05). Biological differences between DFS groups were determined with Gene Set Enrichment Analysis (GSEA) (tTest, FDR<0.25). Common expression profiles according to Notch signaling were examined using ExpressCluster (K-means, mean centered, Euclidean distance metric). The overexpression of HES1, LFNG and PSEN1 was found to be favorable for DFS in lumA, and lowered expression favorable for DFS in TN. GSEA analysis showed that differential Notch signaling is associated with cell cycle, tissue architecture and remodeling. Particularly, targets of E2F, early stage S phase transcription factor, were upregulated in the lumA unfavorable group and the TN favorable group differentiated on a basis of HES1 and PSEN1 expression. Summarizing, our analysis show significance of Notch signaling in BRCA progression through triggering EMT. Moreover, identification of numerous genes which overexpression is associated with disease recurrence may serve as a source of potential targets for a new anticancer therapy. PMID:27888801

  5. Investigating Students' Ideas About Buoyancy and the Influence of Haptic Feedback

    NASA Astrophysics Data System (ADS)

    Minogue, James; Borland, David

    2016-04-01

    While haptics (simulated touch) represents a potential breakthrough technology for science teaching and learning, there is relatively little research into its differential impact in the context of teaching and learning. This paper describes the testing of a haptically enhanced simulation (HES) for learning about buoyancy. Despite a lifetime of everyday experiences, a scientifically sound explanation of buoyancy remains difficult to construct for many. It requires the integration of domain-specific knowledge regarding density, fluid, force, gravity, mass, weight, and buoyancy. Prior studies suggest that novices often focus on only one dimension of the sinking and floating phenomenon. Our HES was designed to promote the integration of the subconcepts of density and buoyant forces and stresses the relationship between the object itself and the surrounding fluid. The study employed a randomized pretest-posttest control group research design and a suite of measures including an open-ended prompt and objective content questions to provide insights into the influence of haptic feedback on undergraduate students' thinking about buoyancy. A convenience sample (n = 40) was drawn from a university's population of undergraduate elementary education majors. Two groups were formed from haptic feedback (n = 22) and no haptic feedback (n = 18). Through content analysis, discernible differences were seen in the posttest explanations sinking and floating across treatment groups. Learners that experienced the haptic feedback made more frequent use of "haptically grounded" terms (e.g., mass, gravity, buoyant force, pushing), leading us to begin to build a local theory of language-mediated haptic cognition.

  6. A genome-wide survey on basic helix-loop-helix transcription factors in giant panda.

    PubMed

    Dang, Chunwang; Wang, Yong; Zhang, Debao; Yao, Qin; Chen, Keping

    2011-01-01

    The giant panda (Ailuropoda melanoleuca) is a critically endangered mammalian species. Studies on functions of regulatory proteins involved in developmental processes would facilitate understanding of specific behavior in giant panda. The basic helix-loop-helix (bHLH) proteins play essential roles in a wide range of developmental processes in higher organisms. bHLH family members have been identified in over 20 organisms, including fruit fly, zebrafish, mouse and human. Our present study identified 107 bHLH family members being encoded in giant panda genome. Phylogenetic analyses revealed that they belong to 44 bHLH families with 46, 25, 15, 4, 11 and 3 members in group A, B, C, D, E and F, respectively, while the remaining 3 members were assigned into "orphan". Compared to mouse, the giant panda does not encode seven bHLH proteins namely Beta3a, Mesp2, Sclerax, S-Myc, Hes5 (or Hes6), EBF4 and Orphan 1. These results provide useful background information for future studies on structure and function of bHLH proteins in the regulation of giant panda development.

  7. Canonical Wnt signaling transiently stimulates proliferation and enhances neurogenesis in neonatal neural progenitor cultures

    SciTech Connect

    Hirsch, Cordula; Campano, Louise M.; Woehrle, Simon; Hecht, Andreas . E-mail: andreas.hecht@mol-med.uni-freiburg.de

    2007-02-01

    Canonical Wnt signaling triggers the formation of heterodimeric transcription factor complexes consisting of {beta}-catenin and T cell factors, and thereby controls the execution of specific genetic programs. During the expansion and neurogenic phases of embryonic neural development canonical Wnt signaling initially controls proliferation of neural progenitor cells, and later neuronal differentiation. Whether Wnt growth factors affect neural progenitor cells postnatally is not known. Therefore, we have analyzed the impact of Wnt signaling on neural progenitors isolated from cerebral cortices of newborn mice. Expression profiling of pathway components revealed that these cells are fully equipped to respond to Wnt signals. However, Wnt pathway activation affected only a subset of neonatal progenitors and elicited a limited increase in proliferation and neuronal differentiation in distinct subsets of cells. Moreover, Wnt pathway activation only transiently stimulated S-phase entry but did not support long-term proliferation of progenitor cultures. The dampened nature of the Wnt response correlates with the predominant expression of inhibitory pathway components and the rapid actuation of negative feedback mechanisms. Interestingly, in differentiating cell cultures activation of canonical Wnt signaling reduced Hes1 and Hes5 expression suggesting that during postnatal neural development, Wnt/{beta}-catenin signaling enhances neurogenesis from progenitor cells by interfering with Notch pathway activity.

  8. Short-lived Her proteins drive robust synchronized oscillations in the zebrafish segmentation clock.

    PubMed

    Ay, Ahmet; Knierer, Stephan; Sperlea, Adriana; Holland, Jack; Özbudak, Ertuğrul M

    2013-08-01

    Oscillations are prevalent in natural systems. A gene expression oscillator, called the segmentation clock, controls segmentation of precursors of the vertebral column. Genes belonging to the Hes/her family encode the only conserved oscillating genes in all analyzed vertebrate species. Hes/Her proteins form dimers and negatively autoregulate their own transcription. Here, we developed a stochastic two-dimensional multicellular computational model to elucidate how the dynamics, i.e. period, amplitude and synchronization, of the segmentation clock are regulated. We performed parameter searches to demonstrate that autoregulatory negative-feedback loops of the redundant repressor Her dimers can generate synchronized gene expression oscillations in wild-type embryos and reproduce the dynamics of the segmentation oscillator in different mutant conditions. Our model also predicts that synchronized oscillations can be robustly generated as long as the half-lives of the repressor dimers are shorter than 6 minutes. We validated this prediction by measuring, for the first time, the half-life of Her7 protein as 3.5 minutes. These results demonstrate the importance of building biologically realistic stochastic models to test biological models more stringently and make predictions for future experimental studies.

  9. Impact of fluid resuscitation with hypertonic-hydroxyethyl starch versus lactated ringer on hemorheology and microcirculation in hemorrhagic shock.

    PubMed

    Guerci, Philippe; Tran, Nguyen; Menu, Patrick; Losser, Marie-Reine; Meistelman, Claude; Longrois, Dan

    2014-01-01

    The choice of volume expander for fluid resuscitation in hemorrhagic shock is still debated. Changes in plasma viscosity (PV) are barely investigated while PV modulates functional capillary density, microcirculation and organ function. The present study evaluated the impact of 2 strategies of fluid resuscitation in hemorrhagic shock in pigs. Ten pigs were subjected to hemorrhagic shock and randomly assigned to a low viscosity fluid regimen (Lactated Ringer's, LR) group or a high viscosity regimen (hypertonic-hydroxyethyl starch, HES) for volume resuscitation. Sublingual microcirculatory flow and tissue oxygen tension were assessed together with macro- and microcirculatory, biochemical and rheological variables at baseline, 30 minutes after hemorrhagic shock, immediately after reaching resuscitation endpoints (R-0), and 60 minutes after resuscitation (R-60). PV decreased similarly in both groups following resuscitation (from 1.36 [1.32-1.38] to 1.21 [1.21-1.23] for LR, and from 1.32 [1.31-1.32] to 1.20 [1.17-1.21] mPa.s for HES). No differences were found between the groups for other rheological variables, microcirculatory flow or tissue oxygen tension at R-0 and R-60. Despite a 6-fold difference in the volumes required to achieve blood flow endpoints, commercially available volume expanders had similar effects on rheological and microcirculatory variables, irrespective of their viscosity. Our findings are consistent with the absence of clinically relevant differences between crystalloid and colloid resuscitation of hemorrhagic shock.

  10. Notch1-mediated signaling regulates proliferation of porcine satellite cells (PSCs).

    PubMed

    Qin, Lili; Xu, Jian; Wu, Zhenfang; Zhang, Zhe; Li, Jiaqi; Wang, Chong; Long, Qiaoming

    2013-02-01

    Notch signaling is an evolutionarily conserved cell-cell communication mechanism involved in the regulation of cell proliferation, differentiation and fate decisions of mammalian cells. In the present study, we investigated the possible requirement for Notch signaling in the proliferation and differentiation of porcine satellite cells. We show that Notch1, 2 and 3 are expressed in cultured porcine satellite cells. Knock-down of NOTCH1, but not NOTCH2 and NOTCH3, decreases the proliferation of porcine satellite cells. In contrast, enhancement of NOTCH1 expression via treatment of porcine satellite cells with recombinant NF-κB increases the proliferation of porcine satellite cells. The alteration of porcine satellite cell proliferation is associated with significant changes in the expression of cell cycle related genes (cyclin B1, D1, D2, E1 and p21), myogenic regulatory factors (MyoD and myogenin) and the Notch effector Hes5. In addition, alteration of Notch1 expression in porcine satellite cells causes changes in the expression of GSK3β-3. Taken together, these findings suggest that of the four notch-related genes, Notch1is likely to be required for regulating the proliferation and therefore the maintenance of porcine satellite cells in vivo, and do so through activation of the Notch effector gene Hes5.

  11. The Notch Pathway Is Important in Maintaining the Cancer Stem Cell Population in Pancreatic Cancer

    PubMed Central

    Abel, Ethan V.; Kim, Edward J.; Wu, Jingjiang; Hynes, Mark; Bednar, Filip; Proctor, Erica; Wang, Lidong; Dziubinski, Michele L.; Simeone, Diane M.

    2014-01-01

    Background Pancreatic cancer stem cells (CSCs) represent a small subpopulation of pancreatic cancer cells that have the capacity to initiate and propagate tumor formation. However, the mechanisms by which pancreatic CSCs are maintained are not well understood or characterized. Methods Expression of Notch receptors, ligands, and Notch signaling target genes was quantitated in the CSC and non-CSC populations from 8 primary human pancreatic xenografts. A gamma secretase inhibitor (GSI) that inhibits the Notch pathway and a shRNA targeting the Notch target gene Hes1 were used to assess the role of the Notch pathway in CSC population maintenance and pancreatic tumor growth. Results Notch pathway components were found to be upregulated in pancreatic CSCs. Inhibition of the Notch pathway using either a gamma secretase inhibitor or Hes1 shRNA in pancreatic cancer cells reduced the percentage of CSCs and tumorsphere formation. Conversely, activation of the Notch pathway with an exogenous Notch peptide ligand increased the percentage of CSCs as well as tumorsphere formation. In vivo treatment of orthotopic pancreatic tumors in NOD/SCID mice with GSI blocked tumor growth and reduced the CSC population. Conclusion The Notch signaling pathway is important in maintaining the pancreatic CSC population and is a potential therapeutic target in pancreatic cancer. PMID:24647545

  12. Parthenogenesis in human oocytes that were collected from resected ovarian tissue and matured in vitro.

    PubMed

    Lee, Ho-Joon; Teixeira, Jose

    2009-01-01

    Currently, a major hurdle in the progress of human embryonic stem (hES) cell research is the lack of human oocytes with which to perform experiments. The collection process is a logistical and ethical challenge and usually involves the use of excess oocytes donated after assisted reproduction procedures. We collected resected human ovarian tissue after routine surgical procedures. Oocytes were isolated from the tissue and matured in vitro to the meiosis II (MII) stage, when the first polar body is extruded. With the large antral and smaller preantral follicles, the efficiencies of the maturation were nearly 50% and 25%, respectively. The quality of the matured oocytes was assessed by inducing parthenogenesis and >50% of the in vitro matured oocytes were competent enough to develop pronuclei and 33% developed at least to the two-cell stage 48 h after activation. Parthenotes continued to develop by 72 h but with significant blastomere fragmentation. These results provide evidence that resected ovarian tissue, which is normally discarded, may be a suitable alternative source for oocytes in hES cell research.

  13. A Simple Method for Labeling Human Embryonic Stem Cells Destined to Lose Undifferentiated Potency

    PubMed Central

    Kumagai, Ayako; Suga, Mika; Yanagihara, Kana; Itoh, Yumi; Furue, Miho K.

    2016-01-01

    Mitochondrial oxidative phosphorylation is a major source of cellular ATP. Its usage as an energy source varies, not only according to the extracellular environment, but also during development and differentiation, as indicated by the reported changes in the flux ratio of glycolysis to oxidative phosphorylation during embryonic stem (ES) cell differentiation. The fluorescent probe JC-1 allows visualization of changes in the mitochondrial membrane potential produced by oxidative phosphorylation. Strong JC-1 signals were localized in the differentiated cells located at the edge of H9 ES colonies that expressed vimentin, an early differentiation maker. The JC-1 signals were further intensified when individual adjacent colonies were in contact with each other. Time-lapse analyses revealed that JC-1-labeled H9 cells under an overconfluent condition were highly differentiated after subculture, suggesting that monitoring oxidative phosphorylation in live cells might facilitate the prediction of induced pluripotent stem cells, as well as ES cells, that are destined to lose their undifferentiated potency. Significance Skillful cell manipulation is a major factor in both maintaining and disrupting the undifferentiation potency of human embryonic stem (hES) cells. Staining with JC-1, a mitochondrial membrane potential probe, is a simple monitoring method that can be used to predict embryonic stem cell quality under live conditions, which might help ensure the future use of hES and human induced pluripotent stem cells after subculture. PMID:26819254

  14. Corilagin suppresses cholangiocarcinoma progression through Notch signaling pathway in vitro and in vivo

    PubMed Central

    GU, YUE; XIAO, LINFENG; MING, YANLIN; ZHENG, ZHIZHONG; LI, WENGANG

    2016-01-01

    Corilagin is a natural plant polyphenol tannic acid with antitumor, anti-inflammatory, and anti-oxidative properties. However, the mechanisms of its actions are largely unknown. Our group reported that corilagin could induce cell inhibition in human breast cancer cell line MCF-7 and human liver hepatocellular carcinoma cell lines HepG2. We report here that corilagin inhibits cholangiocarcinoma (CCA) development through regulating Notch signaling pathway. We found that, in vitro, corilagin inhibited CCA cell proliferation, migration and invasion, promoted CCA cell apoptosis, and inhibited Notch1 and Notch signaling pathway protein expression. Co-immunoprecipitation was used to establish Notch intracellular domain (NICD) interaction with MAML1 and P300 in CCA. Importantly, corilagin reduced Hes1 mRNA level through inhibiting Hes1 promoter activity. In nude mice, corilagin inhibited CCA growth and repressed the expression of Notch1 and mTOR. These results indicate that corilagin may control CCA cell growth by downregulating the expression of Notch1. Therefore, our findings suggest that corilagin may have the potential to become a new therapeutic drug for human CCA. PMID:26935808

  15. The Economic Potential of Two Nuclear-Renewable Hybrid Energy Systems

    SciTech Connect

    Ruth, Mark; Cutler, Dylan; Flores-Espino, Francisco; Stark, Greg; Jenkin, Thomas; Simpkins, Travis; Macknick, Jordan

    2016-08-01

    Tightly coupled nuclear-renewable hybrid energy systems (N-R HESs) are an option that can generate zero-carbon, dispatchable electricity and provide zero-carbon energy for industrial processes at a lower cost than alternatives. N-R HESs are defined as systems that are managed by a single entity and link a nuclear reactor that generates heat, a thermal power cycle for heat to electricity conversion, at least one renewable energy source, and an industrial process that uses thermal and/or electrical energy. This report provides results of an analysis of two N-R HES scenarios. The first is a Texas-synthetic gasoline scenario that includes four subsystems: a nuclear reactor, thermal power cycle, wind power plant, and synthetic gasoline production technology. The second is an Arizona-desalination scenario with its four subsystems a nuclear reactor, thermal power cycle, solar photovoltaics, and a desalination plant. The analysis focuses on the economics of the N-R HESs and how they compare to other options, including configurations without all the subsystems in each N-R HES and alternatives where the energy is provided by natural gas.

  16. Nuclear Hybrid Energy Systems: Imperatives, Prospects, and Challenges

    SciTech Connect

    Steven E. Aumeier

    2010-10-01

    As global population reaches an expected 8 billion people by 2030, primary energy consumption is expected to increase by almost 40% from approximately 520 exajoules consumed today to almost 740 exajoules. Much of this increase is expected to come from non-Organization for Economic Cooperation and Development (OECD) nations, and Asia specifically. In these economies, energy used for transportation is expected to grow substantially, as is industrial, commercial and to a lesser degree residential energy use, creating considerable pressure on global and local energy markets. The magnitude and timing of growth in energy consumption likely will create a global imperative to deploy energy production technologies that balance the three pillars of energy security: • economic stability – related to the affordability of energy products, stability and predictability in their price, and the efficient and effective deployment of global capital resources in their development; • environmental sustainability – related to minimizing the negative impacts of energy production to air, land, and water systems and advancing the long-term viability of using a particular resource in a way that does not limit future generations ability to prosper; • resource security – related to the ability to access energy resources and products where and when necessary, in an affordable and predictable manner. One approach to meeting these objectives is hybrid energy systems (HES). Broadly described, HES are energy product production plants that take two or more energy resource inputs (typically includes both carbon and non-carbon based sources) and produce two or more energy products (e.g. electricity, liquid transportation fuels, industrial chemicals) in an integrated plant. Nuclear energy integration into HES offers intriguing potential, particularly if smaller (<300 MWe) reactors are available. Although the concept of using nuclear energy in a variety of non-electrical process

  17. Modelling the hydrological behaviour of a coffee agroforestry basin in Costa Rica

    NASA Astrophysics Data System (ADS)

    Gómez-Delgado, F.; Roupsard, O.; Moussa, R.; Le Maire, G.; Taugourdeau, S.; Bonnefond, J. M.; Pérez, A.; van Oijen, M.; Vaast, P.; Rapidel, B.; Voltz, M.; Imbach, P.; Harmand, J. M.

    2010-05-01

    The profitability of hydropower in Costa Rica is affected by soil erosion and sedimentation in dam reservoirs, which are in turn influenced by land use, infiltration and aquifer interactions with surface water. In order to foster the provision and payment of Hydrological Environmental Services (HES), a quantitative assessment of the impact of specific land uses on the functioning of drainage-basins is required. The present paper aims to study the water balance partitioning in a volcanic coffee agroforestry micro-basin (1 km2, steep slopes) in Costa Rica, as a first step towards evaluating sediment or contaminant loads. The main hydrological processes were monitored during one year, using flume, eddy-covariance flux tower, soil water profiles and piezometers. A new Hydro-SVAT lumped model is proposed, that balances SVAT (Soil Vegetation Atmosphere Transfer) and basin-reservoir routines. The purpose of such a coupling was to achieve a trade-off between the expected performance of ecophysiological and hydrological models, which are often employed separately and at different spatial scales, either the plot or the basin. The calibration of the model to perform streamflow yielded a NS coefficient equal to 0.80, while the validation of the water balance partitioning was consistent with the independent measurements of actual evapotranspiration (R2=0.79, energy balance closed independently), soil water content (R2=0.49) and water table level (R2=0.90). An uncertainty analysis showed that the streamflow modelling was precise for nearly every time step, while a sensitivity analysis revealed which parameters mostly affected model precision, depending on the season. It was observed that 64% of the incident rainfall R flowed out of the basin as streamflow, 25% as evapotranspiration and the remaining 11% was attributed to deep percolation. The model indicated an interception loss equal to 4% of R, a surface runoff of 5% and an infiltration component of 91%. The modelled

  18. Solubility controlled noble gas fractionation during magmatic degassing: Implications for noble gas compositions of primary melts of OIB and MORB

    NASA Astrophysics Data System (ADS)

    Yamamoto, Junji; Burnard, Pete G.

    2005-02-01

    Noble gas abundances in basaltic glasses from ocean islands (OIBs) are generally lower than those of mid-oceanic ridge basalts (MORBs), contrary to most geodynamic models which usually require that the source of OIBs is less degassed (resulting in higher primordial noble gas abundances) and more trace element enriched (resulting in higher radiogenic noble gas abundances) than the MORB source. Therefore, noble gas abundances in OIBs are often thought to have been reduced by extensive gas loss from the magma before eruption. The extent of magmatic degassing can be tested as it will cause characteristic changes in the composition of the volatiles; notably the 4He/ 40Ar* ratio (where 40Ar* is 40Ar corrected for atmospheric contamination) will increase in residual volatiles due to the higher solubility of He relative to Ar. The degree of He-Ar fractionation for a given fraction of gas loss depends on the ratio of the solubilities, S He/S Ar, which is sensitive to (among other things) the CO 2 and H 2O content of the basalt at the time of degassing. From a global database of OIB and MORB glasses, we show that 4He/ 40Ar* ratios of MORB glasses are broadly consistent with degassing of a magma with an initial 40Ar of ≈1.5 × 10 -5 ccSTP/g, i.e., similar to that of the "popping rock." However, OIB glasses generally have lower 40Ar* concentration for a given 4He/ 40Ar*. While this would appear to require lower 40Ar* abundances in the undegassed OIB magmas, the higher volatile contents of OIBs will reduce S He/S Ar (relative to MORBs) during degassing. By modeling S He/S Ar in OIBs, it is possible to show that extensive degassing of OIBs can occur without dramatically increasing the 4He/ 40Ar* ratio. We show that undegassed 40Ar concentrations of OIB magmas were probably similar to those of MORBs.

  19. At Least Three Transporters Likely Mediate Threonine Uptake Needed for Mouse Embryonic Stem Cell Proliferation

    PubMed Central

    Formisano, Tara M.; Van Winkle, Lon J.

    2016-01-01

    Stem cells are at the forefront of current regenerative and biomedical research. Thus, there exists an imperative and urgent need to understand the mechanisms that drive stem cell function in order to exploit their use as a therapeutic tool. Amino acids are potent inducers of signaling cascades that drive stem cell proliferation and differentiation. With a focus on mouse embryonic stem (mES) cells, Threonine (Thr) is the only amino acid required in culture media for mES cell proliferation. Current research associates this need for Thr with threonine dehydrogenase (TDH), which catabolizes Thr to glycine and acetyl-CoA in mES cells. This theory depends, in part, on the ability of 3- hydroxynorvaline (3-HNV) to inhibit both TDH and mES cell proliferation. However, the concentration of 3-HNV needed to inhibit mES cell proliferation is more than an order of magnitude less than its apparent Ki for TDH inhibition. Additionally, 3-HNV inhibits human embryonic stem (hES) cell proliferation, but hES cells do not express a functional tdh gene. Such findings indicate another mechanism for Thr stimulated mES and hES cell proliferation. Since amino acid transporters may be inducers of signaling cascades, we characterized the Thr transport systems in mES cells. We found that there is a Na+-dependent and a Na+-independent component of substrate-saturable transport, with the Na+-dependent component predominating. We also found that of 20 amino acids tested, the amino acids that were the strongest inhibitors of the Na+-dependent component of radiolabeled Thr transport were Ser, Cys, 4-OH-Pro, Asn, Met, and non-radiolabeled Thr itself. Such findings are consistent with characteristics of the ASC transport system, suggesting that this ASC system is responsible for the majority of Thr transport in mES cells. We confirmed expression of mRNA encoding the ASC system transporters, ASCT1 and ASCT2, in mES cells using RT-PCR. In conclusion, mES cells likely express at least three

  20. Blockade of Notch signaling promotes acetaminophen-induced liver injury.

    PubMed

    Jiang, Longfeng; Ke, Michael; Yue, Shi; Xiao, Wen; Yan, Youde; Deng, Xiaozhao; Ying, Qi-Long; Li, Jun; Ke, Bibo

    2017-03-13

    Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS. Some animals were injected with γ-secretase inhibitor DAPT or DMSO vehicle. For the in vitro study, bone marrow-derived macrophages (BMMs) were transfected with Notch1 siRNA, TLR4 siRNA, and non-specific (NS) siRNA and stimulated with LPS. Indeed, paracetamol/acetaminophen-induced liver damage was worse after Notch blockade with DAPT in wild-type mice, which was accompanied by significantly increased ALT levels, diminished hairy and enhancer of split-1 (Hes1), and phosphorylated Stat3 and Akt but enhanced high mobility group box 1 (HMGB1), TLR4, NF-κB, and NLRP3 activation after APAP challenge. Mice receiving DAPT increased macrophage and neutrophil accumulation and hepatocellular apoptosis. However, TLR4 KO mice that received DAPT reduced APAP-induced liver damage and NF-κB, NLRP3, and cleaved caspase-1 activation. BMMs transfected with Notch1 siRNA reduced Hes1 and phosphorylated Stat3 and Akt but augmented HMGB1, TLR4, NF-κB, and NLRP3. Furthermore, TLR4 siRNA knockdown resulted in decreased NF-κB and NLRP3 and cleaved caspase-1 and IL-1β levels following LPS stimulation. These results demonstrate that Notch signaling regulates innate NLRP3 inflammasome activation through regulation of HMGB1/TLR4/NF-κB activation in APAP-induced liver injury. Our novel findings underscore the critical role of the Notch1-Hes1 signaling cascade in the regulation of innate immunity in APAP-triggered liver inflammation. This might imply a novel therapeutic

  1. Hey bHLH transcription factors.

    PubMed

    Weber, David; Wiese, Cornelia; Gessler, Manfred

    2014-01-01

    Hey bHLH transcription factors are direct targets of canonical Notch signaling. The three mammalian Hey proteins are closely related to Hes proteins and they primarily repress target genes by either directly binding to core promoters or by inhibiting other transcriptional activators. Individual candidate gene approaches and systematic screens identified a number of Hey target genes, which often encode other transcription factors involved in various developmental processes. Here, we review data on interaction partners and target genes and conclude with a model for Hey target gene regulation. Furthermore, we discuss how expression of Hey proteins affects processes like cell fate decisions and differentiation, e.g., in cardiovascular, skeletal, and neural development or oncogenesis and how this relates to the observed developmental defects and phenotypes observed in various knockout mice.

  2. Structure of the human paralemmin gene (PALM), mapping to human chromosome 19p13.3 and mouse chromosome 10, and exclusion of coding mutations in grizzled, mocha, jittery, and hesitant mice.

    PubMed

    Burwinkel, B; Miglierini, G; Jenne, D E; Gilbert, D J; Copeland, N G; Jenkins, N A; Ring, H Z; Francke, U; Kilimann, M W

    1998-05-01

    Paralemmin is a newly identified protein that is associated with the plasma membrane and with intracellular membranes through a lipid anchor. It is abundant in brain, is expressed at intermediate levels in the kidney and in endocrine cells, and occurs at low levels in many other tissues. As it is a candidate for genetic disorders that affect membrane functions, we have determined the structure of the human paralemmin gene, PALM, showing that it is organized into nine exons. Moreover, we have performed chromosomal assignments of the human and mouse paralemmin genes, localizing them to regions of homology at human 19p13.3 and the central mouse chromosome 10. Finally, mutation analysis using RNA from mice homozygous for the mutant genes grizzled (gr), mocha (mh), mocha 2J (mh2J), jittery (ji) and hesitant (ji(hes)), which map to this area, excluded mutations in their Palm coding sequences.

  3. Cool Carbon Stars in the Galactic Halo

    NASA Astrophysics Data System (ADS)

    Gigoyan, K. S.

    2016-06-01

    In this paper we report current status of search and study for Faint High Latitude Carbon Stars (FHLCs). Data for more than 1800 spectroscopically confirmed FHLCs are known, which are found thanks to objective prism surveys and photometric selections. More than half of the detected objects belongs to group of dwarf Carbon (dC) stars. Many-sided investigations based on modern astrophysical databases are necessary to study the space distribution of different groups of the FHLC stars and their possible origin in the Halo of our Galaxy. We report about the selection of FHLCs by the spectroscopic surveys: First Byurakan Survey (FBS), Hamburg/ESO Survey (HES), LAMOST Pilot Survey and SDSS, as well as by photometric selection: APM Survey for Cool Carbon Stars in the Galactic Halo, SDSS and 2MASS JHK colours.

  4. Influence of orange cultivar and mandarin postharvest storage on polyphenols, ascorbic acid and antioxidant activity during gastrointestinal digestion.

    PubMed

    De Ancos, Begoña; Cilla, Antonio; Barberá, Reyes; Sánchez-Moreno, Concepción; Cano, M Pilar

    2017-06-15

    Polyphenols, ascorbic acid content and antioxidant activity of two sweet oranges (Navel-N and Cara Cara-CC) and mandarin (Clementine-M) as well as their bioaccessibilities were evaluated in pulps and compared to those in fresh juice. Thus, pulps of oranges and mandarins displayed higher hesperidin (HES), narirutin (NAR), total flavonoids (TF), total phenols (TP) and antioxidant activity (AAC) than their corresponding juices. Also, CC products presented higher bioactive compounds content than N ones. Bioaccessibility of bioactive compounds and AAC were higher in pulps of both oranges and mandarin than in their corresponding juices. Oranges (N and CC) pulps and juices presented higher bioaccessibilities than mandarin ones. The postharvest storage of mandarin at 12°C during 5weeks not only produced a significant increase of the bioactive compounds but also an increase of their bioaccessibility. The bioaccessibility of Citrus bioactive compounds is necessary for calculating more accurately their daily intake amount.

  5. U.S. hydropower resource assessment for Maine

    SciTech Connect

    Francfort, J.E.; Rinehart, B.N.

    1995-07-01

    The Department of Energy is developing an estimate of the undeveloped hydro-power potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The software measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven software program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the State of Maine.

  6. Adaptive Correlation Concepts for Non-Compatible Imagery.

    DTIC Science & Technology

    1981-10-31

    5.4 Ohio Files 26 and 27 Image Segments . . . . 34 5.5 HSV Files 9 and 10 Image Segments ..... . 35 5.6 Scene 1 , Vertical Profiles Through Peak...Simulation Options Summary .e m "lch c .i a ir t.e j-r.-ct cross c t.e"P- lat absclut - differcr.ce a!a .u iy-i.cidd dif’err.c; - metrics. e 1 T0 1ff ct of...cdlf o spectral bands, di~ffe,-,-rurt tie f loy. "Ind d:;7o T hes’,-e -simu lat i onso ae 1 - s o2( 1 r 1 b- in th I s-,sI 31. / / s. ILI Z1.I I SO .& i

  7. The relationship between leadership styles and empathy among student nurses.

    PubMed

    Gunther, Mary; Evans, Ginger; Mefford, Linda; Coe, Thomas R

    2007-01-01

    Much of the nursing literature on leadership describes the qualities of existing nursing leaders, while emphasizing the need for leadership development in student nurses for both managerial and clinical practice. However, there is a lack of research literature on the characteristics of current students. Conducted by the University of Tennessee College of Nursing Empathy Research Group, this pilot study explores the relationship between leadership styles and empathy (cognitive and affective) levels. This correlational descriptive study involved self-report using 3 instruments. Hogan Empathy Scale (HES) and Emotional Empathy Tendency Scale (EETS) measured cognitive and affective empathy levels. The Multifactoral Leadership Questionnaire (MLQ-5x) was used to determine leadership style. Data analysis yielded evidence of a weak positive correlation between the predominant transformational leadership style and empathy levels in both junior and senior students. This correlation has implications for both nurse educators and future employers.

  8. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome

    PubMed Central

    DeKelver, Russell C.; Choi, Vivian M.; Moehle, Erica A.; Paschon, David E.; Hockemeyer, Dirk; Meijsing, Sebastiaan H.; Sancak, Yasemin; Cui, Xiaoxia; Steine, Eveline J.; Miller, Jeffrey C.; Tam, Phillip; Bartsevich, Victor V.; Meng, Xiangdong; Rupniewski, Igor; Gopalan, Sunita M.; Sun, Helena C.; Pitz, Kathleen J.; Rock, Jeremy M.; Zhang, Lei; Davis, Gregory D.; Rebar, Edward J.; Cheeseman, Iain M.; Yamamoto, Keith R.; Sabatini, David M.; Jaenisch, Rudolf; Gregory, Philip D.; Urnov, Fyodor D.

    2010-01-01

    Isogenic settings are routine in model organisms, yet remain elusive for genetic experiments on human cells. We describe the use of designed zinc finger nucleases (ZFNs) for efficient transgenesis without drug selection into the PPP1R12C gene, a “safe harbor” locus known as AAVS1. ZFNs enable targeted transgenesis at a frequency of up to 15% following transient transfection of both transformed and primary human cells, including fibroblasts and hES cells. When added to this locus, transgenes such as expression cassettes for shRNAs, small-molecule-responsive cDNA expression cassettes, and reporter constructs, exhibit consistent expression and sustained function over 50 cell generations. By avoiding random integration and drug selection, this method allows bona fide isogenic settings for high-throughput functional genomics, proteomics, and regulatory DNA analysis in essentially any transformed human cell type and in primary cells. PMID:20508142

  9. Limbal Stromal Tissue Specific Stem Cells and Their Differentiation Potential to Corneal Epithelial Cells.

    PubMed

    Katikireddy, Kishore Reddy; Jurkunas, Ula V

    2016-01-01

    From the derivation of the first human embryonic stem (hES) cell line to the development of induced pluripotent stem (iPS) cells; it has become evident that tissue specific stem cells are able to differentiate into a specific somatic cell types. The understanding of key processes such as the signaling pathways and the role of the microenvironment in epidermal/epithelial development has provided important clues for the derivation of specific epithelial cell types.Various differentiation protocols/methods were used to attain specific epithelial cell types. Here, we describe in detail the procedure to follow for isolation of tissue specific stem cells, mimicking their microenvironment to attain stem cell characteristics, and their potential differentiation to corneal epithelial cells.

  10. Anti-IL5 therapy for asthma and beyond.

    PubMed

    Mukherjee, Manali; Sehmi, Roma; Nair, Parameswaran

    2014-01-01

    Airway inflammation is considered to be the primary component contributing to the heterogeneity and severity of airway disorders. Therapeutic efficacies of diverse novel biologics targeting the inflammatory pathways are under investigation. One such target is IL-5, a type-1 cytokine that is central to the initiation and sustenance of eosinophilic airway inflammation. Over the past decade, anti-IL5 molecules have been documented to have mixed therapeutic benefits in asthmatics. Post hoc analyses of the trials reiterate the importance of identifying the IL-5-responsive patient endotypes. In fact, the currently available anti-IL5 treatments are being considered beyond asthma management; especially in clinical complications with an underlying eosinophilic pathobiology such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis and polyangitis (EGPA). In addition, closer analyses of the available data indicate alternative mechanisms of tissue eosinophilia that remain uncurbed with the current dosage and delivery platform of the anti-IL5 molecules.

  11. Identification of safety-critical events using kinematic vehicle data and the discrete fourier transform.

    PubMed

    Kluger, Robert; Smith, Brian L; Park, Hyungjun; Dailey, Daniel J

    2016-11-01

    Recent technological advances have made it both feasible and practical to identify unsafe driving behaviors using second-by-second trajectory data. Presented in this paper is a unique approach to detecting safety-critical events using vehicles' longitudinal accelerations. A Discrete Fourier Transform is used in combination with K-means clustering to flag patterns in the vehicles' accelerations in time-series that are likely to be crashes or near-crashes. The algorithm was able to detect roughly 78% of crasjavascript:void(0)hes and near-crashes (71 out of 91 validated events in the Naturalistic Driving Study data used), while generating about 1 false positive every 2.7h. In addition to presenting the promising results, an implementation strategy is discussed and further research topics that can improve this method are suggested in the paper.

  12. Production of Green Fluorescent Protein Transgenic Embryonic Stem Cells Using the GENSAT Bacterial Artificial Chromosome Library

    PubMed Central

    Tomishima, Mark J.; Hadjantonakis, Anna-Katerina; Gong, Shiaoching; Studer, Lorenz

    2010-01-01

    Transgenic green fluorescent protein (GFP) reporter embryonic stem (ES) cells are powerful tools for studying gene regulation and lineage choice during development. Here we present a rapid method for the generation of ES cells expressing GFP under the control of selected genes. Bacterial artificial chromosomes (BACs) from a previously constructed GFP transcriptional fusion library (Gene Expression Nervous System Atlas [GENSAT]) were modified for use in ES cells, and multiple BAC transgenic ES cell lines were generated. Specific GFP expression in transgenic cell lines was confirmed during neural differentiation marking neural stem cells, neuronal precursors, and glial progeny by Hes5, Dll1, and GFAP, respectively. GFP was dynamically regulated in ES cell progeny in response to soluble factors that inhibit Notch signaling and a factor that directs astroglial fate choice. Our protocols provide a simple and efficient strategy to utilize the whole GENSAT BAC library to create hundreds of novel fluorescent cell lines for use in ES cell biology. PMID:16990587

  13. Production of green fluorescent protein transgenic embryonic stem cells using the GENSAT bacterial artificial chromosome library.

    PubMed

    Tomishima, Mark J; Hadjantonakis, Anna-Katerina; Gong, Shiaoching; Studer, Lorenz

    2007-01-01

    Transgenic green fluorescent protein (GFP) reporter embryonic stem (ES) cells are powerful tools for studying gene regulation and lineage choice during development. Here we present a rapid method for the generation of ES cells expressing GFP under the control of selected genes. Bacterial artificial chromosomes (BACs) from a previously constructed GFP transcriptional fusion library (Gene Expression Nervous System Atlas [GENSAT]) were modified for use in ES cells, and multiple BAC transgenic ES cell lines were generated. Specific GFP expression in transgenic cell lines was confirmed during neural differentiation marking neural stem cells, neuronal precursors, and glial progeny by Hes5, Dll1, and GFAP, respectively. GFP was dynamically regulated in ES cell progeny in response to soluble factors that inhibit Notch signaling and a factor that directs astroglial fate choice. Our protocols provide a simple and efficient strategy to utilize the whole GENSAT BAC library to create hundreds of novel fluorescent cell lines for use in ES cell biology.

  14. U.S. hydropower resource assessment for Virginia

    SciTech Connect

    Conner, A.M.; Francfort, J.E.

    1997-12-01

    In June 1989, the US Department of Energy initiated the development of a National Energy Strategy to identify the energy resources available to support the expanding demand for energy in the US. Public hearings conducted as part of the strategy development process indicated that undeveloped hydropower resources were not well defined. As a result, the Department of Energy established an interagency Hydropower Resource Assessment Team to ascertain the undeveloped hydropower potential. In connection with these efforts by the Department of Energy, the Idaho National Engineering Laboratory designed the Hydropower Evaluation Software (HES), which has been used to perform a resource assessment of the undeveloped conventional hydropower potential in over 30 states. This report presents the results of the hydropower resource assessment for the State of Virginia. Undeveloped pumped storage hydropower potential is not included.

  15. Operator/service team cuts cost of completing marginal gas wells

    SciTech Connect

    Walker, R.N.; Watson, P. ); Buchanan, L.; Martin, C.D. )

    1995-01-16

    By combining optimized drilling and completion procedures with an operator/service company alliance, Union Pacific Resources Corp. (UPRC) decreased drilling/completion costs by 24%/well in its East Texas Cotton Valley gas production operations. Improved design of tubulars, cement, mud system, bits, fracturing gel, and zone isolation led to the steep decline in drilling and completion costs. In the past, gas reserves easily justified well costs of $1 million/well. However, for marginal areas this cost had to be substantially reduced. Many areas considered margin at $1 million are feasible at one-half that cost. The exploit marginal-acreage team (EMAT) of UPRC and Halliburton Energy Services (HES) personnel was formed in March 1993 to find ways to improve the economics of completing wells in marginal areas. The paper discusses drilling cost, completion styles, fracture stimulation, zone isolation, the alliance and its benefits.

  16. Antimicrobial stewardship: a collaborative partnership between infection preventionists and health care epidemiologists.

    PubMed

    Moody, Julia; Cosgrove, Sara E; Olmsted, Russell; Septimus, Edward; Aureden, Kathy; Oriola, Shannon; Patel, Gita Wasan; Trivedi, Kavita K

    2012-03-01

    It is clear that the widespread and injudicious use of antimicrobials has greatly increased the presence of MDROs that threaten the health of all. There is worldwide acknowledgement that this threat is growing, and that prudent use of antimicrobials combined with infection prevention can prevent harm and improve patient safety. Antimicrobial stewardship programs must harness the talents of all members of the health care team to effectively identify the organism, determine its susceptibility, institute any precautions required, and prescribe the narrowest-acting antibiotic that will destroy it. IPs/HEs play a pivotal role in this approach, by assisting with early organism and infected patient identification, by promoting compliance with standard and transmission-based precautions and other infection prevention strategies such as care bundle practices, hand hygiene, and by educating staff, patients, and visitors.

  17. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

    PubMed

    Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

    2016-01-01

    Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

  18. Comparation of enhanced green fluorescent protein gene transfected and wild-type porcine neural stem cells.

    PubMed

    Zheng, Yue-Mao; An, Zhi-Xing; Zhao, Xiao-E; Quan, Fu-Sheng; Zhao, Hui-Ying; Zhang, Ya-Rong; Liu, Jun; He, Xiao-Ying; He, Xiao-Ning

    2010-02-01

    The aim of this study was to transfect and express the enhanced green fluorescence protein (EGFP) gene into porcine neural stem cells (NSCs) to determine whether EGFP can be used as a marker to monitor NSCs. NSCs were isolated from embryonic day 30 fetal pig brain and transfected with EGFP gene using lipofection. Transfected and wild-type NSCs were induced to differentiate into cells of neuronal and myogenic lineages. Markers of passage three NSCs and their differentiated cells were tested by reverse transcription polymerase chain reaction. The results showed that EGFP could be expressed in NSCs and the differentiated cells. NSCs expressed Nestin, NogoA, DCX, Hes1, Oct4, CD-90 and Sox2. NSCs could differentiated into astrocyte (GFAP(+)), oligodendrocyte (GalC(+)), neuron (NF(+), NSE(+) and MAP2(+)) and myocyte (myf-6(+) and myoD(+)). We concluded that EGFP can be used as a marker in monitoring NSCs.

  19. Carbohydrate-Based Nanocarriers Exhibiting Specific Cell Targeting with Minimum Influence from the Protein Corona.

    PubMed

    Kang, Biao; Okwieka, Patricia; Schöttler, Susanne; Winzen, Svenja; Langhanki, Jens; Mohr, Kristin; Opatz, Till; Mailänder, Volker; Landfester, Katharina; Wurm, Frederik R

    2015-06-15

    Whenever nanoparticles encounter biological fluids like blood, proteins adsorb on their surface and form a so-called protein corona. Although its importance is widely accepted, information on the influence of surface functionalization of nanocarriers on the protein corona is still sparse, especially concerning how the functionalization of PEGylated nanocarriers with targeting agents will affect protein corona formation and how the protein corona may in turn influence the targeting effect. Herein, hydroxyethyl starch nanocarriers (HES-NCs) were prepared, PEGylated, and modified on the outer PEG layer with mannose to target dendritic cells (DCs). Their interaction with human plasma was then studied. Low overall protein adsorption with a distinct protein pattern and high specific affinity for DC binding were observed, thus indicating an efficient combination of "stealth" and targeting behavior.

  20. Test Report :

    SciTech Connect

    Rose, David Martin; Schenkman, Benjamin L.; Borneo, Daniel R.

    2013-10-01

    The Department of Energy Office of Electricity (DOE/OE), Sandia National Laboratories (SNL) and the Base Camp Integration Lab (BCIL) partnered together to incorporate an energy storage system into a microgrid configured Forward Operating Base to reduce the fossil fuel consumption and to ultimately save lives. Energy storage vendors will be sending their systems to SNL Energy Storage Test Pad (ESTP) for functional testing and then to the BCIL for performance evaluation. The technologies that will be tested are electro-chemical energy storage systems comprising of lead acid, lithium-ion or zinc-bromide. GS Battery and EPC Power have developed an energy storage system that utilizes zinc-bromide flow batteries to save fuel on a military microgrid. This report contains the testing results and some limited analysis of performance of the GS Battery, EPC Power HES RESCU.

  1. Hawaii Energy Strategy program. [First Annual Report

    SciTech Connect

    Not Available

    1992-01-01

    The Hawaii Energy Strategy (HES) program began on March 2, 1992, under United States Department of Energy Cooperative Agreement DE-FC03-92F19168, and is scheduled for completion by December 31, 1994. As outlined in the Statement of Joint Objectives: The purpose of the study is to develop an integrated State of Hawaii energy strategy, including an assessment of the State's fossil fuel reserve requirements and the most effective way to meet those needs, the availability and practicality of increasing the use of native energy resources, potential alternative fossil energy technologies such as coal gasification and potential energy efficiency measures which could lead to demand reduction. This work contributes to the DOE mission, will reduce the State's vulnerability to energy supply disruptions and contributes to the public good.

  2. Hawaii Energy Strategy program. Annual report, 1992

    SciTech Connect

    Not Available

    1992-12-31

    The Hawaii Energy Strategy (HES) program began on March 2, 1992, under United States Department of Energy Cooperative Agreement DE-FC03-92F19168, and is scheduled for completion by December 31, 1994. As outlined in the Statement of Joint Objectives: The purpose of the study is to develop an integrated State of Hawaii energy strategy, including an assessment of the State`s fossil fuel reserve requirements and the most effective way to meet those needs, the availability and practicality of increasing the use of native energy resources, potential alternative fossil energy technologies such as coal gasification and potential energy efficiency measures which could lead to demand reduction. This work contributes to the DOE mission, will reduce the State`s vulnerability to energy supply disruptions and contributes to the public good.

  3. Multiple cerebral infarctions in a young patient with heroin-induced hypereosinophilic syndrome.

    PubMed

    Bolz, Jan; Meves, Saskia H; Kara, Kaffer; Reinacher-Schick, Anke; Gold, Ralf; Krogias, Christos

    2015-09-15

    Hypereosinophilic syndrome represents a rare cause for cerebral infarctions and inflammatory neurological disorders. Various possible pathogenic mechanisms for cerebral infarctions have already been discussed. Complex mechanisms including a local hypercoagulability by eosinophilic granules as well as a direct damage to endothelial cells, leading to alterations of the microcirculation seem to be involved. The changing pattern of heroin use to inhalation/sniffing leading to an increasing abuse may cause a rise in the prevalence of Heroin induced eosinophilia, as it has been reported in a case of eosinophilic pneumonia associated with heroin inhalation. To our knowledge, the present case report displays the first description of stroke in the setting of heroin induced hypereosinophilia. Thus, besides usual vasoconstriction, HES should be considered in drug-induced cerebral infarctions.

  4. US Hydropower Resource Assessment for Massachusetts

    SciTech Connect

    Francfort, J.E.; Rinehart, B.N.

    1995-07-01

    The Department of Energy is developing an estimate of the undeveloped hydropower potential in the United States. The Hydropower Evaluation Software (HES) is a computer model that was developed by the Idaho National Engineering Laboratory for this purpose. The software measures the undeveloped hydropower resources available in the United States, using uniform criteria for measurement. The software was developed and tested using hydropower information and data provided by the Southwestern Power Administration. It is a menu-driven software program that allows the personal computer user to assign environmental attributes to potential hydropower sites, calculate development suitability factors for each site based on the environmental attributes present, and generate reports based on these suitability factors. This report details the resource assessment results for the Commonwealth of Massachusetts.

  5. Organization of monitoring the state of structures at the Sayano-Shushenskoe Hydroelectric Station

    SciTech Connect

    Bryzgalov, V.I.; Stafievskii, V.A.

    1994-06-01

    Engineering art when reference is to the reliability of an engineering structure should not depend on the political situation in the country. For example, in stagnant years it was decided to replace the type of dam at the Krasnoyarsk hydroelectric station (HES). Despite the insistence of the design organization for a so-called buttress dam, the engineering corps of like-minded persons - the construction engineers and customer headed by the chief of the construction project - categorically objected to the proposed design: in the construction industry the technology was not ready for openwork construction under harsh climatic conditions, and, what really matters, millions of people living downstream of the dam should be safeguarded against disasters. As a result a gravity dam was adopted.

  6. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome.

    PubMed

    DeKelver, Russell C; Choi, Vivian M; Moehle, Erica A; Paschon, David E; Hockemeyer, Dirk; Meijsing, Sebastiaan H; Sancak, Yasemin; Cui, Xiaoxia; Steine, Eveline J; Miller, Jeffrey C; Tam, Phillip; Bartsevich, Victor V; Meng, Xiangdong; Rupniewski, Igor; Gopalan, Sunita M; Sun, Helena C; Pitz, Kathleen J; Rock, Jeremy M; Zhang, Lei; Davis, Gregory D; Rebar, Edward J; Cheeseman, Iain M; Yamamoto, Keith R; Sabatini, David M; Jaenisch, Rudolf; Gregory, Philip D; Urnov, Fyodor D

    2010-08-01

    Isogenic settings are routine in model organisms, yet remain elusive for genetic experiments on human cells. We describe the use of designed zinc finger nucleases (ZFNs) for efficient transgenesis without drug selection into the PPP1R12C gene, a "safe harbor" locus known as AAVS1. ZFNs enable targeted transgenesis at a frequency of up to 15% following transient transfection of both transformed and primary human cells, including fibroblasts and hES cells. When added to this locus, transgenes such as expression cassettes for shRNAs, small-molecule-responsive cDNA expression cassettes, and reporter constructs, exhibit consistent expression and sustained function over 50 cell generations. By avoiding random integration and drug selection, this method allows bona fide isogenic settings for high-throughput functional genomics, proteomics, and regulatory DNA analysis in essentially any transformed human cell type and in primary cells.

  7. How I treat hypereosinophilic syndromes

    PubMed Central

    2015-01-01

    Hypereosinophilic syndromes (HESs) are a group of rare disorders characterized by peripheral blood eosinophilia of 1.5 × 109/L or higher and evidence of end organ manifestations attributable to the eosinophilia and not otherwise explained in the clinical setting. HESs are pleomorphic in clinical presentation and can be idiopathic or associated with a variety of underlying conditions, including allergic, rheumatologic, infectious, and neoplastic disorders. Moreover, the etiology of the eosinophilia in HESs can be primary (myeloid), secondary (lymphocyte-driven), or unknown. Although corticosteroids remain the first-line therapy for most forms of HESs, the availability of an increasing number of novel therapeutic agents, including tyrosine kinase inhibitors and monoclonal antibodies, has necessarily altered the approach to treatment of HESs. This review presents an updated treatment-based approach to the classification of patients with presumed HES and discusses the roles of conventional and novel agents in the management of these patients. PMID:25964669

  8. Modeling HE systems using DSD

    SciTech Connect

    Aslam, T.D.; Bdzil, J.B.

    1997-12-01

    As a high explosive (HE) ages, those properties of the HE dependent on its global energy-release rate (e.g. shock initiation and detonation propagation speed) are the most likely to be affected. Similarly, any HE replacement will bring with it changes in these same reaction rate dependent characteristics of the HE, in that the new material will not be identical to that being replaced. In this paper the authors describe how detonation shock dynamics (DSD) theory can be used to model how changes in the energy-release rate (as they are embodied in the HE`s detonation speed vs curvature relation) influence the speed of detonation propagation and in turn the performance of a system.

  9. Aerodynamics of Vortical Type Flows in Three Dimensions: Conference Proceedings Held at Rotterdam, Netherlands on 25-28 April 1983.

    DTIC Science & Technology

    1983-07-01

    O -Tip Figure 9. Loadmng edge radus -0. 03 %C, Pre"’r d ~bt’ swO* 45’ ncidnce * Reynolds No..* 2.1. 10’ 01 - - tC.- Figure 1. Leading edge radus...NASA L*IQO&V CDW.&odyfln"@W do ff NASA (Lmwev, 1 ~ ~F 2 To.,dlo d ’-t an. dto,W LEaw w, n~ ONERA Mp2 d’ulw il# m/*; PfINACA.2_ 12 5 W....,. b w o ...iop. f&,f c) w .,hes d.sifb, d , . ). Vc 0,5 10’ b , 2101~ Em. &u, .,, NASA E e,, .ad d F. 3 - Aw"~ de o ~ W~ ~n Ea..-W ENEAA a

  10. [The late results of short-term chemotherapy in benign forms of tuberculosis in children].

    PubMed

    Anastasatu, C; Anastasatu, O; Murgoci, G; Dobre, M; Bîscă, N; Calciu, M; Popescu, E; Tifescu, R; Didilescu, C; Burdujan, M

    1991-01-01

    The study included 359 cases of primary tuberculosis (benign forms) in children aged 0-14 years, out of which 181 non-complicated and 178 complicated forms. The therapeutical regimens were: 3HEZ2/3HE2 (study subgroup) and 6HE2/3H2 (control) for non-complicated forms, and 3HRZ2/3HR2 (study subgroup) and 3HES2/3HE2/3H2 (control) for complicated ones. Late results (5 years after treatment end) were very good (from clinical, radiological, bacteriological points of view) in 100% of cases. Thus, short-course regimens are preferable to longer ones (over 6 months) in the chemotherapy of the benign forms of pulmonary tuberculosis in children.

  11. Notch signaling in the epididymal epithelium regulates sperm motility and is transferred at a distance within epididymosomes.

    PubMed

    Murta, D; Batista, M; Silva, E; Trindade, A; Henrique, D; Duarte, A; Lopes-da-Costa, L

    2016-03-01

    Spermatozoa undergo sequential maturation changes during their transit along the epididymis. These changes are modulated by the epididymal epithelium and require a finely tuned gene expression. The Notch cell signaling pathway is a major regulator of cell fate decisions in several tissues, including the testis. Here, we evaluated the transcription and expression patterns of Notch components (Notch1-3, Dll1, Dll4, and Jagged1) and effectors (Hes1-2 and Hes5) in the adult mouse epididymis, and evaluated the role of Notch signaling in the epididymis through its in vivo blockade following administration of an inhibitor (DAPT). Notch components and effectors were dynamically transcribed and expressed in the epididymis and vas deferens, each segment exhibiting a specific combination of epithelial receptor/ligand/effector expression patterns. Nuclear detection of Notch effectors indicates that Notch signaling was active. Notch components (but not effectors) were identified in the cytoplasmic droplet of spermatozoa, in a dynamic and specific pattern along the epididymis. In addition, Notch components were identified within large and small vesicles in the epididymal lumen. A purified population of these membranous vesicles from different epididymal segments was obtained, and through dot blot analysis, it was confirmed that Notch components were carried within these vesicles in a dynamic pattern along the epididymal lumen. We hypothesize that these vesicles (epididymosomes) allow Notch signaling at distance from epididymal epithelial cells to spermatozoa. DAPT-induced in vivo Notch signaling blockade, although showing a low efficiency, disrupted the expression patterns of Notch components and effectors in the epididymal epithelium and in spermatozoa, and significantly decreased sperm motility, although not affecting male fertility. These results prompt for a regulatory role of Notch signaling in epididymal epithelial function and sperm maturation.

  12. Functional redundancy of the Notch pathway in ovarian cancer cell lines.

    PubMed

    Silva, Fernanda; Félix, Ana; Serpa, Jacinta

    2016-10-01

    Epithelial ovarian cancer is the most lethal gynecologic malignancy, despite advances in treatment. The most common histological type, high-grade ovarian serous carcinoma (OSC) is usually diagnosed at an advanced stage, and although these types of tumors frequently respond to surgery and platinum-based chemotherapy, they usually recur. Ovarian clear cell carcinoma (OCCC) is an unusual histological type, which is known to be intrinsically chemoresistant and is associated with poor prognosis in advanced stages. In recent years, genetic alterations and epigenetic modulation of signaling pathways have been reported in OSC and OCCC, including the overexpression of Notch pathway elements and histone deacetylases. Histone deacetylase inhibitors (HDACis), including vorinostat (suberoylanilide hydroxamic acid), alter the transcription of genes involved in cell growth, survival and apoptosis, and have become an attractive therapeutic approach. However, no previous work has addressed the effect of HDACis, and in particular vorinostat, on Notch signaling in ovarian cancer. Therefore, the present study aimed to investigate the modulation of the Notch pathway by vorinostat in ovarian cancer. Using immunofluorescence and quantitative polymerase chain reaction, the present results revealed that vorinostat activated the Notch pathway in OCCC and OSC cell lines, through different Notch ligands. In OCCC, the activation of the Notch pathway appeared to occur through Delta-like (Dll) ligands 1, 2 and 3, whereas in OSC Dll1 and Jagged 1 and 2 ligands were involved. The activation of the Notch pathway by vorinostat, in OCCC and OSC cell lines, culminated in the increased expression of the same downstream transcription factors, hairy enhancer of split (Hes) 1 and 5, and Hes-related proteins 1 and 2. In conclusion, vorinostat modulates the expression of several downstream targets of the Notch pathway and independent Notch receptors and ligands that are expressed in OSC and OCCC. This

  13. HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

    PubMed

    Fan, Yan; Gao, Xiang; Chen, Jinhui; Liu, Ying; He, Johnny J

    2016-11-02

    Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics.

  14. Honokiol inhibits melanoma stem cells by targeting notch signaling.

    PubMed

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A; Anant, Shrikant; Mammen, Joshua M V

    2015-12-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling.

  15. Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.

    PubMed

    Mann, Christopher D; Bastianpillai, Christopher; Neal, Christopher P; Masood, Muhammad M; Jones, Donald J L; Teichert, Friederike; Singh, Rajinder; Karpova, Elena; Berry, David P; Manson, Margaret M

    2012-01-01

    In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

  16. Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes

    SciTech Connect

    Lai, Peng-Yeh; Tsai, Chong-Bin; Tseng, Min-Jen

    2013-01-18

    Highlights: ► Notch4IC modulates the ERK pathway and cell cycle to promote 3T3-L1 proliferation. ► Notch4IC facilitates 3T3-L1 differentiation by up-regulating proadipogenic genes. ► Notch4IC promotes proliferation during the early stage of 3T3-L1 adipogenesis. ► Notch4IC enhances differentiation during subsequent stages of 3T3-L1 adipogenesis. -- Abstract: Adipose tissue is composed of adipocytes, which differentiate from precursor cells in a process called adipogenesis. Many signal molecules are involved in the transcriptional control of adipogenesis, including the Notch pathway. Previous adipogenic studies of Notch have focused on Notch1 and HES1; however, the role of other Notch receptors in adipogenesis remains unclear. Q-RT-PCR analyses showed that the augmentation of Notch4 expression during the differentiation of 3T3-L1 preadipocytes was comparable to that of Notch1. To elucidate the role of Notch4 in adipogenesis, the human active form Notch4 (N4IC) was transiently transfected into 3T3-L1 cells. The expression of HES1, Hey1, C/EBPδ and PPARγ was up-regulated, and the expression of Pref-1, an adipogenic inhibitor, was down-regulated. To further characterize the effect of N4IC in adipogenesis, stable cells expressing human N4IC were established. The expression of N4IC promoted proliferation and enhanced differentiation of 3T3-L1 cells compared with those of control cells. These data suggest that N4IC promoted proliferation through modulating the ERK pathway and the cell cycle during the early stage of 3T3-L1 adipogenesis and facilitated differentiation through up-regulating adipogenic genes such as C/EBPα, PPARγ, aP2, LPL and HSL during the middle and late stages of 3T3-L1 adipogenesis.

  17. Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution.

    PubMed

    Zeng, Qinghong; Langereis, Martijn A; van Vliet, Arno L W; Huizinga, Eric G; de Groot, Raoul J

    2008-07-01

    The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs). Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events. Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor. We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts. Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation. This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding. Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies. We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S. Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.

  18. Deciphering the onychophoran 'segmentation gene cascade': Gene expression reveals limited involvement of pair rule gene orthologs in segmentation, but a highly conserved segment polarity gene network.

    PubMed

    Janssen, Ralf; Budd, Graham E

    2013-10-01

    The hallmark of the arthropods is their segmented body, although origin of segmentation, however, is unresolved. In order to shed light on the origin of segmentation we investigated orthologs of pair rule genes (PRGs) and segment polarity genes (SPGs) in a member of the closest related sister-group to the arthropods, the onychophorans. Our gene expression data analysis suggests that most of the onychophoran PRGs do not play a role in segmentation. One possible exception is the even-skipped (eve) gene that is expressed in the posterior end of the onychophoran where new segments are likely patterned, and is also expressed in segmentation-gene typical transverse stripes in at least a number of newly formed segments. Other onychophoran PRGs such as runt (run), hairy/Hes (h/Hes) and odd-skipped (odd) do not appear to have a function in segmentation at all. Onychophoran PRGs that act low in the segmentation gene cascade in insects, however, are potentially involved in segment-patterning. Most obvious is that from the expression of the pairberry (pby) gene ortholog that is expressed in a typical SPG-pattern. Since this result suggested possible conservation of the SPG-network we further investigated SPGs (and associated factors) such as Notum in the onychophoran. We find that the expression patterns of SPGs in arthropods and the onychophoran are highly conserved, suggesting a conserved SPG-network in these two clades, and indeed also in an annelid. This may suggest that the common ancestor of lophotrochozoans and ecdysozoans was already segmented utilising the same SPG-network, or that the SPG-network was recruited independently in annelids and onychophorans/arthropods.

  19. Transcriptional regulation of WNT2B based on the balance of Hedgehog, Notch, BMP and WNT signals.

    PubMed

    Katoh, Masuko; Katoh, Masaru

    2009-05-01

    We cloned and characterized human WNT2B in 1996, and then others cloned and characterized mouse, chicken, and zebrafish WNT2B orthologs. WNT2B is expressed in several types of human cancer, such as basal cell carcinoma, gastric cancer, breast cancer, head/neck squamous cell carcinoma, cervical cancer and leukemia. WNT2B is one of canonical WNTs transducing signals through Frizzled (FZD) and LRP5/LRP6 receptors to beta-catenin-TCF/LEF signaling cascade. Here, refined integrative genomic analyses on WNT2B orthologs were carried out to elucidate its transcriptional mechanisms. GLI-, double FOX-, HES/HEY-, bHLH-, and Sp1-binding sites within mammalian WNT2B promoter were well conserved. Because GLI1, FOXA2, FOXC2, FOXE1, FOXF1 and FOXL1 are direct target genes of Hedgehog-GLI2 signaling cascade, Hedgehog signals should induce WNT2B upregulation through GLI family members as well as FOX family members. Notch, BMP and Hedgehog signals inhibit WNT2B expression via HES/HEY-binding to N-box, whereas BMP and WNT signals inhibit bHLH transcription factor-induced WNT2B expression via ID1, ID2, ID3, MSX1 or MSX2. Together these facts indicate that Hedgehog signals and bHLH transcription factors are involved in WNT2B upregulation, which is counteracted by BMP, WNT and Notch signals. Mesenchymal BMP induces IHH expression in gastrointestinal epithelial cells, and then epithelial Hedgehog induces WNT2B and BMP4 expression in mesenchymal cells. NF-kappaB signals induce SHH upregulation, and WNT2B is upregulated in inflammatory bowel disease (IBD). BMP-IHH and inflammation-SHH signaling loops are involved in WNT2B up-regulation during embryogenesis, adult tissue homeostasis, and carcinogenesis.

  20. A minimal nitrogen fixation gene cluster from Paenibacillus sp. WLY78 enables expression of active nitrogenase in Escherichia coli.

    PubMed

    Wang, Liying; Zhang, Lihong; Liu, Zhanzhi; Liu, Zhangzhi; Zhao, Dehua; Liu, Xiaomeng; Zhang, Bo; Xie, Jianbo; Hong, Yuanyuan; Li, Pengfei; Chen, Sanfeng; Dixon, Ray; Li, Jilun

    2013-01-01

    Most biological nitrogen fixation is catalyzed by molybdenum-dependent nitrogenase, an enzyme complex comprising two component proteins that contains three different metalloclusters. Diazotrophs contain a common core of nitrogen fixation nif genes that encode the structural subunits of the enzyme and components required to synthesize the metalloclusters. However, the complement of nif genes required to enable diazotrophic growth varies significantly amongst nitrogen fixing bacteria and archaea. In this study, we identified a minimal nif gene cluster consisting of nine nif genes in the genome of Paenibacillus sp. WLY78, a gram-positive, facultative anaerobe isolated from the rhizosphere of bamboo. We demonstrate that the nif genes in this organism are organized as an operon comprising nifB, nifH, nifD, nifK, nifE, nifN, nifX, hesA and nifV and that the nif cluster is under the control of a σ(70) (σ(A))-dependent promoter located upstream of nifB. To investigate genetic requirements for diazotrophy, we transferred the Paenibacillus nif cluster to Escherichia coli. The minimal nif gene cluster enables synthesis of catalytically active nitrogenase in this host, when expressed either from the native nifB promoter or from the T7 promoter. Deletion analysis indicates that in addition to the core nif genes, hesA plays an important role in nitrogen fixation and is responsive to the availability of molybdenum. Whereas nif transcription in Paenibacillus is regulated in response to nitrogen availability and by the external oxygen concentration, transcription from the nifB promoter is constitutive in E. coli, indicating that negative regulation of nif transcription is bypassed in the heterologous host. This study demonstrates the potential for engineering nitrogen fixation in a non-nitrogen fixing organism with a minimum set of nine nif genes.

  1. Development and validation of risk prediction model for venous thromboembolism in postpartum women: multinational cohort study

    PubMed Central

    Sultan, Alyshah Abdul; West, Joe; Grainge, Matthew J; Riley, Richard D; Tata, Laila J; Stephansson, Olof; Fleming, Kate M; Nelson-Piercy, Catherine; Ludvigsson, Jonas F

    2016-01-01

    Objective To develop and validate a risk prediction model for venous thromboembolism in the first six weeks after delivery (early postpartum). Design Cohort study. Setting Records from England based Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and data from Sweden based registry. Participants All pregnant women registered with CPRD-HES linked data between 1997 and 2014 and Swedish medical birth registry between 2005 and 2011 with postpartum follow-up. Main outcome measure Multivariable logistic regression analysis was used to develop a risk prediction model for postpartum venous thromboembolism based on the English data, which was externally validated in the Swedish data. Results 433 353 deliveries were identified in the English cohort and 662 387 in the Swedish cohort. The absolute rate of venous thromboembolism was 7.2 per 10 000 deliveries in the English cohort and 7.9 per 10 000 in the Swedish cohort. Emergency caesarean delivery, stillbirth, varicose veins, pre-eclampsia/eclampsia, postpartum infection, and comorbidities were the strongest predictors of venous thromboembolism in the final multivariable model. Discrimination of the model was similar in both cohorts, with a C statistic above 0.70, with excellent calibration of observed and predicted risks. The model identified more venous thromboembolism events than the existing national English (sensitivity 68% v 63%) and Swedish guidelines (30% v 21%) at similar thresholds. Conclusion A new prediction model that quantifies absolute risk of postpartum venous thromboembolism has been developed and externally validated. It is based on clinical variables that are available in many developed countries at the point of delivery and could serve as the basis for real time decisions on obstetric thromboprophylaxis. PMID:27919934

  2. Proteomic Analyses Reveal Common Promiscuous Patterns of Cell Surface Proteins on Human Embryonic Stem Cells and Sperms

    PubMed Central

    Gu, Bin; Zhang, Jiarong; Wu, Ying; Zhang, Xinzong; Tan, Zhou; Lin, Yuanji; Huang, Xiao; Chen, Liangbiao; Yao, Kangshou; Zhang, Ming

    2011-01-01

    Background It has long been proposed that early embryos and reproductive organs exhibit similar gene expression profiles. However, whether this similarity is propagated to the protein level remains largely unknown. We have previously characterised the promiscuous expression pattern of cell surface proteins on mouse embryonic stem (mES) cells. As cell surface proteins also play critical functions in human embryonic stem (hES) cells and germ cells, it is important to reveal whether a promiscuous pattern of cell surface proteins also exists for these cells. Methods and Principal Findings Surface proteins of hES cells and human mature sperms (hSperms) were purified by biotin labelling and subjected to proteomic analyses. More than 1000 transmembrane or secreted cell surface proteins were identified on the two cell types, respectively. Proteins from both cell types covered a large variety of functional categories including signal transduction, adhesion and transporting. Moreover, both cell types promiscuously expressed a wide variety of tissue specific surface proteins, and some surface proteins were heterogeneously expressed. Conclusions/Significance Our findings indicate that the promiscuous expression of functional and tissue specific cell surface proteins may be a common pattern in embryonic stem cells and germ cells. The conservation of gene expression patterns between early embryonic cells and reproductive cells is propagated to the protein level. These results have deep implications for the cell surface signature characterisation of pluripotent stem cells and germ cells and may lead the way to a new area of study, i.e., the functional significance of promiscuous gene expression in pluripotent and germ cells. PMID:21559292

  3. Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut.

    PubMed

    Obieglo, Katja; Feng, Xiaogang; Bollampalli, Vishnu Priya; Dellacasa-Lindberg, Isabel; Classon, Cajsa; Österblad, Markus; Helmby, Helena; Hewitson, James P; Maizels, Rick M; Gigliotti Rothfuchs, Antonio; Nylén, Susanne

    2016-03-01

    Helminth infections have been suggested to impair the development and outcome of Th1 responses to vaccines and intracellular microorganisms. However, there are limited data regarding the ability of intestinal nematodes to modulate Th1 responses at sites distal to the gut. In this study, we have investigated the effect of the intestinal nematode Heligmosomoides polygyrus bakeri on Th1 responses to Mycobacterium bovis bacillus Calmette-Guérin (BCG). We found that H. polygyrus infection localized to the gut can mute BCG-specific CD4(+) T cell priming in both the spleen and skin-draining lymph nodes. Furthermore, H. polygyrus infection reduced the magnitude of delayed-type hypersensitivity (DTH) to PPD in the skin. Consequently, H. polygyrus-infected mice challenged with BCG had a higher mycobacterial load in the liver compared with worm-free mice. The excretory-secretory product from H. polygyrus (HES) was found to dampen IFN-γ production by mycobacteria-specific CD4(+) T cells. This inhibition was dependent on the TGF-βR signaling activity of HES, suggesting that TGF-β signaling plays a role in the impaired Th1 responses observed coinfection with worms. Similar to results with mycobacteria, H. polygyrus-infected mice displayed an increase in skin parasite load upon secondary infection with Leishmania major as well as a reduction in DTH responses to Leishmania Ag. We show that a nematode confined to the gut can mute T cell responses to mycobacteria and impair control of secondary infections distal to the gut. The ability of intestinal helminths to reduce DTH responses may have clinical implications for the use of skin test-based diagnosis of microbial infections.

  4. Transmitted HIV Type 1 drug resistance and Non-B subtypes prevalence among seroconverters and newly diagnosed patients from 1992 to 2005 in Italy.

    PubMed

    Riva, Chiara; Lai, Alessia; Caramma, Ilaria; Corvasce, Stefano; Violin, Michela; Dehò, Lorenzo; Prati, Francesca; Rossi, Cristina; Colombo, Maria Chiara; Capetti, Amedeo; Franzetti, Marco; Rossini, Valeria; Tambussi, Giuseppe; Ciccozzi, Massimo; Suligoi, Barbara; Mussini, Cristina; Rezza, Giovanni; Balotta, Claudia

    2010-01-01

    The patterns of transmitted drug-resistant (TDR) HIV-1 variants, non-B subtype spread, and epidemiological trends were evaluated either in seroconverters or in newly diagnosed individuals in Italy over a 13-year period. We analyzed 119 seroconverters, enrolled from 1992 to 2003 for the CASCADE study, and 271 newly diagnosed individuals of the SPREAD study (2002-2005), of whom 42 had a known seroconversion date. Overall, TDR was 15.1% in the CASCADE and 12.2% in the SPREAD study. In the 1992-2003 period, men having sex with men (MSMs) and heterosexuals (HEs) were 48.7% and 36.8%, respectively; TDR was found to be higher in MSMs compared to HEs (78.9% vs. 21%, p = 0.006). The same groups were 39.1% and 53.3% in the SPREAD study; however, no association was detected between modality of infection and TDR. Overall, 9.2% and 22.1% of individuals harbored a non-B clade virus in the CASCADE and SPREAD study, respectively. As evidence of onward transmission, 40% (24/60) of non-B variants were carried by European individuals in the latter study; among these patients the F1 subtype was highly prevalent (p = 0.00001). One of every eight patients who received a diagnosis of HIV-1 in recent years harbored a resistant variant, reinforcing the arguments for baseline resistance testing to customize first-line therapy in newly infected individuals. The spread of non-B clades may act as a dilution factor of TDR concealing the proportion of TDR in seroconverters and MSMs.

  5. Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells.

    PubMed

    Cechin, Sirlene; Alvarez-Cubela, Silvia; Giraldo, Jaime A; Molano, Ruth D; Villate, Susana; Ricordi, Camillo; Pileggi, Antonello; Inverardi, Luca; Fraker, Christopher A; Domínguez-Bendala, Juan

    2014-03-01

    The possibility of using human embryonic stem (hES) cell-derived β cells as an alternative to cadaveric islets for the treatment of type 1 diabetes is now widely acknowledged. However, current differentiation methods consistently fail to generate meaningful numbers of mature, functional β cells. In order to address this issue, we set out to explore the role of oxygen modulation in the maturation of pancreatic progenitor (PP) cells differentiated from hES cells. We have previously determined that oxygenation is a powerful driver of murine PP differentiation along the endocrine lineage of the pancreas. We hypothesized that targeting physiological oxygen partial pressure (pO2) levels seen in mature islets would help the differentiation of PP cells along the β-cell lineage. This hypothesis was tested both in vivo (by exposing PP-transplanted immunodeficient mice to a daily hyperbaric oxygen regimen) and in vitro (by allowing PP cells to mature in a perfluorocarbon-based culture device designed to carefully adjust pO2 to a desired range). Our results show that oxygen modulation does indeed contribute to enhanced maturation of PP cells, as evidenced by improved engraftment, segregation of α and β cells, body weight maintenance, and rate of diabetes reversal in vivo, and by elevated expression of pancreatic endocrine makers, β-cell differentiation yield, and insulin production in vitro. Our studies confirm the importance of oxygen modulation as a key variable to consider in the design of β-cell differentiation protocols and open the door to future strategies for the transplantation of fully mature β cells.

  6. Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitors Aid in Functional Recovery of Sensory Pathways following Contusive Spinal Cord Injury

    PubMed Central

    All, Angelo H.; Bazley, Faith A.; Gupta, Siddharth; Pashai, Nikta; Hu, Charles; Pourmorteza, Amir; Kerr, Candace

    2012-01-01

    Background Transplantations of human stem cell derivatives have been widely investigated in rodent models for the potential restoration of function of neural pathways after spinal cord injury (SCI). Studies have already demonstrated cells survival following transplantation in SCI. We sought to evaluate survival and potential therapeutic effects of transplanted human embryonic stem (hES) cell-derived oligodendrocyte progenitor cells (OPCs) in a contusive injury in rats. Bioluminescence imaging was utilized to verify survivability of cells up to 4 weeks, and somatosensory evoked potential (SSEPs) were recorded at the cortex to monitor function of sensory pathways throughout the 6-week recovery period. Principal Findings hES cells were transduced with the firefly luciferase gene and differentiated into OPCs. OPCs were transplanted into the lesion epicenter of rat spinal cords 2 hours after inducing a moderate contusive SCI. The hES-treatment group showed improved SSEPs, including increased amplitude and decreased latencies, compared to the control group. The bioluminescence of transplanted OPCs decreased by 97% in the injured spinal cord compared to only 80% when injected into an uninjured spinal cord. Bioluminescence increased in both experimental groups such that by week 3, no statistical difference was detected, signifying that the cells survived and proliferated independent of injury. Post-mortem histology of the spinal cords showed integration of human cells expressing mature oligodendrocyte markers and myelin basic protein without the expression of markers for astrocytes (GFAP) or pluripotent cells (OCT4). Conclusions hES-derived OPCs transplanted 2 hours after contusive SCI survive and differentiate into OLs that produce MBP. Treated rats demonstrated functional improvements in SSEP amplitudes and latencies compared to controls as early as 1 week post-injury. Finally, the hostile injury microenvironment at 2 hours post-injury initially caused increased cell

  7. Testing of heat exchangers in membrane oxygenators using air pressure.

    PubMed

    Hamilton, Carole; Stein, Jutta; Seidler, Rainer; Kind, Robert; Beck, Karin; Tosok, Jürgen; Upterfofel, Jörg

    2006-03-01

    All heat exchangers (HE) in membrane oxygenators are tested by the manufacturer for water leaks during the production phase. However, for safety reasons, it is highly recommended that HEs be tested again before clinical use. The most common method is to attach the heater-cooler to the HE and allow the water to recirculate for at least 10 min, during which time a water leak should be evident. To improve the detection of water leaks, a test was devised using a pressure manometer with an integrated bulb used to pressurize the HE with air. The cardiopulmonary bypass system is set up as per protocol. A pressure manometer adapted to a 1/2" tubing is connected to the water inlet side of the oxygenator. The water outlet side is blocked with a short piece of 1/2" deadend tubing. The HE is pressurized with 250 mmHg for at least 30 sec and observed for any drop. Over the last 2 years, only one oxygenator has been detected with a water leak in which the air-method leaktest was performed. This unit was sent back to the manufacturer who confirmed the failure. Even though the incidence of water leaks is very low, it does occur and it is, therefore, important that all HEs are tested before they are used clinically. This method of using a pressure manometer offers many advantages, as the HE can be tested outside of the operating room (OR), allowing earlier testing of the oxygenator, no water contact is necessary, and it is simple, easy and quick to perform.

  8. Hawaii demand-side management resource assessment. Final report: DSM opportunity report

    SciTech Connect

    1995-08-01

    The Hawaii Demand-Side Management Resource Assessment was the fourth of seven projects in the Hawaii Energy Strategy (HES) program. HES was designed by the Department of Business, Economic Development, and Tourism (DBEDT) to produce an integrated energy strategy for the State of Hawaii. The purpose of Project 4 was to develop a comprehensive assessment of Hawaii`s demand-side management (DSM) resources. To meet this objective, the project was divided into two phases. The first phase included development of a DSM technology database and the identification of Hawaii commercial building characteristics through on-site audits. These Phase 1 products were then used in Phase 2 to identify expected energy impacts from DSM measures in typical residential and commercial buildings in Hawaii. The building energy simulation model DOE-2.1E was utilized to identify the DSM energy impacts. More detailed information on the typical buildings and the DOE-2.1E modeling effort is available in Reference Volume 1, ``Building Prototype Analysis``. In addition to the DOE-2.1E analysis, estimates of residential and commercial sector gas and electric DSM potential for the four counties of Honolulu, Hawaii, Maui, and Kauai through 2014 were forecasted by the new DBEDT DSM Assessment Model. Results from DBEDTs energy forecasting model, ENERGY 2020, were linked with results from DOE-2.1E building energy simulation runs and estimates of DSM measure impacts, costs, lifetime, and anticipated market penetration rates in the DBEDT DSM Model. Through its algorithms, estimates of DSM potential for each forecast year were developed. Using the load shape information from the DOE-2.1E simulation runs, estimates of electric peak demand impacts were developed. 10 figs., 55 tabs.

  9. Effects of economic status and education level on the height and weight of community adolescents in Nepal.

    PubMed

    Joshi, Nira; Rikimaru, Toru; Pandey, Sharada

    2005-08-01

    There is scarce information on the relative importance of socio-economic factors in determining the adolescent anthropometric measurements. The objective of this study was to examine the effects of economic status, education level, and food consumption on the height and weight of community adolescents in Nepal. The study was done in the communities of the Kathmandu Valley area in Nepal. All together 426 unmarried adolescent girls aged 14-19 y were selected. The adolescents were interviewed regarding socioeconomic background (education, occupation and property possessions) and frequency of foods consumption. Height and weight were determined and BMI was calculated. Z-scores of height-for-age and weight-for-age were calculated based on the WHO/NCHS standard to avoid bias by age. The adolescents participating in the survey were categorized into three groups using the various indicators of economic status: Low Economic Status (LES) group, Middle Economic Status (MES) group and High Economic Status (HES) group. The Z-scores of height and weight were significantly lower in the LES group than in the MES and HES groups (p<0.05). The Z-score of height was significantly increased with education level even under the condition of controlling economic level (p<0.05). Since the frequency of milk consumption was significantly related not only with height (p<0.05), but also with economic (chi2=31.6, df=4, p<0.001) and education levels (chi2=22.4, df=6, p<0.01), the increased height in the groups of the better economic status or the better education level was interpreted to be due to the outcome of the higher frequency of milk consumption. This study indicated that education was a more important factor affecting the height of the adolescents via improved food habits even under adverse economic conditions.

  10. United Kingdom National Ophthalmology Database Study: Diabetic Retinopathy; Report 1: prevalence of centre-involving diabetic macular oedema and other grades of maculopathy and retinopathy in hospital eye services

    PubMed Central

    Keenan, T D L; Johnston, R L; Donachie, P H J; Sparrow, J M; Stratton, I M; Scanlon, P

    2013-01-01

    Aims To report estimates of the prevalence of diabetic retinopathy (DR) and maculopathy grades for a large cohort of patients managed by the UK hospital eye service (HES). Methods Anonymised data were extracted from 30 UK NHS hospital trusts using a single ophthalmic electronic medical record (EMR) for the period from April 2000 to November 2010 to create the National Ophthalmology Database (NOD). From 2007, the EMR facilitated capture of a nationally agreed-upon standardised data set (DR Structured Assessment) relating to the presence or absence of clinical signs of DR and maculopathy. An algorithm in the software automatically calculated the Early Treatment of Diabetic Retinopathy Study grades of retinopathy and maculopathy. Results Between 2007 and 2010, 307 538 patients had data on the NOD, with 76 127 (24.8%) patients having been recorded as having diabetes. The proportion of patients with diabetes who had a structured assessment increased from 50.7% (2007) to 86.8% (2010). In each NHS year, 12.6–20.6% of eyes with structured assessments had no DR; 59.6–67.3% had non-proliferative DR; and 18.3–20.9% had active or regressed proliferative DR. Clinically significant macular oedema was present in 15.8–18.1% of eyes, and in 8.7–10.0% of eyes, this involved the central macula. Conclusion This study provides contemporary estimates of the prevalence of retinopathy and maculopathy grades in a large cohort of patients with diabetes managed by the UK HES. Centre-involving diabetic macular oedema, potentially amenable to anti-VEGF therapy, is present in the eyes of almost 10% of these patients. This information is useful for clinicians, health-care economists, and commissioners involved in planning and delivering diabetic eye services. PMID:24051410

  11. Lingo-1 shRNA and Notch signaling inhibitor DAPT promote differentiation of neural stem/progenitor cells into neurons.

    PubMed

    Wang, Jue; Ye, Zhizhong; Zheng, Shuhui; Chen, Luming; Wan, Yong; Deng, Yubin; Yang, Ruirui

    2016-03-01

    Determination of the exogenous factors that regulate differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes is an important step in the clinical therapy of spinal cord injury (SCI). The Notch pathway inhibits the differentiation of neural stem/progenitor cells and Lingo-1 is a strong negative regulator for myelination and axon growth. While Lingo-1 shRNA and N-[N-(3, 5-difluorophenacetyl)-1-alanyl]-S-Phenylglycinet-butylester (DAPT), a Notch pathway inhibitor, have been used separately to help repair SCI, the results have been unsatisfactory. Here we investigated and elucidated the preliminary mechanism for the effect of Lingo-1 shRNA and DAPT on neural stem/progenitor cells differentiation. We found that neural stem/progenitor cells from E14 rat embryos expressed Nestin, Sox-2 and Lingo-1, and we optimized the transduction of neural stem/progenitor cells using lentiviral vectors encoding Lingo-1 shRNA. The addition of DAPT decreased the expression of Notch intracellular domain (NICD) as well as the downstream genes Hes1 and Hes5. Expression of NeuN, CNPase and GFAP in DAPT treated cells and expression of NeuN in Lingo-1 shRNA treated cells confirmed differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes. These results revealed that while Lingo-1 shRNA and Notch signaling inhibitor DAPT both promoted differentiation of neural stem cells into neurons, only DAPT was capable of driving neural stem/progenitor cells differentiation into oligodendrocytes and astrocytes. Since we were able to show that both Lingo-1 shRNA and DAPT could drive neural stem/progenitor cells differentiation, our data might aid the development of more effective SCI therapies using Lingo-1 shRNA and DAPT.

  12. [Knockdown of RUNX3 inhibits hypoxia-induced endothelial-to-mesenchymal transition of human cardiac microvascular endothelial cells].

    PubMed

    Liu, Yanhua; Li, Bingong; Wang, Yuqin; Wang, Delong; Zou, Jin; Ke, Xuan; Hao, Yanqin

    2016-12-01

    Objective To investigate the effects of Runt-related transcription factor 3 (RUNX3) knockdown on hypoxia-induced endothelial-to-mesenchymal transition (EndoMT) of human cardiac microvascular endothelial cells (HCMECs), and elucidate the underlying molecular mechanism. Methods HCMECs were cultured in hypoxic conditions and infected with RUNX3-RNAi lentivirus to knock-down the expression of RUNX3. Reverse transcription PCR was performed to detect the mRNA expressions of RUNX3 and EndoMT related genes such as CD31, vascular endothelial cadherin (VE-cadherin), α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1); Western blotting was used to determine the protein expressions of RUNX3, CD31, α-SMA and another molecules involved in EndoMT; and immunofluorescence cytochemistry was applied to observe the colocalization of CD31 and α-SMA. Results Hypoxia induced the transition of HCMECs to mesenchymal cells. Hypoxia up-regulated the expression of TGF-β2, Smad2/3, phosphorylation of Smad2/3 (p-Smad2/3), Notch-1, Hes1, and Hey1; knockdown of RUNX3 down-regulated the levels of Smad2/3, p-Smad2/3, Hes1, and Hey1 to different extents, and raised the levels of TGF-β2 and Notch-1. Conclusion Knockdown of RUNX3 in HCMECs attenuates hypoxia-induced EndoMT via partially inhibiting TGF-β and Notch signaling pathway.

  13. Arsenic inhibits stem cell differentiation by altering the interplay between the Wnt3a and Notch signaling pathways

    PubMed Central

    Bain, Lisa J.; Liu, Jui-Tung; League, Ryan E.

    2016-01-01

    Millions of people are exposed to arsenic through their drinking water and food, but the mechanisms by which it impacts embryonic development are not well understood. Arsenic exposure during embryogenesis is associated with neurodevelopmental effects, reduced weight gain, and altered locomotor activity, and in vitro data indicates that arsenic exposure inhibits stem cell differentiation. This study investigated whether arsenic disrupted the Wnt3a signaling pathway, critical in the formation of myotubes and neurons, during the differentiation in P19 mouse embryonic stem cells. Cells were exposed to 0, 0.1, or 0.5 μM arsenite, with or without exogenous Wnt3a, for up to 9 days of differentiation. Arsenic exposure alone inhibits the differentiation of stem cells into neurons and skeletal myotubes, and reduces the expression of both β-catenin and GSK3β mRNA to ~55% of control levels. Co-culture of the arsenic-exposed cells with exogenous Wnt3a rescues the morphological phenotype, but does not alter transcript, protein, or phosphorylation status of GSK3β or β-catenin. However, arsenic exposure maintains high levels of Hes5 and decreases the expression of MASH1 by 2.2-fold, which are anti- and pro-myogenic and neurogenic genes, respectively, in the Notch signaling pathway. While rescue with exogenous Wnt3a reduced Hes5 levels, MASH1 levels stay repressed. Thus, while Wnt3a can partially rescue the inhibition of differentiation from arsenic, it does so by also modulating Notch target genes rather than only working through the canonical Wnt signaling pathway. These results indicate that arsenic alters the interplay between multiple signaling pathways, leading to reduced stem cell differentiation. PMID:27158593

  14. Changing nuclear landscape and unique PML structures during early epigenetic transitions of human embryonic stem cells.

    PubMed

    Butler, John T; Hall, Lisa L; Smith, Kelly P; Lawrence, Jeanne B

    2009-07-01

    The complex nuclear structure of somatic cells is important to epigenomic regulation, yet little is known about nuclear organization of human embryonic stem cells (hESC). Here we surveyed several nuclear structures in pluripotent and transitioning hESC. Observations of centromeres, telomeres, SC35 speckles, Cajal Bodies, lamin A/C and emerin, nuclear shape and size demonstrate a very different "nuclear landscape" in hESC. This landscape is remodeled during a brief transitional window, concomitant with or just prior to differentiation onset. Notably, hESC initially contain abundant signal for spliceosome assembly factor, SC35, but lack discrete SC35 domains; these form as cells begin to specialize, likely reflecting cell-type specific genomic organization. Concomitantly, nuclear size increases and shape changes as lamin A/C and emerin incorporate into the lamina. During this brief window, hESC exhibit dramatically different PML-defined structures, which in somatic cells are linked to gene regulation and cancer. Unlike the numerous, spherical somatic PML bodies, hES cells often display approximately 1-3 large PML structures of two morphological types: long linear "rods" or elaborate "rosettes", which lack substantial SUMO-1, Daxx, and Sp100. These occur primarily between Day 0-2 of differentiation and become rare thereafter. PML rods may be "taut" between other structures, such as centromeres, but clearly show some relationship with the lamina, where PML often abuts or fills a "gap" in early lamin A/C staining. Findings demonstrate that pluripotent hES cells have a markedly different overall nuclear architecture, remodeling of which is linked to early epigenomic programming and involves formation of unique PML-defined structures.

  15. Vildagliptin vs sulfonylurea in Indian Muslim diabetes patients fasting during Ramadan

    PubMed Central

    Shete, Abhijit; Shaikh, Aheson; Nayeem, K Javeed; Rodrigues, Lily; Ali, Mohamed Sheikamunadeen Sadiq; Shah, Parag; Khanna, Rajiv; Majid, Sarfaraj; Rasheed, Sabeer A; Shaikh, Shehla; Rahman, Tawfiqur

    2013-01-01

    AIM: To compare the use of vildagliptin and sulfonylurea with or without metformin in Indian Muslim patients with type 2 diabetes mellitus, fasting during Ramadan. METHODS: This was a 4-wk, multicenter, non-interventional, open-label, observational study. Incidence of hypoglycemic events (HEs), adverse events, and changes in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, postprandial plasma glucose and body weight were measured pre- and post-Ramadan. RESULTS: Totally, 97 patients were recruited and all completed the study (vildagliptin group, n = 55; sulfonylurea group, n = 42). HEs were reported in low frequencies in both the vildagliptin and the sulfonylurea groups [0 vs 2 (4.8%) patients, respectively]. Interestingly, HbA1c reduced by -0.43% (-4.71 mmol/mol) in the vildagliptin group [8.75% (72.10 mmol/mol) to 8.32% (67.38 mmol/mol), P = 0.009] while in the sulfonylurea group there was a small increase by 0.01% [0.08 mmol/mol; 8.64% (70.92 mmol/mol) to 8.65% (71.00 mmol/mol), P = 0.958]. Higher percentage of vildagliptin-treated patients achieved HbA1c < 7.0% (< 53 mmol/mol) compared with sulfonylurea (16.4% vs 4.8%). Mean decrease in the body weight was 1.2 kg and 0.03 kg, respectively (P < 0.001). Both treatment groups were well tolerated during Ramadan. CONCLUSION: Vildagliptin is an attractive treatment option for Indian patients with type 2 diabetes mellitus who are fasting during Ramadan. PMID:24379927

  16. Use of multiresponse statistical techniques to optimize the separation of diosmin, hesperidin, diosmetin and hesperitin in different pharmaceutical preparations by high performance liquid chromatography with UV-DAD.

    PubMed

    Sammani, Mohamad Subhi; Clavijo, Sabrina; Portugal, Lindomar; Suárez, Ruth; Seddik, Hassan; Cerdà, Víctor

    2017-05-15

    A new method for the separation and determination of four flavonoids: hesperidin (HES), diosmin (DIO), hesperitin (HTIN), and diosmetin (DTIN) in pure form and pharmaceutical formulations has been developed by using high performance liquid chromatography (HPLC) with UV-DAD detection. Multivariate statistics (2(k) full factorial and Box Behnken Designs) has been used for the multiresponse optimization of the chromatographic separation, which was completed in 22min, and carried out on a symmetry® C18 column (250×3mm; 5µm) as stationary phase. Separation was conducted by gradient elution mode using a mixture of methanol, acetonitrile and water pH: 2.5 (CH3COOH), as mobile phase. Analytes were separated setting the column at 22°C, with a flow rate of 0.58mLmin(-1) and detected at 285nm. Under the optimized conditions, the flavonoids showed retention times of: 8.62, 11.53, 18.55 and 19.94min for HES, DIO, HTIN and DTIN, respectively. Limits of detection and quantification were <0.0156µgmL(-1) and <0.100µgmL(-1), respectively. Linearity was achieved with good correlation coefficients values (r(2)=0.999; n=5). Intra-day and inter-day precision were found to be less than 3.44% (n=7). Finally, the proposed method was successfully applied to determine the target flavonoids in pharmaceutical preparations with satisfactory recoveries (between 95.2% and 107.9%), demonstrating that should also find application in the quality control, as well as in the pharmacokinetic studies of these drugs.

  17. High-throughput screening for various classes of doping agents using a new 'dilute-and-shoot' liquid chromatography-tandem mass spectrometry multi-target approach.

    PubMed

    Guddat, S; Solymos, E; Orlovius, A; Thomas, A; Sigmund, G; Geyer, H; Thevis, M; Schänzer, W

    2011-01-01

    A new multi-target approach based on liquid chromatography--electrospray ionization tandem mass spectrometry (LC-(ESI)-MS/MS) is presented to screen for various classes of prohibited substances using direct injection of urine specimens. With a highly sensitive new generation hybrid mass spectrometer classic groups of drugs--for example, diuretics, beta2-agonists--stimulants and narcotics are detectable at concentration levels far below the required limits. Additionally, more challenging and various new target compounds could be implemented. Model compounds of stimulant conjugates were studied to investigate a possible screening without complex sample preparation. As a main achievement, the integration of the plasma volume expanders dextran and hydroxyethyl starch (HES), commonly analyzed in time-consuming, stand-alone procedures, is accomplished. To screen for relatively new prohibited compounds, a common metabolite of the selective androgen receptor modulator (SARMs) andarine, a metabolite of growth hormone releasing peptide (GHRP-2), and 5-amino-4-imidazolecarboxyamide ribonucleoside (AICAR) are analyzed. Following a completely new approach, conjugates of di(2-ethylhexyl) phthalate (DEHP) metabolites are monitored to detect abnormally high levels of plasticizers indicating for illicit blood transfusion. The assay was fully validated for qualitative purposes considering the parameters specificity, intra- (3.2-16.6%) and inter-day precision (0.4-19.9%) at low, medium and high concentration, robustness, limit of detection (1-70 ng/ml, dextran: 30 µg/ml, HES: 10 µg/ml) and ion suppression/enhancement effects. The analyses of post-administration and routine doping control samples demonstrates