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Sample records for essential downstream target

  1. The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

    Science.gov (United States)

    Hyde, B B; Liesa, M; Elorza, A A; Qiu, W; Haigh, S E; Richey, L; Mikkola, H K; Schlaeger, T M; Shirihai, O S

    2012-01-01

    The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-me−/− mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-me−/− erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-me−/− erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-me−/− erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. PMID:22240895

  2. Downstream targets of WRKY33

    DEFF Research Database (Denmark)

    Petersen, Klaus; Fiil, Berthe Katrine; Mundy, John

    2008-01-01

    . Transcriptome analysis of a wrky33 loss-of-function mutant identified a subset of defense-related genes as putative targets of WRKY33. These genes include PAD3 and CYP71A13, which encode cytochrome P450 monoxygenases required for synthesis of the antimicrobial phytoalexin camalexin. Chromatin...

  3. Targeting pathways downstream of KRAS in lung adenocarcinoma.

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    Zhu, Zehua; Golay, Hadrien G; Barbie, David A

    2014-08-01

    Oncogenic KRAS activation is responsible for the most common genetic subtype of lung cancer. Although many of the major downstream signaling pathways that KRAS engages have been defined, these discoveries have yet to translate into effective targeted therapy. Much of the current focus has been directed at inhibiting the activation of RAF/MAPK and PI3K/AKT signaling, but clinical trials combining multiple different agents that target these pathways have failed to show significant activity. In this article, we will discuss the evidence for RAF and PI3K as key downstream RAS effectors, as well as the RAL guanine exchange factor, which is equally essential for transformation. Furthermore, we will delineate alternative pathways, including cytokine activation and autophagy, which are co-opted by oncogenic RAS signaling and also represent attractive targets for therapy. Finally, we will present strategies for combining inhibitors of these downstream KRAS signaling pathways in a rational fashion, as multitargeted therapy will be required to achieve a cure.

  4. Targets downstream of Cdk8 in Dictyostelium development

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    Skelton Jason

    2011-01-01

    Full Text Available Abstract Background Cdk8 is a component of the mediator complex which facilitates transcription by RNA polymerase II and has been shown to play an important role in development of Dictyostelium discoideum. This eukaryote feeds as single cells but starvation triggers the formation of a multicellular organism in response to extracellular pulses of cAMP and the eventual generation of spores. Strains in which the gene encoding Cdk8 have been disrupted fail to form multicellular aggregates unless supplied with exogenous pulses of cAMP and later in development, cdk8- cells show a defect in spore production. Results Microarray analysis revealed that the cdk8- strain previously described (cdk8-HL contained genome duplications. Regeneration of the strain in a background lacking detectable gene duplication generated strains (cdk8-2 with identical defects in growth and early development, but a milder defect in spore generation, suggesting that the severity of this defect depends on the genetic background. The failure of cdk8- cells to aggregate unless rescued by exogenous pulses of cAMP is consistent with a failure to express the catalytic subunit of protein kinase A. However, overexpression of the gene encoding this protein was not sufficient to rescue the defect, suggesting that this is not the only important target for Cdk8 at this stage of development. Proteomic analysis revealed two potential targets for Cdk8 regulation, one regulated post-transcriptionally (4-hydroxyphenylpyruvate dioxygenase (HPD and one transcriptionally (short chain dehydrogenase/reductase (SDR1. Conclusions This analysis has confirmed the importance of Cdk8 at multiple stages of Dictyostelium development, although the severity of the defect in spore production depends on the genetic background. Potential targets of Cdk8-mediated gene regulation have been identified in Dictyostelium which will allow the mechanism of Cdk8 action and its role in development to be determined.

  5. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

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    Wang, Yelin [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Hu, Chen; Cheng, Jun [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Chen, Binquan [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Ke, Qinghong; Lv, Zhen; Wu, Jian [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Zhou, Yanfeng, E-mail: zyfhdj@yahoo.com [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China)

    2014-04-18

    Highlights: • MiR-145 expression is down-regulated in HCC tissues and inversely related with IRS1 levels. • MiR-145 directly targets IRS1 in HCC cells. • Restored expression of miR-145 suppressed HCC cell proliferation and growth. • MiR-145 induced IRS1 under-expression potentially reduced downstream AKT signaling. - Abstract: Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.

  6. Proteomics analysis of cellular imatinib targets and their candidate downstream effectors.

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    Breitkopf, Susanne B; Oppermann, Felix S; Keri, Gyorgy; Grammel, Markus; Daub, Henrik

    2010-11-05

    Inhibition of deregulated protein kinases by small molecule drugs has evolved into a major therapeutic strategy for the treatment of human malignancies. Knowledge about direct cellular targets of kinase-selective drugs and the identification of druggable downstream mediators of oncogenic signaling are relevant for both initial therapy selection and the nomination of alternative targets in case molecular resistance emerges. To address these issues, we performed a proof-of-concept proteomics study designed to monitor drug effects on the pharmacologically tractable subproteome isolated by affinity purification with immobilized, nonselective kinase inhibitors. We applied this strategy to chronic myeloid leukemia cells that express the transforming Bcr-Abl fusion kinase. We used SILAC to measure how cellular treatment with the Bcr-Abl inhibitor imatinib affects protein binding to a generic kinase inhibitor resin and further quantified site-specific phosphorylations on resin-retained proteins. Our integrated approach indicated additional imatinib target candidates, such as flavine adenine dinucleotide synthetase, as well as repressed phosphorylation events on downstream effectors not yet implicated in imatinib-regulated signaling. These included activity-regulating phosphorylations on the kinases Btk, Fer, and focal adhesion kinase, which may qualify them as alternative target candidates in Bcr-Abl-driven oncogenesis. Our approach is rather generic and may have various applications in kinase drug discovery.

  7. Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

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    Spinazzola, Janelle M.; Kunkel, Louis M.

    2016-01-01

    Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation. PMID:28670506

  8. Identification of downstream metastasis-associated target genes regulated by LSD1 in colon cancer cells.

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    Chen, Jiang; Ding, Jie; Wang, Ziwei; Zhu, Jian; Wang, Xuejian; Du, Jiyi

    2017-03-21

    This study aims to identify downstream target genes regulated by lysine-specific demethylase 1 (LSD1) in colon cancer cells and investigate the molecular mechanisms of LSD1 influencing invasion and metastasis of colon cancer. We obtained the expression changes of downstream target genes regulated by small-interfering RNA-LSD1 and LSD1-overexpression via gene expression profiling in two human colon cancer cell lines. An Affymetrix Human Transcriptome Array 2.0 was used to identify differentially expressed genes (DEGs). We screened out LSD1-target gene associated with proliferation, metastasis, and invasion from DEGs via Gene Ontology and Pathway Studio. Subsequently, four key genes (CABYR, FOXF2, TLE4, and CDH1) were computationally predicted as metastasis-related LSD1-target genes. ChIp-PCR was applied after RT-PCR and Western blot validations to detect the occupancy of LSD1-target gene promoter-bound LSD1. A total of 3633 DEGs were significantly upregulated, and 4642 DEGs were downregulated in LSD1-silenced SW620 cells. A total of 4047 DEGs and 4240 DEGs were upregulated and downregulated in LSD1-overexpressed HT-29 cells, respectively. RT-PCR and Western blot validated the microarray analysis results. ChIP assay results demonstrated that LSD1 might be negative regulators for target genes CABYR and CDH1. The expression level of LSD1 is negatively correlated with mono- and dimethylation of histone H3 lysine4(H3K4) at LSD1- target gene promoter region. No significant mono-methylation and dimethylation of H3 lysine9 methylation was detected at the promoter region of CABYR and CDH1. LSD1- depletion contributed to the upregulation of CABYR and CDH1 through enhancing the dimethylation of H3K4 at the LSD1-target genes promoter. LSD1- overexpression mediated the downregulation of CABYR and CDH1expression through decreasing the mono- and dimethylation of H3K4 at LSD1-target gene promoter in colon cancer cells. CABYR and CDH1 might be potential LSD1-target genes in colon

  9. Proliferating cell nuclear antigen (Pcna) as a direct downstream target gene of Hoxc8

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    Min, Hyehyun; Lee, Ji-Yeon; Bok, Jinwoong; Chung, Hyun Joo [Department of Anatomy, Embryology Laboratory, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Kim, Myoung Hee, E-mail: mhkim1@yuhs.ac [Department of Anatomy, Embryology Laboratory, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)

    2010-02-19

    Hoxc8 is a member of Hox family transcription factors that play crucial roles in spatiotemporal body patterning during embryogenesis. Hox proteins contain a conserved 61 amino acid homeodomain, which is responsible for recognition and binding of the proteins onto Hox-specific DNA binding motifs and regulates expression of their target genes. Previously, using proteome analysis, we identified Proliferating cell nuclear antigen (Pcna) as one of the putative target genes of Hoxc8. Here, we asked whether Hoxc8 regulates Pcna expression by directly binding to the regulatory sequence of Pcna. In mouse embryos at embryonic day 11.5, the expression pattern of Pcna was similar to that of Hoxc8 along the anteroposterior body axis. Moreover, Pcna transcript levels as well as cell proliferation rate were increased by overexpression of Hoxc8 in C3H10T1/2 mouse embryonic fibroblast cells. Characterization of 2.3 kb genomic sequence upstream of Pcna coding region revealed that the upstream sequence contains several Hox core binding sequences and one Hox-Pbx binding sequence. Direct binding of Hoxc8 proteins to the Pcna regulatory sequence was verified by chromatin immunoprecipitation assay. Taken together, our data suggest that Pcna is a direct downstream target of Hoxc8.

  10. Deregulation of c-Src tyrosine kinase and its downstream targets in pre-eclamptic placenta.

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    Irtegun, Sevgi; Akcora-Yıldız, Dilara; Pektanc, Gulsum; Karabulut, Cagla

    2017-08-01

    Pre-eclampsia is a serious pregnancy disorder characterized by the new onset of hypertension and proteinuria in the second trimester of pregnancy. The determination of a key signaling regulatory mechanism involved in placental functions is critical to understanding the pathogenesis of pre-eclampsia. The aim of this study was to examine the activity of c-Src and its downstream targets, extracellular signal-regulated kinase 1/2, p38 and Jun N-terminal kinase, as well as nuclear factor (NF)-ĸB in placental tissues collected from women with pre-eclampsia. Ten pre-eclamptic (PE) placentas and 10 control placentas were used in this study. The Western blot method was performed to evaluate the c-Src/ mitogen activated protein kinase/NF-ĸB signaling pathway in each group. c-Src phosphorylation at Tyr-416, used as a measure of c-Src activity, was significantly decreased in PE placentas relative to the control. Reduced c-Src activity resulted in the suppression of extracellular signal-regulated kinase 1/2 phosphorylation and a significant reduction in the phosphorylation of p38 and Jun N-terminal kinase in PE placentas. Moreover, IĸBα phosphorylation was significantly elevated, while NF-ĸB phosphorylation was suppressed in PE placentas. The c-Src/MAPK/NF-ĸB signaling pathway may contribute to the pathogenesis of pre-eclampsia. © 2017 Japan Society of Obstetrics and Gynecology.

  11. Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

    NARCIS (Netherlands)

    Kuijper, Arno; Groep, P. van der; Wall, E. van der; Diest, P.J. van

    2005-01-01

    INTRODUCTION Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance

  12. Targeting the Synthetic Essential Kinases of Breast Cancers

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    2016-05-01

    kinases in mitosis and tumorigenesis. Mol Cancer Res 2007, 5(1):1-10. 12. Kufer TA, Sillje HH, Korner R, Gruss OJ, Meraldi P, Nigg EA: Human TPX2 is...AWARD NUMBER: W81XWH-15-1-0027 TITLE: Targeting the synthetic essential kinases of breast cancers PRINCIPAL INVESTIGATOR: Jen-Tsan...Targeting the synthetic essential kinases of breast cancers 5b. GRANT NUMBER W81XWH-15-1-0027 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT

  13. Activated Ras alters lens and corneal development through induction of distinct downstream targets

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    Reneker Lixing

    2010-01-01

    results suggest that Ras activation a induces distinct sets of downstream targets in the lens and cornea resulting in distinct cellular responses and b is sufficient for initiation but not completion of lens fiber differentiation.

  14. Transcription Factors Expressed in Lateral Organ Boundaries: Identification of Downstream Targets

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    Springer, Patricia S

    2010-07-12

    The processes of lateral organ initiation and patterning are central to the generation of mature plant form. Characterization of the molecular mechanisms underlying these processes is essential to our understanding of plant development. Communication between the shoot apical meristem and initiating organ primordia is important both for functioning of the meristem and for proper organ patterning, and very little is known about this process. In particular, the boundary between meristem and leaf is emerging as a critical region that is important for SAM maintenance and regulation of organogenesis. The goal of this project was to characterize three boundary-expressed genes that encode predicted transcription factors. Specifically, we have studied LATERAL ORGAN BOUNDARIES (LOB), LATERAL ORGAN FUSION1 (LOF1), and LATERAL ORGAN FUSION2 (LOF2). LOB encodes the founding member of the LOB-DOMAIN (LBD) plant-specific DNA binding transcription factor family and LOF1 and LOF2 encode paralogous MYB-domain transcription factors. We characterized the genetic relationship between these three genes and other boundary and meristem genes. We also used an ectopic inducible expression system to identify direct targets of LOB.

  15. Serum uric acid and target organ damage in essential hypertension.

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    Ofori, Sandra N; Odia, Osaretin J

    2014-01-01

    Hypertension is a major risk factor for cardiovascular mortality, as it acts through its effects on target organs, such as the heart and kidneys. Hyperuricemia increases cardiovascular risk in patients with hypertension. To assess the relationship between serum uric acid and target organ damage (left ventricular hypertrophy and microalbuminuria) in untreated patients with essential hypertension. A cross-sectional study was carried out in 130 (85 females, 45 males) newly diagnosed, untreated patients with essential hypertension. Sixty-five healthy age- and sex-matched non-hypertensive individuals served as controls for comparison. Left ventricular hypertrophy was evaluated by cardiac ultrasound scan, and microalbuminuria was assessed in an early morning midstream urine sample by immunoturbidimetry. Blood samples were collected for assessing uric acid levels. Mean serum uric acid was significantly higher among the patients with hypertension (379.7±109.2 μmol/L) than in the controls (296.9±89.8 μmol/L; P<0.001), and the prevalence of hyperuricemia was 46.9% among the hypertensive patients and 16.9% among the controls (P<0.001). Among the hypertensive patients, microalbuminuria was present in 54.1% of those with hyperuricemia and in 24.6% of those with normal uric acid levels (P=0.001). Similarly, left ventricular hypertrophy was more common in the hypertensive patients with hyperuricemia (70.5% versus 42.0%, respectively; P=0.001). There was a significant linear relationship between mean uric acid levels and the number of target organ damage (none versus one versus two: P=0.012). These results indicate that serum uric acid is associated with target organ damage in patients with hypertension, even at the time of diagnosis; thus, it is a reliable marker of cardiovascular damage in our patient population.

  16. Serum uric acid and target organ damage in essential hypertension

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    Ofori SN

    2014-05-01

    Full Text Available Sandra N Ofori, Osaretin J OdiaDepartment of Internal Medicine, University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, NigeriaBackground: Hypertension is a major risk factor for cardiovascular mortality, as it acts through its effects on target organs, such as the heart and kidneys. Hyperuricemia increases cardiovascular risk in patients with hypertension.Objective: To assess the relationship between serum uric acid and target organ damage (left ventricular hypertrophy and microalbuminuria in untreated patients with essential hypertension.Patients and methods: A cross-sectional study was carried out in 130 (85 females, 45 males newly diagnosed, untreated patients with essential hypertension. Sixty-five healthy age- and sex-matched non-hypertensive individuals served as controls for comparison. Left ventricular hypertrophy was evaluated by cardiac ultrasound scan, and microalbuminuria was assessed in an early morning midstream urine sample by immunoturbidimetry. Blood samples were collected for assessing uric acid levels.Results: Mean serum uric acid was significantly higher among the patients with hypertension (379.7±109.2 µmol/L than in the controls (296.9±89.8 µmol/L; P<0.001, and the prevalence of hyperuricemia was 46.9% among the hypertensive patients and 16.9% among the controls (P<0.001. Among the hypertensive patients, microalbuminuria was present in 54.1% of those with hyperuricemia and in 24.6% of those with normal uric acid levels (P=0.001. Similarly, left ventricular hypertrophy was more common in the hypertensive patients with hyperuricemia (70.5% versus 42.0%, respectively; P=0.001. There was a significant linear relationship between mean uric acid levels and the number of target organ damage (none versus one versus two: P=0.012.Conclusion: These results indicate that serum uric acid is associated with target organ damage in patients with hypertension, even at the time of diagnosis; thus, it is a reliable

  17. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer

    DEFF Research Database (Denmark)

    Bracken, Adrian P; Pasini, Diego; Capra, Maria

    2003-01-01

    expression during embryonic development. Here we demonstrate that both EZH2 and EED are essential for the proliferation of both transformed and non-transformed human cells. In addition, the pRB-E2F pathway tightly regulates their expression and, consistent with this, we find that EZH2 is highly expressed...

  18. Basic helix-loop-helix transcription factor TCF21 is a downstream target of the male sex determining gene SRY.

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    Ramji K Bhandari

    Full Text Available The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex determining factor SRY as the basic-helix-loop-helix (bHLH transcription factor TCF21. SRY was found to bind to the Tcf21 promoter and activate gene expression. Mutagenesis of SRY/SOX9 response elements in the Tcf21 promoter eliminated the actions of SRY. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response elements in vivo during fetal rat testis development. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to induce precursor Sertoli cell differentiation. TCF21 and SRY had similar effects on the in vitro sex reversal gonadal cell transcriptomes. Therefore, SRY acts directly on the Tcf21 promoter to in part initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development.

  19. An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma.

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    Chang-Min Lee

    Full Text Available The downstream of kinase (DOK-1 is involved in the protein tyrosine kinase (PTK pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases.

  20. NF-kB activation and its downstream target genes expression after heavy ions exposure

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    Chishti, Arif Ali; Baumstark-Khan, Christa; Hellweg, Christine; Schmitz, Claudia; Koch, Kristina; Feles, Sebastian

    2016-07-01

    To enable long-term human space flight cellular radiation response to densely ionizing radiation needs to be better understood for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut. The biological effectiveness of accelerated heavy ions (which constitute the most important radiation type in space) with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern not only for space missions but also for new regimes of tumor radiotherapy. In the current research study, the contribution of NF-κB in response to space-relevant radiation qualities was determined by a NF-κB reporter cell line (HEK-pNF-κB-d2EGFP/Neo L2). The NF-κB dependent reporter gene expression (d2EGFP) after ionizing radiation (X-rays and heavy ions) exposure was evaluated by flow cytometry. Because of differences in the extent of NF-κB activation after X-irradiation and heavy ions exposure, it was expected that radiation quality (LET) might play an important role in the cellular radiation response. In addition, the biological effectiveness (RBE) of NF-κB activation and reduction of cellular survival was examined for heavy ions having a broad range of LET (˜0.3 - 9674 keV/µm). Furthermore, the effect of LET on NF-κB target gene expression was analyzed by real time reverse transcriptase quantitative PCR (RT-qPCR). In this study it was proven that NF-κB activation and NF-κB dependent gene expression comprises an early step in cellular radiation response. Taken together, this study clearly demonstrates that NF-κB activation and NF-κB-dependent gene expression by heavy ions are highest in the LET range of ˜50-200 keV/μupm. The up-regulated chemokines and cytokines (CXCL1, CXCL2, CXCL10, IL-8 and TNF) might be important for cell-cell communication among hit as well as unhit cells (bystander effect). The results obtained suggest the NF-κB pathway to be a

  1. Downstream targets of altered sphingolipid metabolism in response to inhibition of ENOX2 by phenoxodiol.

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    De Luca, Thomas; Bosneaga, Elena; Morré, Dorothy M; Morré, D James

    2008-01-01

    Phenoxodiol, an ENOX2 inhibitor, alters cytosolic NADH levels to initiate a regulatory cascade linking sphingolipid metabolism and the PI3K/Akt pathway to programmed cell death. Specifically, the pyridine nucleotide products of plasma membrane redox, NAD+ and NADH, directly modulate in a recriprocal manner two key plasma membrane enzymes. NADH stimulation of sphingomyelinase and NADH inhibition of sphingosine kinase potentially lead to G1 arrest (increase in ceramide) and apoptosis (loss of sphingosine-1-phosphate). The findings link plasma membrane electron transport and the anticancer action of several clinically-relevant anticancer agents targeted to ENOX2 such as phenoxodiol. Growth inhibition by phenoxodiol is unaffected by inhibitors of protein or mRNA synthesis. Findings with okadiaic acid, an inhibitor of serine/threonine phosphatases, suggest that hyperphosphorylation of intracellular substrates does not affect the action of phenoxodiol on ENOX2. Our findings and those of others are consistent with operation of the FAS signaling pathway of apoptosis and its suppression by sphingosine-1-phosphate. The prevailing hypothesis is that products of Akt activation, c-FLIP and XIAP, which exhibit anticaspase activities to block FAS signaling when sphingosine-1-phospate is elevated, are down regulated to permit apoptosis when sphingosine-1-phosphate is decreased by inhibition of sphingosine kinase under conditions of elevated cytosolic NADH associated with anticancer drug inhibition of ENOX2.

  2. Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim.

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    Ren, Xiaoxia; Zhao, Wenjing; Du, Yongxing; Zhang, Taiping; You, Lei; Zhao, Yupei

    2016-12-01

    Gemcitabine is a commonly used chemotherapy drug in pancreatic cancer. The function of activator protein 1 (AP-1) is cell-specific, and its function depends on the expression of other complex members. In the present study, we added gemcitabine to the media of Panc-1 and SW1990 cells at clinically achieved concentrations (10 µM). Compared with constitutive c-Fos expression, c-Jun expression increased in a dose-dependent manner upon gemcitabine treatment. c-Jun overexpression increased gemcitabine-induced apoptosis through Bim activation, while cell apoptosis and Bim expression decreased following c-Jun knockdown. Furthermore, gemcitabine-induced apoptosis and Bim levels decreased when c-Jun phosphorylation was blocked by SP600125. Our findings suggest that c-Jun, which is a member of the AP-1 complex, functions in gemcitabine-induced apoptosis by regulating its downstream target Bim in pancreatic cancer cells.

  3. Wingless effects mesoderm patterning and ectoderm segmentation events via induction of its downstream target sloppy paired.

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    Lee, H H; Frasch, M

    2000-12-01

    Inactivation of either the secreted protein Wingless (Wg) or the forkhead domain transcription factor Sloppy Paired (Slp) has been shown to produce similar effects in the developing Drosophila embryo. In the ectoderm, both gene products are required for the formation of the segmental portions marked by naked cuticle. In the mesoderm, Wg and Slp activities are crucial for the suppression of bagpipe (bap), and hence visceral mesoderm formation, and the promotion of somatic muscle and heart formation within the anterior portion of each parasegment. In this report, we show that, during these developmental processes, wg and slp act in a common pathway in which slp serves as a direct target of Wg signals that mediates Wg effects in both germ layers. We present evidence that the induction of slp by Wg involves binding of the Wg effector Pangolin (Drosophila Lef-1/TCF) to multiple binding sites within a Wg-responsive enhancer that is located in 5' flanking regions of the slp1 gene. Based upon our genetic and molecular analysis, we conclude that Wg signaling induces striped expression of Slp in the mesoderm. Mesodermal Slp is then sufficient to abrogate the induction of bagpipe by Dpp/Tinman, which explains the periodic arrangement of trunk visceral mesoderm primordia in wild type embryos. Conversely, mesodermal Slp is positively required, although not sufficient, for the specification of somatic muscle and heart progenitors. We propose that Wg-induced slp provides striped mesodermal domains with the competence to respond to subsequent slp-independent Wg signals that induce somatic muscle and heart progenitors. We also propose that in wg-expressing ectodermal cells, slp is an integral component in an autocrine feedback loop of Wg signaling.

  4. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Wada, Takeyoshi; Asahi, Toru; Sawamura, Naoya

    2016-01-01

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.

  5. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Wada, Takeyoshi [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Asahi, Toru [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Sawamura, Naoya, E-mail: naoya.sawamura@gmail.com [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan)

    2016-08-26

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.

  6. Tungsten carbide-cobalt particles activate Nrf2 and its downstream target genes in JB6 cells possibly by ROS generation.

    Science.gov (United States)

    Zhang, Xing-Dong; Zhao, Jinshun; Bowman, Linda; Shi, Xianglin; Castranova, Vincent; Ding, Min

    2010-01-01

    Hard metal consisting of a mixture of tungsten carbide (WC) and metallic cobalt (Co) was evaluated as a possible carcinogen in humans by IARC in 2003. Studies have suggested that nuclear factor erythroid 2-related factor 2 (Nrf2) constitutes one of the chemical-sensing and transcription systems that play an essential role(s) in chemical toxicity, carcinogenesis, and pathological processes. To elucidate the mechanisms of health hazards of WC-Co, effects of nano-WC-Co particles on Nrf2 signaling pathway were investigated in the present study in a JB6 cell line. After a 5 h treatment with nano-WC-Co particles, Nrf2 was released from Keap1 in the cytoplasm and translocated into the nucleus. Enzymatic activities of Nrf2 target genes, including glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), increased at 24 and 48 h after the treatment. Studies using reactive oxygen species (ROS) sensitive dyes indicated that ROS were produced in nano-WC-Co particle-treated cells. Pretreatment of the cells with catalase, but not sodium formate, resulted in a significant inhibitory effect on nano-WC-Co particle-induced Nrf2 target gene activation. These findings suggest that activation of Nrf2 and its downstream genes may be initiated by ROS generation, and ROS may act as a major contributor in nano-WC-Co particle-induced adverse health effects.

  7. Clinical and in vitro analysis of Osteopontin as a prognostic indicator and unveil its potential downstream targets in bladder cancer

    Science.gov (United States)

    Wong, Janet P.C.; Wei, Ran; Lyu, Peng; Tong, Olivia L.H.; Zhang, Shu Dong; Wen, Qing; Yuen, Hiu Fung; El-Tanani, Mohamed; Kwok, Hang Fai

    2017-01-01

    Osteopontin (OPN) plays an important role in cancer progression, however its prognostic significance and its downstream factors are largely elusive. In this study, we have shown that expression of OPN was significantly higher in bladder cancer specimens with higher T-stage or tumor grades. In addition, a high level of OPN was significantly associated with poorer survival in two independent bladder cancer patient cohorts totaling 389 bladder cancer patients with available survival data. We further identified Matrix metallopeptidase 9 (MMP9) and S100 calcium-binding protein A8 (S100A8) were both downstream factors for OPN in bladder cancer specimens and bladder cancer cell lines. Expression of OPN was significantly positively associated with that of MMP9 and S100A8, while overexpression of OPN resulted in upregulation of MMP9 and S100A8, and knockdown of OPN showed consistent downregulation of MMP9 and S100A8 expression levels. Importantly, expression levels of both MMP9 and S100A8 were significantly associated with higher T-stage, higher tumor grade and a shorter survival time in the bladder cancer patients. Interestingly, OPN expression only predicted survival in MMP9-high, but not MMP9-low subgroups, and in S100A8-low but not S100A8-high subgroups. Our results suggest that OPN, MMP9 and S100A8 all play a significant role in bladder cancer progression and are potential prognostic markers and therapeutic targets in bladder cancer. The mechanistic link between these three genes and bladder cancer progression warrants further investigation. PMID:29209142

  8. Anoctamin 6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages

    Science.gov (United States)

    Ousingsawat, Jiraporn; Wanitchakool, Podchanart; Kmit, Arthur; Romao, Ana M.; Jantarajit, Walailak; Schreiber, Rainer; Kunzelmann, Karl

    2015-02-01

    Purinergic P2X7 receptors (P2X7R) are fundamental to innate immune response. In macrophages, transient stimulation of P2X7R activates several transport mechanisms and induces the scrambling of phospholipids with subsequent membrane blebbing and apoptosis. These processes support phagocytosis and subsequent killing of phagocytosed bacteria. Here we demonstrate that the stimulation of P2X7 receptors activates anoctamin 6 (ANO6, TMEM16F), a protein that functions as Ca2+ dependent phospholipid scramblase and Ca2+-activated Cl- channel. Inhibition or knockdown of ANO6 attenuates ATP-induced cell shrinkage, cell migration and phospholipid scrambling. In mouse macrophages, Ano6 produces large ion currents by stimulation of P2X7 receptors and contributes to ATP-induced membrane blebbing and apoptosis, which is largely reduced in macrophages from Ano6-/- mice. ANO6 supports bacterial phagocytosis and killing by mouse and human THP-1 macrophages. Our data demonstrate that anoctamin 6 is an essential component of the immune defense by macrophages.

  9. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    International Nuclear Information System (INIS)

    Zhang, Pengpeng; Shan, Tizhong; Liang, Xinrong; Deng, Changyan; Kuang, Shihuan

    2014-01-01

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor flox/flox mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor flox/flox mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function

  10. p300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer

    NARCIS (Netherlands)

    Vleugel, M.M.; Shvarts, D.; Wall, E. van der; Diest, P.J. van

    2006-01-01

    In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)–1a in breast cancer, especially the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition

  11. Transcription factors down-stream of Ras as molecular indicators for targeting malignancies with oncolytic herpes virus.

    Science.gov (United States)

    Esfandyari, Tuba; Tefferi, Ayalew; Szmidt, Anna; Alain, Tommy; Zwolak, Pawel; Lasho, Terra; Lee, Patrick W; Farassati, Faris

    2009-12-01

    Overactivation in Ras signaling has been under intensive study as the molecular basis for development of cancer. Such overactivation can occur in the presence or absence of mutations in Ras gene resulting in activation of a series of down-stream effectors such as transcription factors. Different studies have shown the activation of Ras down-stream effectors in non-Hodgkin lymphoma (NHL) although mutations in Ras are not prevalent in this malignancy. Since overactivation in Ras signaling also increases permissiveness of cancer cells to infection by oncolytic versions of herpes simplex virus (e.g. R3616), we were interested in evaluating the value of transcription factors down-stream of Ras as molecular indicators for permissiveness to herpes therapy. In order to accomplish this, and also to assess the permissiveness of lymphoma cells to infection with R3616, we used NHL cell lines Daudi, Jurkat, NC37, Raji, Ramos and ST486. Once the levels of phosphorylation (activation) of extracellular-signal regulated kinase (ERK, a Ras effector pathway) and its down-stream transcription factor ELK were evaluated, Raji and NC37 showed a significant increase in the phosphorylation levels of both molecules while ATF2 (another transcription factor down-stream of p38-kinase pathway) seemed to be activated in all studied cells. Raji and NC37 cells were also most permissive cells to infection with R3616 while their permissiveness was decreased upon treatment of cells with an inhibitor of ELK-DNA binding portraying ERK/ELK as a suitable predictive indicator for selection of cancer cells with increased sensitivity to R3616. This study, therefore, for the first time documents permissiveness of lymphoma cells to oncolytic herpes viruses and introduces ELK as a suitable factor for predicting tumor susceptibility to these novel anticancer agents.

  12. Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Pengpeng [Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Shan, Tizhong; Liang, Xinrong [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Deng, Changyan [Key Laboratory of Swine Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Kuang, Shihuan, E-mail: skuang@purdue.edu [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States)

    2014-09-12

    Highlights: • mTOR is a critical regulator of many biological processes yet its function in heart is not well understood. • MCK-Cre/Mtor{sup flox/flox} mice were established to delete Mtor in cardiomyocytes. • The mTOR-mKO mice developed normally but die prematurely within 5 weeks after birth due to heart disease. • The mTOR-mKO mice had dilated myocardium and increased cell death. • mTOR-mKO hearts had reduced expression of metabolic genes and activation of mTOR target proteins. - Abstract: Mammalian target of rapamycin (mTOR) is a critical regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive knockout of Mtor leads to embryonic lethality, the in vivo function of mTOR in perinatal development and postnatal growth of heart is not well defined. In this study, we established a muscle-specific mTOR conditional knockout mouse model (mTOR-mKO) by crossing MCK-Cre and Mtor{sup flox/flox} mice. Although the mTOR-mKO mice survived embryonic and perinatal development, they exhibited severe postnatal growth retardation, cardiac muscle pathology and premature death. At the cellular level, the cardiac muscle of mTOR-mKO mice had fewer cardiomyocytes due to apoptosis and necrosis, leading to dilated cardiomyopathy. At the molecular level, the cardiac muscle of mTOR-mKO mice expressed lower levels of fatty acid oxidation and glycolysis related genes compared to the WT littermates. In addition, the mTOR-mKO cardiac muscle had reduced Myh6 but elevated Myh7 expression, indicating cardiac muscle degeneration. Furthermore, deletion of Mtor dramatically decreased the phosphorylation of S6 and AKT, two key targets downstream of mTORC1 and mTORC2 mediating the normal function of mTOR. These results demonstrate that mTOR is essential for cardiomyocyte survival and cardiac muscle function.

  13. Brassinosteriod Insensitive 2 (BIN2) acts as a downstream effector of the Target of Rapamycin (TOR) signaling pathway to regulate photoautotrophic growth in Arabidopsis.

    Science.gov (United States)

    Xiong, Fangjie; Zhang, Rui; Meng, Zhigang; Deng, Kexuan; Que, Yumei; Zhuo, Fengping; Feng, Li; Guo, Sundui; Datla, Raju; Ren, Maozhi

    2017-01-01

    The components of the target of rapamycin (TOR) signaling pathway have been well characterized in heterotrophic organisms from yeast to humans. However, because of rapamycin insensitivity, embryonic lethality in tor null mutants and a lack of reliable ways of detecting TOR protein kinase in higher plants, the key players upstream and downstream of TOR remain largely unknown in plants. Using engineered rapamycin-sensitive Binding Protein 12-2 (BP12-2) plants, the present study showed that combined treatment with rapamycin and active-site TOR inhibitors (asTORis) results in synergistic inhibition of TOR activity and plant growth in Arabidopsis. Based on this system, we revealed that TOR signaling plays a crucial role in modulating the transition from heterotrophic to photoautotrophic growth in Arabidopsis. Ribosomal protein S6 kinase 2 (S6K2) was identified as a direct downstream target of TOR, and the growth of TOR-suppressed plants could be rescued by up-regulating S6K2. Systems, genetic, and biochemical analyses revealed that Brassinosteriod Insensitive 2 (BIN2) acts as a novel downstream effector of S6K2, and the phosphorylation of BIN2 depends on TOR-S6K2 signaling in Arabidopsis. By combining pharmacological with genetic and biochemical approaches, we determined that the TOR-S6K2-BIN2 signaling pathway plays important roles in regulating the photoautotrophic growth of Arabidopsis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  14. Drug target prediction and prioritization: using orthology to predict essentiality in parasite genomes

    Directory of Open Access Journals (Sweden)

    Hall Ross S

    2010-04-01

    Full Text Available Abstract Background New drug targets are urgently needed for parasites of socio-economic importance. Genes that are essential for parasite survival are highly desirable targets, but information on these genes is lacking, as gene knockouts or knockdowns are difficult to perform in many species of parasites. We examined the applicability of large-scale essentiality information from four model eukaryotes, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus and Saccharomyces cerevisiae, to discover essential genes in each of their genomes. Parasite genes that lack orthologues in their host are desirable as selective targets, so we also examined prediction of essential genes within this subset. Results Cross-species analyses showed that the evolutionary conservation of genes and the presence of essential orthologues are each strong predictors of essentiality in eukaryotes. Absence of paralogues was also found to be a general predictor of increased relative essentiality. By combining several orthology and essentiality criteria one can select gene sets with up to a five-fold enrichment in essential genes compared with a random selection. We show how quantitative application of such criteria can be used to predict a ranked list of potential drug targets from Ancylostoma caninum and Haemonchus contortus - two blood-feeding strongylid nematodes, for which there are presently limited sequence data but no functional genomic tools. Conclusions The present study demonstrates the utility of using orthology information from multiple, diverse eukaryotes to predict essential genes. The data also emphasize the challenge of identifying essential genes among those in a parasite that are absent from its host.

  15. Experimental and numerical study on the flow pattern of the ADS windowless spallation target with a second free surface downstream using model fluid water

    International Nuclear Information System (INIS)

    Xiong, Zhenqin; Gu, Hanyang; Gong, Shenjie

    2015-01-01

    Highlights: • A windowless spallation target with a buffer tank is tested. • Shape of the main free surface is recorded. • Streamline is obtained with the planar laser induced fluorescence method. • Stability of free surface is improved by the buffer tank. • Flow structure is simulated using RNG k-e turbulence model and VOF model. - Abstract: The windowless spallation targets are a promising design solution for accelerator driven system (ADS) due to their extended life compared to the spallation targets with a window. Keeping the stability of the free surface and reducing the recirculation zone is one of the key tasks for the design of a windowless spallation target. A windowless spallation target with a second free surface downstream (which is a buffer used to stabilize the main free surface of the flow) is studied experimentally and numerically using water at atmospheric pressure. By using planar laser induced fluorescence technique (LIF), the flow pattern inside the target zone is visualized for Reynolds numbers varying between 3.5 × 10 4 and 7.0 × 10 4 and pressure differences from 100 to 804 Pa. The experimental results reveal that the stability of the free surface is improved by adding a buffer in the downstream thus making it easier to control the height of the surface. The effect of the pressure difference between the void above the second free surface (high pressure side) and beam pipe (low pressure side) on the flow pattern is analyzed, as well as the inlet flow rate. The height of the surface length decreases with an increase in the pressure difference. The formation of the spallation zone is simulated with Fluent using the LES turbulence model and VOF model. The interface predicted agrees well with the experimental results

  16. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.

    Science.gov (United States)

    Harati, Sahar; Cooper, Lee A D; Moran, Josue D; Giuste, Felipe O; Du, Yuhong; Ivanov, Andrei A; Johns, Margaret A; Khuri, Fadlo R; Fu, Haian; Moreno, Carlos S

    2017-01-01

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.

  17. Vitamin D supplementation reduces some AT1-AA-induced downstream targets implicated in preeclampsia including hypertension.

    Science.gov (United States)

    Faulkner, Jessica L; Amaral, Lorena M; Cornelius, Denise C; Cunningham, Mark W; Ibrahim, Tarek; Heep, Autumn; Campbell, Nathan; Usry, Nathan; Wallace, Kedra; Herse, Florian; Dechend, Ralf; LaMarca, Babbette

    2017-01-01

    Autoantibodies to the ANG II type I receptor (AT 1 -AA) are associated with preeclampsia (PE). We found that vitamin D supplementation reduced AT 1 -AA and blood pressure (MAP) in the RUPP rat model of PE. However, it was undetermined whether the decrease in AT 1 -AA was the mechanism whereby vitamin D lowered MAP or if it were through factors downstream of AT 1 -AA. Uterine artery resistance index, placental ET-1, and soluble FMS-like tyrosine kinase-1 are increased with AT 1 -AA-induced hypertension and are considered markers of PE in pregnant women. Therefore, we hypothesized that vitamin D would reduce PE factors during AT 1 -AA-induced hypertension and could lower blood pressure in a model of hypertension during pregnancy without PE features. Either ANG II (50 ng·kg -1 ·day) or AT 1 -AA (1:40) was infused from gestational day (GD) 12-19. vitamin D 2 (VD2, 270 IU/day) or vitamin D 3 (VD3, 15 IU/day) was administered orally from GD14-GD18. MAP (mmHg) increased in AT 1 -AA (121 ± 4) and ANG II (113 ± 1)-infused pregnant rats compared with normal pregnant rats (NP) (101 ± 2) but was lower in AT 1 -AA+VD2 (105 ± 2), AT 1 -AA+VD3 (109 ± 2), ANG II+VD2 (104 ± 4), and ANG II+VD3 (104 ± 3). VD2 and/or VD3 improved PE features associated with AT 1 -AA during pregnancy, while ANG II did not induce such features, supporting the hypothesis that AT 1 -AA induces PE features during pregnancy, and these are improved with vitamin D. In this study, we demonstrate that vitamin D improved many factors associated with PE and reduced blood pressure in a hypertensive model without PE features, indicating that vitamin D could be beneficial for various hypertensive disorders of pregnancy. Copyright © 2017 the American Physiological Society.

  18. Tenebrio molitor Gram-negative-binding protein 3 (TmGNBP3) is essential for inducing downstream antifungal Tenecin 1 gene expression against infection with Beauveria bassiana JEF-007.

    Science.gov (United States)

    Yang, Yi-Ting; Lee, Mi Rong; Lee, Se Jin; Kim, Sihyeon; Nai, Yu-Shin; Kim, Jae Su

    2017-05-23

    The Toll signaling pathway is responsible for defense against both Gram-positive bacteria and fungi. Gram-negative binding protein 3 (GNBP3) has a strong affinity for the fungal cell wall component, β-1,3-glucan, which can activate the prophenoloxidase (proPO) cascade and induce the Toll signaling pathway. Myeloid differentiation factor 88 (MyD88) is an intracellular adaptor protein involved in the Toll signaling pathway. In this study, we monitored the response of 5 key genes (TmGNBP3, TmMyD88, and Tenecin 1, 2, and 3) in the Toll pathway of the mealworm Tenebrio molitor immune system against the fungus Beauveria bassiana JEF-007 using RT-PCR. TmGNBP3, Tenecin 1, and Tenecin 2 were significantly upregulated after fungal infection. To better understand the roles of the Toll signaling pathway in the mealworm immune system, TmGNBP3 and TmMyD88 were knocked down by RNAi silencing. Target gene expression levels decreased at 2 d postknockdown and were dramatically reduced at 6 d post-dsRNA injection. Therefore, mealworms were compromised by B. bassiana JEF-007 at 6 d post-dsRNA injection. Silencing of TmMyD88 and TmGNBP3 resulted in reduced resistance of the host to fungal infection. Particularly, reducing TmGNBP3 levels obviously downregulated Tenecin 1 and Tenecin 2 expression levels, whereas silencing TmMyD88 expression resulted in decreased Tenecin 2 expression. These results indicate that TmGNBP3 is essential to induce downstream antifungal peptide Tenecin 1 expression against B. bassiana JEF-007. © 2017 Institute of Zoology, Chinese Academy of Sciences.

  19. Simultaneous siRNA targeting of Src and downstream signaling molecules inhibit tumor formation and metastasis of a human model breast cancer cell line.

    Directory of Open Access Journals (Sweden)

    Jeffrey D Bjorge

    2011-04-01

    Full Text Available Src and signaling molecules downstream of Src, including signal transducer and activator of transcription 3 (Stat3 and cMyc, have been implicated in the development, maintenance and/or progression of several types of human cancers, including breast cancer. Here we report the ability of siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc to inhibit the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S, a widely used model for breast cancer research.Src and its downstream signaling partners were specifically targeted and knocked-down using siRNA. Changes in the growth properties of the cultured cancer cells/tumors were documented using assays that included anchorage-dependent and -independent (in soft agar cell growth, apoptosis, and both primary and metastatic tumor growth in the mouse tumor model. siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc inhibited the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S. This knock-down resulted in reduced growth in monolayer and soft agar cultures, and a reduced ability to form primary tumors in NOD/SCID mice. In addition, direct intra-tumoral injection of siRNAs targeting these signaling molecules resulted in a substantial inhibition of tumor metastases as well as of primary tumor growth. Simultaneous knock-down of Src and Stat3, and/or Myc exhibited the greatest effects resulting in substantial inhibition of primary tumor growth and metastasis.These findings demonstrate the effectiveness of simultaneous targeting of Src and the downstream signaling partners Stat3 and/or cMyc to inhibit the growth and oncogenic properties of a human cancer cell line. This knowledge may be very useful in the development of future therapeutic approaches involving targeting of specific genes products involved in tumor growth and metastasis.

  20. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals.

    Science.gov (United States)

    Su, Y C; Maurel-Zaffran, C; Treisman, J E; Skolnik, E Y

    2000-07-01

    We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck. dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process; however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct

  1. CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets

    Science.gov (United States)

    Barbagallo, Davide; Condorelli, Angelo Giuseppe; Piro, Salvatore; Parrinello, Nunziatina; Fløyel, Tina; Ragusa, Marco; Rabuazzo, Agata Maria; Størling, Joachim; Purrello, Francesco; Di Pietro, Cinzia; Purrello, Michele

    2014-01-01

    Transcription factor CEBPA has been widely studied for its involvement in hematopoietic cell differentiation and causal role in hematological malignancies. We demonstrate here that it also performs a causal role in cytokine-induced apoptosis of pancreas β cells. Treatment of two mouse pancreatic α and β cell lines (αTC1-6 and βTC1) with proinflammatory cytokines IL-1β, IFN-γ, and TNF-α at doses that specifically induce apoptosis of βTC1 significantly increased the amount of mRNA and protein encoded by Cebpa and its proapoptotic targets, Arl6ip5 and Tnfrsf10b, in βTC1 but not in αTC1-6. Cebpa knockdown in βTC1 significantly decreased cytokine-induced apoptosis, together with the amount of Arl6ip5 and Tnfrsf10b. Analysis of the network comprising CEBPA, its targets, their first interactants, and proteins encoded by genes known to regulate cytokine-induced apoptosis in pancreatic β cells (genes from the apoptotic machinery and from MAPK and NFkB pathways) revealed that CEBPA, ARL6IP5, TNFRSF10B, TRAF2, and UBC are the top five central nodes. In silico analysis further suggests TRAF2 as trait d'union node between CEBPA and the NFkB pathway. Our results strongly suggest that Cebpa is a key regulator within the apoptotic network activated in pancreatic β cells during insulitis, and Arl6ip5, Tnfrsf10b, Traf2, and Ubc are key executioners of this program. PMID:24943845

  2. Improved Algorithms for Blending Dam Releases to Meet Downstream Water-Temperature Targets in the CE-QUAL-W2 Water-Quality Model

    Science.gov (United States)

    Rounds, S. A.; Buccola, N. L.

    2014-12-01

    The two-dimensional (longitudinal, vertical) water-quality model CE-QUAL-W2, version 3.7, was enhanced with new features to help dam operators and managers efficiently explore and optimize potential solutions for temperature management downstream of thermally stratified reservoirs. Such temperature management often is accomplished by blending releases from multiple dam outlets that access water of different temperatures at different depths in the reservoir. The original blending algorithm in this version of the model was limited to mixing releases from two outlets at a time, and few constraints could be imposed. The new enhanced blending algorithm allows the user to (1) specify a time-series of target release temperatures, (2) designate from 2 to 10 floating or fixed-elevation outlets for blending, (3) impose maximum head constraints as well as minimum and maximum flow constraints for any blended outlet, and (4) set a priority designation for each outlet that allows the model to choose which outlets to use and how to balance releases among them. The modified model was tested against a previously calibrated model of Detroit Lake on the North Santiam River in northwestern Oregon, and the results compared well. The enhanced model code is being used to evaluate operational and structural scenarios at multiple dam/reservoir systems in the Willamette River basin in Oregon, where downstream temperature management for endangered fish is a high priority for resource managers and dam operators. These updates to the CE-QUAL-W2 blending algorithm allow scenarios involving complicated dam operations and/or hypothetical outlet structures to be evaluated more efficiently with the model, with decreased need for multiple/iterative model runs or preprocessing of model inputs to fully characterize the operational constraints.

  3. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1.

    Science.gov (United States)

    McWhirter, J R; Goulding, M; Weiner, J A; Chun, J; Murre, C

    1997-09-01

    Pbx1 is a homeodomain transcription factor that has the ability to form heterodimers with homeodomain proteins encoded by the homeotic selector (Hox) gene complexes and increase their DNA-binding affinity and specificity. A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development. In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A. The E2A-Pbx1 fusion protein should therefore activate transcription of genes normally regulated by Pbx1. We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1. We show that E2A-Pbx1 can directly activate transcription of a novel member of the fibroblast growth factor family of intercellular signalling molecules, FGF-15. The FGF-15 gene is expressed in a regionally restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and patterning within specific regions of the embryonic brain, spinal cord and sensory organs.

  4. Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation.

    Science.gov (United States)

    Quan, Taihao; Xu, Yiru; Qin, Zhaoping; Robichaud, Patrick; Betcher, Stephanie; Calderone, Ken; He, Tianyuan; Johnson, Timothy M; Voorhees, John J; Fisher, Gary J

    2014-04-01

    Yes-associated protein (YAP) is a transcriptional co-activator of hippo signaling pathway, which plays an important role in organ size control and tumorigenesis. Here we report that YAP and its downstream transcriptional targets CCN1 and CCN2 are markedly elevated in keratinocytes in human skin basal cell carcinoma tumor islands. In human keratinocytes, knockdown of YAP significantly reduced expression of CCN1 and CCN2, and repressed proliferation and survival. This inhibition of proliferation and survival was rescued by restoration of CCN1 expression, but not by CCN2 expression. In basal cell carcinoma stroma, CCN2-regulated genes type I collagen, fibronectin, and α-smooth muscle actin were highly expressed. Furthermore, atomic force microscopy revealed increased tissue stiffness in basal cell carcinoma stroma compared to normal dermis. These data provide evidence that up-regulation of YAP in basal cell carcinoma impacts both aberrant keratinocyte proliferation, via CCN1, and tumor stroma cell activation and stroma remodeling, via CCN2. Targeting YAP and/or CCN1 and CCN2 may provide clinical benefit in basal cell carcinoma. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data

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    Xin Li

    2008-06-01

    Full Text Available Abstract Background Target genes of a transcription factor (TF Pou5f1 (Oct3/4 or Oct4, which is essential for pluripotency maintenance and self-renewal of embryonic stem (ES cells, have previously been identified based on their response to Pou5f1 manipulation and occurrence of Chromatin-immunoprecipitation (ChIP-binding sites in promoters. However, many responding genes with binding sites may not be direct targets because response may be mediated by other genes and ChIP-binding site may not be functional in terms of transcription regulation. Results To reduce the number of false positives, we propose to separate responding genes into groups according to direction, magnitude, and time of response, and to apply the false discovery rate (FDR criterion to each group individually. Using this novel algorithm with stringent statistical criteria (FDR Pou5f1 suppression and published ChIP data, we identified 420 tentative target genes (TTGs for Pou5f1. The majority of TTGs (372 were down-regulated after Pou5f1 suppression, indicating that the Pou5f1 functions as an activator of gene expression when it binds to promoters. Interestingly, many activated genes are potent suppressors of transcription, which include polycomb genes, zinc finger TFs, chromatin remodeling factors, and suppressors of signaling. Similar analysis showed that Sox2 and Nanog also function mostly as transcription activators in cooperation with Pou5f1. Conclusion We have identified the most reliable sets of direct target genes for key pluripotency genes – Pou5f1, Sox2, and Nanog, and found that they predominantly function as activators of downstream gene expression. Thus, most genes related to cell differentiation are suppressed indirectly.

  6. Enhancement of the anti-tumor activity of FGFR1 inhibition in squamous cell lung cancer by targeting downstream signaling involved in glucose metabolism

    Science.gov (United States)

    Fumarola, Claudia; Cretella, Daniele; La Monica, Silvia; Bonelli, Mara A.; Alfieri, Roberta; Caffarra, Cristina; Quaini, Federico; Madeddu, Denise; Falco, Angela; Cavazzoni, Andrea; Digiacomo, Graziana; Mazzaschi, Giulia; Vivo, Valentina; Barocelli, Elisabetta; Tiseo, Marcello; Petronini, Pier Giorgio; Ardizzoni, Andrea

    2017-01-01

    Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism. PMID:29190880

  7. N-Myc Downstream-Regulated Gene 2 (Ndrg2) Is Involved in Ischemia-Hypoxia-Induced Astrocyte Apoptosis: a Novel Target for Stroke Therapy.

    Science.gov (United States)

    Ma, Yu-Long; Zhang, Li-Xia; Liu, Guang-Lin; Fan, Yanhong; Peng, Ye; Hou, Wu-Gang

    2017-07-01

    Nearly all clinical trials that have attempted to develop effective strategies against ischemic stroke have failed, excluding those for thrombolysis, and most of these trials focused only on preventing neuronal loss. However, astrocytes have gradually become a target for neuroprotection in stroke. In previous studies, we showed that the newly identified molecular N-myc downstream-regulated gene 2 (Ndrg2) is specifically expressed in astrocytes in the brain and involved in some neurodegenerative diseases. However, the role of NDRG2 in ischemic stroke remained unclear. In this study, we investigated the role of NDRG2 in middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia and in oxygen-glucose deprivation (OGD)-induced cellular apoptosis in the M1800 astrocyte cell line. NDRG2 mRNA and protein expression began to increase at 6 and 2 h after reperfusion and peaked at 24 h in the ischemic penumbra and in M1800 cells, as detected by RT-PCR and Western blotting. Double immunofluorescence staining showed that the number of apoptotic cells increased as the NDRG2-positive signal increased and that the NDRG2 signal was sometimes co-localized with TUNEL-positive cells and translocated from the cytoplasm to the nucleus in both the ischemic penumbra and the M1800 cells. Using a lentivirus, we successfully constructed two stable astrocytic cell lines in which NDRG2 expression was significantly up- or down-regulated. NDRG2 silencing had a proliferative effect and reduced the percentage of apoptotic cells, reactive oxygen species (ROS) production, and cleaved Caspase-3 protein expression following OGD, whereas NDRG2 over-expression had the opposite effects. In conclusion, NDRG2 is involved in astrocyte apoptosis following ischemic-hypoxic injury, and inhibiting NDRG2 expression significantly reduces ROS production and astrocyte apoptosis. These findings provide insight into the role of NDRG2 in ischemic-hypoxic injury and provide potential targets for future

  8. Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer.

    Science.gov (United States)

    Cai, Bing; Chen, Wei; Pan, Yue; Chen, Hongde; Zhang, Yirong; Weng, Zhiliang; Li, Yeping

    2017-07-01

    We investigated the prognostic potential and regulatory mechanism of microRNA-500 (miR-500), and human gene of tissue factor pathway inhibitor (TFPI) in prostate cancer. MiR-500 expression was assessed by qRT-PCR in prostate cancer cell lines and primary tumors. Cancer patients' clinicopathological factors and overall survival were analyzed according to endogenous miR-500 level. MiR-500 was downregulated in DU145 and VCaP cells. Its effect on prostate cancer proliferation, invasion in vitro, and tumorigenicity in vivo, were probed. Possible downstream target of miR-500, TFPI was assessed by luciferase assay and qRT-PCR in prostate cancer cells. In miR-500-downregulated DU145 and VCaP cells, TFPI was silenced to see whether it was directly involved in the regulation of miR-500 in prostate cancer. TFPI alone was either upregulated or downregulated in DU145 and VCaP cells. Their effect on prostate cancer development was further evaluated. MiR-500 is upregulated in both prostate cancer cells and primary tumors. In prostate cancer patients, high miR-500 expression is associated with poor prognosis and overall survival. In DU145 and VCaP cells, miR-500 downregulation inhibited cancer proliferation, invasion in vitro, and explant growth in vivo. TFPI was verified to be associated with miR-500 in prostate cancer. Downregulation of TFPI reversed anti-cancer effects of miR-500 downregulation in prostate cancer cells. However, neither TFPI upregulation nor downregulation alone had any functional impact on prostate cancer development. MiR-500 may be a potential biomarker and molecular target in prostate cancer. TFPI may conditionally regulate prostate cancer in miR-500-downregualted prostate cancer cells. © 2017 Wiley Periodicals, Inc.

  9. Exploring Pharmacological Mechanisms of Lavender (Lavandula angustifolia) Essential Oil on Central Nervous System Targets.

    Science.gov (United States)

    López, Víctor; Nielsen, Birgitte; Solas, Maite; Ramírez, Maria J; Jäger, Anna K

    2017-01-01

    Lavender essential oil is traditionally used and approved by the European Medicines Agency (EMA) as herbal medicine to relieve stress and anxiety. Some animal and clinical studies reveal positive results in models of anxiety and depression although very little research has been done on molecular mechanisms. Our work consisted of evaluating the effects of lavender ( Lavandula angustifolia ) essential oil on central nervous system well-established targets, such as MAO-A, SERT, GABA A and NMDA receptors as well as in vitro models of neurotoxicity. The results showed that lavender essential oil and its main components exert affinity for the glutamate NMDA-receptor in a dose-dependent manner with an IC 50 value of 0.04 μl/mL for lavender oil. In addition, lavender and linalool were also able to bind the serotonin transporter (SERT) whereas they did not show affinity for GABA A -benzodiazepine receptor. In three different models of neurotoxicity, lavender did not enhance the neurotoxic insult and improved viability of SH-SY5Y cells treated with hydrogen peroxide. According to our data, the anxiolytic and antidepressant-like effects attributed to lavender may be due to an antagonism on the NMDA-receptor and inhibition of SERT. This study suggests that lavender essential oil may exert pharmacological properties via modulating the NMDA receptor, the SERT as well as neurotoxicity induced by hydrogen peroxide.

  10. Exploring Pharmacological Mechanisms of Lavender (Lavandula angustifolia Essential Oil on Central Nervous System Targets

    Directory of Open Access Journals (Sweden)

    Víctor López

    2017-05-01

    Full Text Available Lavender essential oil is traditionally used and approved by the European Medicines Agency (EMA as herbal medicine to relieve stress and anxiety. Some animal and clinical studies reveal positive results in models of anxiety and depression although very little research has been done on molecular mechanisms. Our work consisted of evaluating the effects of lavender (Lavandula angustifolia essential oil on central nervous system well-established targets, such as MAO-A, SERT, GABAAand NMDA receptors as well as in vitro models of neurotoxicity. The results showed that lavender essential oil and its main components exert affinity for the glutamate NMDA-receptor in a dose-dependent manner with an IC50 value of 0.04 μl/mL for lavender oil. In addition, lavender and linalool were also able to bind the serotonin transporter (SERT whereas they did not show affinity for GABAA-benzodiazepine receptor. In three different models of neurotoxicity, lavender did not enhance the neurotoxic insult and improved viability of SH-SY5Y cells treated with hydrogen peroxide. According to our data, the anxiolytic and antidepressant-like effects attributed to lavender may be due to an antagonism on the NMDA-receptor and inhibition of SERT. This study suggests that lavender essential oil may exert pharmacological properties via modulating the NMDA receptor, the SERT as well as neurotoxicity induced by hydrogen peroxide.

  11. Mining predicted essential genes of Brugia malayi for nematode drug targets.

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    Sanjay Kumar

    Full Text Available We report results from the first genome-wide application of a rational drug target selection methodology to a metazoan pathogen genome, the completed draft sequence of Brugia malayi, a parasitic nematode responsible for human lymphatic filariasis. More than 1.5 billion people worldwide are at risk of contracting lymphatic filariasis and onchocerciasis, a related filarial disease. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. The recent publication of the draft genomic sequence for B. malayi enables a genome-wide search for new drug targets. However, there is no functional genomics data in B. malayi to guide the selection of potential drug targets. To circumvent this problem, we have utilized the free-living model nematode Caenorhabditis elegans as a surrogate for B. malayi. Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Further incorporation of human host genome sequence data and a custom algorithm for prioritization enables us to collect and rank nearly 600 drug target candidates. Previously identified potential drug targets cluster near the top of our prioritized list, lending credibility to our methodology. Over-represented Gene Ontology terms, predicted InterPro domains, and RNAi phenotypes of C. elegans orthologs associated with the potential target pool are identified. By virtue of the selection procedure, the potential B. malayi drug targets highlight components of key processes in nematode biology such as central metabolism, molting and regulation of gene expression.

  12. Anatomic Targeting of the Optimal Location for Thalamic Deep Brain Stimulation in Patients with Essential Tremor.

    Science.gov (United States)

    King, Nicolas K K; Krishna, Vibhor; Sammartino, Francesco; Bari, Ausaf; Reddy, Gaddum Duemani; Hodaie, Mojgan; Kalia, Suneil K; Fasano, Alfonso; Munhoz, Renato P; Lozano, Andres M; Hamani, Clement

    2017-11-01

    Thalamic deep brain stimulation (DBS) is an effective strategy for treatment of essential tremor (ET). With limitations of imaging modalities, targeting largely relies on indirect methods. This study was designed to determine the optimal target for DBS in ET and construct a targeting method based on probabilistic maps. Patients with ET who had sustained tremor reduction at 1 year and optimal microelectrode recordings were selected. Stimulation volume was individually modeled in standard space, and a final optimal region was derived for the whole population. A fornix (FX) targeting method was developed to determine the location of the optimal stimulation site relative to the FX and posterior commissure (PC) in the anteroposterior plane, the border between the thalamus and internal capsule in the mediolateral plane, and the anterior commissure (AC)-PC (AC-PC) plane in the dorsoventral axis. Following comparative analyses with other standard indirect methods (25% of AC-PC and PC + 6 mm), the FX method was studied in relation to diffusion tensor imaging. Using the FX method, the optimal stimulation site was at the intersection of two thirds and one third of the PC-FX distance (mean of 28% ± 1.5 AC-PC length) and 4 mm medial to the lateral border of the thalamus. Compared with previously used methods, there was a significant reduction in variability of the optimal stimulation site with the FX method. The target defined using this strategy was found to be within the boundaries of the dentatorubrothalamic tract. The FX method may be an additional targeting strategy in patients undergoing thalamic DBS surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Eukaryotic initiation factor 2α--a downstream effector of mammalian target of rapamycin--modulates DNA repair and cancer response to treatment.

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    Liron Tuval-Kochen

    Full Text Available In an effort to circumvent resistance to rapamycin--an mTOR inhibitor--we searched for novel rapamycin-downstream-targets that may be key players in the response of cancer cells to therapy. We found that rapamycin, at nM concentrations, increased phosphorylation of eukaryotic initiation factor (eIF 2α in rapamycin-sensitive and estrogen-dependent MCF-7 cells, but had only a minimal effect on eIF2α phosphorylation in the rapamycin-insensitive triple-negative MDA-MB-231 cells. Addition of salubrinal--an inhibitor of eIF2α dephosphorylation--decreased expression of a surface marker associated with capacity for self renewal, increased senescence and induced clonogenic cell death, suggesting that excessive phosphorylation of eIF2α is detrimental to the cells' survival. Treating cells with salubrinal enhanced radiation-induced increase in eIF2α phosphorylation and clonogenic death and showed that irradiated cells are more sensitive to increased eIF2α phosphorylation than non-irradiated ones. Similar to salubrinal--the phosphomimetic eIF2α variant--S51D--increased sensitivity to radiation, and both abrogated radiation-induced increase in breast cancer type 1 susceptibility gene, thus implicating enhanced phosphorylation of eIF2α in modulation of DNA repair. Indeed, salubrinal inhibited non-homologous end joining as well as homologous recombination repair of double strand breaks that were induced by I-SceI in green fluorescent protein reporter plasmids. In addition to its effect on radiation, salubrinal enhanced eIF2α phosphorylation and clonogenic death in response to the histone deacetylase inhibitor--vorinostat. Finally, the catalytic competitive inhibitor of mTOR--Ku-0063794--increased phosphorylation of eIF2α demonstrating further the involvement of mTOR activity in modulating eIF2α phosphorylation. These experiments suggest that excessive phosphorylation of eIF2α decreases survival of cancer cells; making eIF2α a worthy target for

  14. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM.

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    Anjan Debnath

    2017-12-01

    Full Text Available Primary Amoebic Meningoencephalitis (PAM is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51 target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.

  15. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)

    Science.gov (United States)

    Debnath, Anjan; Calvet, Claudia M.; Aksenov, Alexander; Abagyan, Ruben; Nes, W. David; McKerrow, James H.

    2017-01-01

    Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered “rare” (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug ‘repurposing’—a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially ‘druggable’ target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM. PMID:29284029

  16. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).

    Science.gov (United States)

    Debnath, Anjan; Calvet, Claudia M; Jennings, Gareth; Zhou, Wenxu; Aksenov, Alexander; Luth, Madeline R; Abagyan, Ruben; Nes, W David; McKerrow, James H; Podust, Larissa M

    2017-12-01

    Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.

  17. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

    Science.gov (United States)

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology.

  18. Analysis of essential Arabidopsis nuclear genes encoding plastid-targeted proteins.

    Science.gov (United States)

    Savage, Linda J; Imre, Kathleen M; Hall, David A; Last, Robert L

    2013-01-01

    The Chloroplast 2010 Project (http://www.plastid.msu.edu/) identified and phenotypically characterized homozygous mutants in over three thousand genes, the majority of which encode plastid-targeted proteins. Despite extensive screening by the community, no homozygous mutant alleles were available for several hundred genes, suggesting that these might be enriched for genes of essential function. Attempts were made to generate homozygotes in ~1200 of these lines and 521 of the homozygous viable lines obtained were deposited in the Arabidopsis Biological Resource Center (http://abrc.osu.edu/). Lines that did not yield a homozygote in soil were tested as potentially homozygous lethal due to defects either in seed or seedling development. Mutants were characterized at four stages of development: developing seed, mature seed, at germination, and developing seedlings. To distinguish seed development or seed pigment-defective mutants from seedling development mutants, development of seeds was assayed in siliques from heterozygous plants. Segregating seeds from heterozygous parents were sown on supplemented media in an attempt to rescue homozygous seedlings that could not germinate or survive in soil. Growth of segregating seeds in air and air enriched to 0.3% carbon dioxide was compared to discover mutants potentially impaired in photorespiration or otherwise responsive to CO2 supplementation. Chlorophyll fluorescence measurements identified CO2-responsive mutants with altered photosynthetic parameters. Examples of genes with a viable mutant allele and one or more putative homozygous-lethal alleles were documented. RT-PCR of homozygotes for potentially weak alleles revealed that essential genes may remain undiscovered because of the lack of a true null mutant allele. This work revealed 33 genes with two or more lethal alleles and 73 genes whose essentiality was not confirmed with an independent lethal mutation, although in some cases second leaky alleles were identified.

  19. Analysis of essential Arabidopsis nuclear genes encoding plastid-targeted proteins.

    Directory of Open Access Journals (Sweden)

    Linda J Savage

    Full Text Available The Chloroplast 2010 Project (http://www.plastid.msu.edu/ identified and phenotypically characterized homozygous mutants in over three thousand genes, the majority of which encode plastid-targeted proteins. Despite extensive screening by the community, no homozygous mutant alleles were available for several hundred genes, suggesting that these might be enriched for genes of essential function. Attempts were made to generate homozygotes in ~1200 of these lines and 521 of the homozygous viable lines obtained were deposited in the Arabidopsis Biological Resource Center (http://abrc.osu.edu/. Lines that did not yield a homozygote in soil were tested as potentially homozygous lethal due to defects either in seed or seedling development. Mutants were characterized at four stages of development: developing seed, mature seed, at germination, and developing seedlings. To distinguish seed development or seed pigment-defective mutants from seedling development mutants, development of seeds was assayed in siliques from heterozygous plants. Segregating seeds from heterozygous parents were sown on supplemented media in an attempt to rescue homozygous seedlings that could not germinate or survive in soil. Growth of segregating seeds in air and air enriched to 0.3% carbon dioxide was compared to discover mutants potentially impaired in photorespiration or otherwise responsive to CO2 supplementation. Chlorophyll fluorescence measurements identified CO2-responsive mutants with altered photosynthetic parameters. Examples of genes with a viable mutant allele and one or more putative homozygous-lethal alleles were documented. RT-PCR of homozygotes for potentially weak alleles revealed that essential genes may remain undiscovered because of the lack of a true null mutant allele. This work revealed 33 genes with two or more lethal alleles and 73 genes whose essentiality was not confirmed with an independent lethal mutation, although in some cases second leaky alleles

  20. siRNAs with decreased off-target effect facilitate the identification of essential genes in cancer cells.

    Science.gov (United States)

    Li, Chunyan; Liu, Zhenzhen; Yang, Fang; Liu, Wensheng; Wang, Di; Dong, Encheng; Wang, Yu; Wu, Chung-I; Lu, Xuemei

    2015-08-28

    Since the essential genes are crucial to the proliferation and survival of cancer cells, the interference of these genes is promising to be an option for cancer therapy to overcome heterogeneity. However, the essential genes are highly overestimated by RNA interference (RNAi) screenings, which is mainly caused by the pervasive off-target effect of small interference RNA (siRNA) and short hairpin RNA (shRNA). In the present study, we designed Match-Mismatch paired siRNAs to discriminate the on-target effect from off-target effect of siRNAs on cell viability. Only one of the 7 potential essential genes was validated as essential to cell viability, which demonstrates the high false positive rate in RNAi screenings. We modified the siRNA by introducing random nucleotides (N) into the guide strand to mitigate the off-target effect, without significantly compromising the on-target effect. The whole transcriptome profile analysis of cells transfected with siRNAs with or without Nindicates that siRNA-dN (with Ns on both the 2nd and the 18th bases of the guide strand) weakens the off-target effect by decreasing the unintended targets. The optimized siRNAs can be applied in the characterization of essential genes in cancer cells.

  1. Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma

    Directory of Open Access Journals (Sweden)

    Eberhart Charles G

    2010-11-01

    Full Text Available Abstract Background The Sonic hedgehog (Shh signaling pathway is critical for cell growth and differentiation. Impairment of this pathway can result in both birth defects and cancer. Despite its importance in cancer development, the Shh pathway has not been thoroughly investigated in tumorigenesis of brain tumors. In this study, we sought to understand the regulatory roles of GLI1, the immediate downstream activator of the Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6 in medulloblastoma and astrocytic tumors. Methods We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples. Results Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63% and primary astrocytoma tumor samples (32%, but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas. Conclusions Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes.

  2. Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma

    International Nuclear Information System (INIS)

    Shahi, Mehdi H; Afzal, Mohammad; Sinha, Subrata; Eberhart, Charles G; Rey, Juan A; Fan, Xing; Castresana, Javier S

    2010-01-01

    The Sonic hedgehog (Shh) signaling pathway is critical for cell growth and differentiation. Impairment of this pathway can result in both birth defects and cancer. Despite its importance in cancer development, the Shh pathway has not been thoroughly investigated in tumorigenesis of brain tumors. In this study, we sought to understand the regulatory roles of GLI1, the immediate downstream activator of the Shh signaling pathway on its downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6 in medulloblastoma and astrocytic tumors. We silenced GLI1 expression in medulloblastoma and astrocytic cell lines by transfection of siRNA against GLI1. Subsequently, we performed RT-PCR and quantitative real time RT-PCR (qRT-PCR) to assay the expression of downstream target genes PTCH1, Cyclin D2, Plakoglobin, NKX2.2 and PAX6. We also attempted to correlate the pattern of expression of GLI1 and its regulated genes in 14 cell lines and 41 primary medulloblastoma and astrocytoma tumor samples. We also assessed the methylation status of the Cyclin D2 and PTCH1 promoters in these 14 cell lines and 58 primary tumor samples. Silencing expression of GLI1 resulted up-regulation of all target genes in the medulloblastoma cell line, while only PTCH1 was up-regulated in astrocytoma. We also observed methylation of the cyclin D2 promoter in a significant number of astrocytoma cell lines (63%) and primary astrocytoma tumor samples (32%), but not at all in any medulloblastoma samples. PTCH1 promoter methylation was less frequently observed than Cyclin D2 promoter methylation in astrocytomas, and not at all in medulloblastomas. Our results demonstrate different regulatory mechanisms of Shh-GLI1 signaling. These differences vary according to the downstream target gene affected, the origin of the tissue, as well as epigenetic regulation of some of these genes

  3. Targeting an Essential GTPase Obg for the Development of Broad-Spectrum Antibiotics.

    Directory of Open Access Journals (Sweden)

    Josephine A Bonventre

    Full Text Available A promising new drug target for the development of novel broad-spectrum antibiotics is the highly conserved small GTPase Obg (YhbZ, CgtA, a protein essential for the survival of all bacteria including Neisseria gonorrhoeae (GC. GC is the agent of gonorrhea, a prevalent sexually transmitted disease resulting in serious consequences on reproductive and neonatal health. A preventive anti-gonorrhea vaccine does not exist, and options for effective antibiotic treatments are increasingly limited. To address the dire need for alternative antimicrobial strategies, we have designed and optimized a 384-well GTPase assay to identify inhibitors of Obg using as a model Obg protein from GC, ObgGC. The assay was validated with a pilot screen of 40,000 compounds and achieved an average Z' value of 0.58 ± 0.02, which suggests a robust assay amenable to high-throughput screening. We developed secondary assessments for identified lead compounds that utilize the interaction between ObgGC and fluorescent guanine nucleotide analogs, mant-GTP and mant-GDP, and an ObgGC variant with multiple alterations in the G-domains that prevent nucleotide binding. To evaluate the broad-spectrum potential of ObgGC inhibitors, Obg proteins of Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus were assessed using the colorimetric and fluorescence-based activity assays. These approaches can be useful in identifying broad-spectrum Obg inhibitors and advancing the therapeutic battle against multidrug resistant bacteria.

  4. Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance.

    Science.gov (United States)

    Belle, J I; Petrov, J C; Langlais, D; Robert, F; Cencic, R; Shen, S; Pelletier, J; Gros, P; Nijnik, A

    2016-05-01

    p53 is a central mediator of cellular stress responses, and its precise regulation is essential for the normal progression of hematopoiesis. MYSM1 is an epigenetic regulator essential for the maintenance of hematopoietic stem cell (HSC) function, hematopoietic progenitor survival, and lymphocyte development. We recently demonstrated that all developmental and hematopoietic phenotypes of Mysm1 deficiency are p53-mediated and rescued in the Mysm1(-/-)p53(-/-) mouse model. However, the mechanisms triggering p53 activation in Mysm1(-/-) HSPCs, and the pathways downstream of p53 driving different aspects of the Mysm1(-/-) phenotype remain unknown. Here we show the transcriptional activation of p53 stress responses in Mysm1(-/-) HSPCs. Mechanistically, we find that the MYSM1 protein associates with p53 and colocalizes to promoters of classical p53-target genes Bbc3/PUMA (p53 upregulated modulator of apoptosis) and Cdkn1a/p21. Furthermore, it antagonizes their p53-driven expression by modulating local histone modifications (H3K27ac and H3K4me3) and p53 recruitment. Using double-knockout mouse models, we establish that PUMA, but not p21, is an important mediator of p53-driven Mysm1(-/-) hematopoietic dysfunction. Specifically, Mysm1(-/-)Puma(-/-) mice show full rescue of multipotent progenitor (MPP) viability, partial rescue of HSC quiescence and function, but persistent lymphopenia. Through transcriptome analysis of Mysm1(-/-)Puma(-/-) MPPs, we demonstrate strong upregulation of other p53-induced mediators of apoptosis and cell-cycle arrest. The full viability of Mysm1(-/-)Puma(-/-) MPPs, despite strong upregulation of many other pro-apoptotic mediators, establishes PUMA as the essential non-redundant effector of p53-induced MPP apoptosis. Furthermore, we identify potential mediators of p53-dependent but PUMA-independent Mysm1(-/-)hematopoietic deficiency phenotypes. Overall, our study provides novel insight into the cell-type-specific roles of p53 and its downstream

  5. Essential pathway identification: from in silico analysis to potential antifungal targets in Aspergillus fumigatus

    DEFF Research Database (Denmark)

    Thykær, Jette; Andersen, Mikael Rørdam; Baker, S. E.

    2009-01-01

    Computational metabolic flux modeling has been a great aid for both understanding and manipulating microbial metabolism. A previously developed metabolic flux model for Aspergillus niger, an economically important biotechnology fungus known for protein and organic acid production, is comprised...... of 1190 biochemically unique reactions that are associated with 871 open reading frames. Through a systematic in silico deletion of single metabolic reactions using this model, several essential metabolic pathways were identified for A. niger. A total of 138 reactions were identified as being essential...... biochemical reactions during growth on a minimal glucose medium. The majority of the reactions grouped into essential biochemical pathways covering cell wall biosynthesis, amino acid biosynthesis, energy metabolism and purine and pyrimidine metabolism. Based on the A. niger open reading frames associated...

  6. Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature.

    Science.gov (United States)

    Slemc, Lucija; Kunej, Tanja

    2016-11-01

    Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS ( http://apps.webofknowledge.com/ ), HGNC ( http://www.genenames.org/ ), NCBI ( http://www.ncbi.nlm.nih.gov/ ), Ensemblv.84 ( http://www.ensembl.org/index.html ), DAVID Bioinformatics Resources ( https://david.ncifcrf.gov /), and Disease Ontology database ( http://disease-ontology.org/ ). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.

  7. Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer.

    Science.gov (United States)

    Pan, Huafeng; Zhu, Yudi; Wei, Wei; Shao, Siliang; Rui, Xin

    2018-03-20

    Prostate cancer is a common malignancy and the second leading cause of cancer death in men. Elevated expression of the transcription factor FoxM1 and c-Myc has been identified in prostate cancer. However, the potential mechanism of elevated FoxM1 and c-Myc to the development of prostate cancer has not been identified. In this report, the mRNA level of FoxM1 and c-Myc was detected in 30 prostate cancer and para-cancer tissues. Then, we detected the expression level of FoxM1 by real-time PCR and Western blot after disturbance of the expression level of c-Myc in PC-3 cells. Whether c-Myc could bind to FoxM1 promoter was identified by ChIP assay. Finally, the migratory, invasive, and proliferative abilities in FoxM1 overexpressing and silencing PC-3 cells were detected by wound healing, transwell assay, CCK-8 assays, and Ki-67 protein level. We found that the expression level of FoxM1 and c-Myc were both increased in prostate cancer samples compared with para-cancer samples. The expression level of FoxM1 was changed consistent with the protein level of c-Myc. ChIP assay detected the direct binding of c-Myc in FoxM1 gene promoter. Lastly, overexpression of FoxM1 increased the migratory, invasive, and proliferative abilities of PC-3 cells, and its downregulation significantly decreased the migratory, invasive, and proliferative abilities. In conclusion, FoxM1 was significantly increased in prostate cancer samples, and it could regulate the proliferative and invasive ability of prostate cancer cells which might be a new target for prostate cancer. Besides, c-Myc could regulate the expression level of FoxM1 by directly binding to its gene promoter.

  8. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality.

    Science.gov (United States)

    McIntyre, Alan; Harris, Adrian L

    2015-04-01

    Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6-8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table 1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  9. Erythropoietin mediates brain-vascular-kidney crosstalk and may be a treatment target for pulmonary and resistant essential hypertension.

    Science.gov (United States)

    Onal, Emine Meltem; Sag, Alan Alper; Sal, Oguzhan; Yerlikaya, Aslihan; Afsar, Baris; Kanbay, Mehmet

    2017-01-01

    Organ crosstalk pathways represent the next frontier for target-mining in molecular medicine for existing syndromes. Pulmonary hypertension and resistant essential hypertension are syndromes that have been proven elusive in etiology, and frequently refractory to first-line management. Underlying crosstalk mechanisms, not yet considered in these treatments, may hinder outcomes or unlock novel treatments. This review focuses systematically on erythropoietin, a synthesizable molecule, as a mediator of brain-kidney crosstalk. Insights gained from this review will be applied to cardiovascular diseases in a clinician-directed fashion.

  10. Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase--a comprehensive drug target database for Lymphatic filariasis.

    Science.gov (United States)

    Sharma, Om Prakash; Kumar, Muthuvel Suresh

    2016-01-25

    Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in.

  11. Targeting polo-like kinase 1 suppresses essential functions of alloreactive T cells.

    Science.gov (United States)

    Berges, Carsten; Chatterjee, Manik; Topp, Max S; Einsele, Hermann

    2016-06-01

    Acute graft-versus-host disease (aGvHD) is still a major cause of transplant-related mortality after allogeneic stem cell transplantation (ASCT). It requires immunosuppressive treatments that broadly abrogate T cell responses including beneficial ones directed against tumor cells or infective pathogens. Polo-like kinase 1 (PLK1) is overexpressed in many cancer types including leukemia, and clinical studies demonstrated that targeting PLK1 using selective PLK1 inhibitors resulted in inhibition of proliferation and induction of apoptosis predominantly in tumor cells, supporting the feasibility of PLK1 as target for anticancer therapy. Here, we show that activation of alloreactive T cells (Tallo) up-regulate expression of PLK1, suggesting that PLK1 is a potential new candidate for dual therapy of aGvHD and leukemia after ASCT. Inhibition of PLK1, using PLK1-specific inhibitor GSK461364A selectively depletes Tallo by preventing activation and by inducing apoptosis in already activated Tallo, while memory T cells are preserved. Activated Tallo cells which survive exposure to PLK1 undergo inhibition of proliferation by induction of G2/M cell cycle arrest, which is accompanied by accumulation of cell cycle regulator proteins p21(WAF/CIP1), p27(Kip1), p53 and cyclin B1, whereas abundance of CDK4 decreased. We also show that suppressive effects of PLK1 inhibition on Tallo were synergistically enhanced by concomitant inhibition of molecular chaperone Hsp90. Taken together, our data suggest that PLK1 inhibition represents a reasonable dual strategy to suppress residual tumor growth and efficiently deplete Tallo, and thus provide a rationale to selectively prevent and treat aGvHD.

  12. Alginate-whey protein dry powder optimized for target delivery of essential oils to the intestine of chickens.

    Science.gov (United States)

    Zhang, Y; Gong, J; Yu, H; Guo, Q; Defelice, C; Hernandez, M; Yin, Y; Wang, Q

    2014-10-01

    In poultry production, there is a lack of effective and convenient approaches to deliver bioactive compounds such as some essential oils, which have been proposed as alternatives to antibiotic growth promoters. The objective of this research was to develop a method for target delivery of essential oils in feed to the lower intestines of chickens. Carvacrol was used as a model essential oil, and 2 food-grade biopolymers, alginate and whey protein, were selected to encapsulate carvacrol in microparticles. The effects of a medium molecular weight alginate, a low molecular weight alginate (LBA), and whey protein concentrations on the properties of carvacrol-loaded microparticles were investigated using response surface methodology. The encapsulation efficiencies for all the tested formulations were ≥ 98% and carvacrol content in the dry microparticles was 72 ± 2% (wt/wt). The microparticles showed good gastric resistance and rapid intestinal release under simulated gastrointestinal conditions. Alginate concentrations had the strongest influence on the gastric resistance of microparticles, whereas whey protein was the dominant parameter in controlling the intestinal release. The concentration of LBA was found to be the critical factor affecting the mechanical strength of the microparticles. A predicted optimum formulation from in vitro optimization was tested in chickens. It was found that a negligible amount of carvacrol was detected in the intestines of chickens fed with unencapsulated carvacrol. Microparticles of predicted optimum formulation delivered a remarkably higher concentration of carvacrol to the jejunum and ileum regions. The high concentration was sustained for more than 3 h after oral administration. The in vivo release of carvacrol from the microparticles appeared faster than release from in vitro simulation. Nonetheless, the in vitro simulation provided good indications of the in vivo performance, and thus may serve as a useful tool for formula

  13. Effects of inhibitors of vascular endothelial growth factor receptor 2 and downstream pathways of receptor tyrosine kinases involving phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin or mitogen-activated protein kinase in canine hemangiosarcoma cell lines.

    Science.gov (United States)

    Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Sakai, Hiroki; Takagi, Satoshi

    2016-07-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm with no current effective treatment. Previous studies showed that receptor tyrosine kinases and molecules within their downstream pathways involving phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (m-TOR) or mitogen-activated protein kinase (MAPK) were overexpressed in canine, human, and murine tumors, including HSA. The present study investigated the effects of inhibitors of these pathways in canine splenic and hepatic HSA cell lines using assays of cell viability and apoptosis. Inhibitors of the MAPK pathway did not affect canine HSA cell viability. However, cell viability was significantly reduced by exposure to inhibitors of vascular endothelial growth factor receptor 2 and the PI3K/Akt/m-TOR pathway; these inhibitors also induced apoptosis in these cell lines. These results suggest that these inhibitors reduce the proliferation of canine HSA cells by inducing apoptosis. Further study of these inhibitors, using xenograft mouse models of canine HSA, are warranted to explore their potential for clinical application.

  14. Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis.

    Science.gov (United States)

    Carlson, Kaitlin S; Whitney, Meredith S; Gadziola, Marie A; Deneris, Evan S; Wesson, Daniel W

    2016-01-01

    The neurotransmitter serotonin (5-HT) is considered a powerful modulator of sensory system organization and function in a wide range of animals. The olfactory system is innervated by midbrain 5-HT neurons into both its primary and secondary odor-processing stages. Facilitated by this circuitry, 5-HT and its receptors modulate olfactory system function, including odor information input to the olfactory bulb. It is unknown, however, whether the olfactory system requires 5-HT for even its most basic behavioral functions. To address this question, we established a conditional genetic approach to specifically target adult brain tryptophan hydroxylase 2 ( Tph2 ), encoding the rate-limiting enzyme in brain 5-HT synthesis, and nearly eliminate 5-HT from the mouse forebrain. Using this novel model, we investigated the behavior of 5-HT-depleted mice during performance in an olfactory go/no-go task. Surprisingly, the near elimination of 5-HT from the forebrain, including the olfactory bulbs, had no detectable effect on the ability of mice to perform the odor-based task. Tph2 -targeted mice not only were able to learn the task, but also had levels of odor acuity similar to those of control mice when performing coarse odor discrimination. Both groups of mice spent similar amounts of time sampling odors during decision-making. Furthermore, odor reversal learning was identical between 5-HT-depleted and control mice. These results suggest that 5-HT neurotransmission is not necessary for the most essential aspects of olfaction, including odor learning, discrimination, and certain forms of cognitive flexibility.

  15. Downstream product marketing

    International Nuclear Information System (INIS)

    Pantelidis, J.

    1997-01-01

    Petro-Canada's views regarding energy deregulation were presented. Their experience with gasoline retailing and their response to competition was also discussed. Petro-Canada regards deregulation as a good thing in terms of its promotion of fair competition. Industrial and residential consumers of energy will benefit from more efficient and innovative service. Today's consumers are very well informed about existing energy products and while they are incredibly price sensitive, they still want to buy value. The relevance of brand names in a competitive market was examined. One reaction to the demanding customer has been to augment the base product (the fuel) with other things, such as convenience store items, car washes, specialized bay businesses and promotional offerings. Petro-Canada has been successful in improving sales volumes with these sales strategies, and profits achieved indicate good target audience acceptance. Shareholders and the board of directors also appear to be in agreement with the Corporation's performance to date

  16. An array of Escherichia coli clones over-expressing essential proteins: A new strategy of identifying cellular targets of potent antibacterial compounds

    International Nuclear Information System (INIS)

    Xu, H. Howard; Real, Lilian; Bailey, Melissa Wu

    2006-01-01

    With the advancement of high throughput screening, it has become easier and faster to discover hit compounds that inhibit proliferation of bacterial cells. However, development in technologies used to identify cellular targets of potent antibacterial inhibitors has lagged behind. Here, we describe a novel strategy of target identification for antibacterial inhibitors using an array of Escherichia coli clones each over-expressing one essential protein. In a proof-of-concept study, eight essential genes were cloned into pLex5BA vector under the control of an inducible promoter. Over-expression of target proteins was confirmed. For two clones, one over-expressing FabI and the other over-expressing MurA enzymes, the host cells became 17- and 139-fold more resistant to the specific inhibitors triclosan and phosphomycin, respectively, while the susceptibility of other clones towards these inhibitors remained unchanged after induction of gene expression. Target identification via target protein over-expression was demonstrated using both mixed clone and individual clone assay formats

  17. Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome.

    Directory of Open Access Journals (Sweden)

    Yukie Yoshii

    Full Text Available Fatty acid synthase (FASN expression is elevated in several cancers, and this over-expression is associated with poor prognosis. Inhibitors of FASN, such as orlistat, reportedly show antitumor effects against cancers that over-express FASN, making FASN a promising therapeutic target. However, large variations in FASN expression levels in individual tumors have been observed, and methods to predict FASN-targeted therapy outcome before treatment are required to avoid unnecessary treatment. In addition, how FASN inhibition affects tumor progression remains unclear. Here, we showed the method to predict FASN-targeted therapy outcome using radiolabeled acetate uptake and presented mechanisms of FASN inhibition with human prostate cancer cell lines, to provide the treatment strategy of FASN-targeted therapy. We revealed that tumor uptake of radiolabeled acetate reflected the FASN expression levels and sensitivity to FASN-targeted therapy with orlistat in vitro and in vivo. FASN-targeted therapy was noticeably effective against tumors with high FASN expression, which was indicated by high acetate uptake. To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray-based gene expression profiling. FASN inhibition not only suppressed cell proliferation but prevented pseudopodia formation and suppressed cell adhesion, migration, and invasion. FASN inhibition also suppressed genes involved in production of intracellular second messenger arachidonic acid and androgen hormones, both of which promote tumor progression. Collectively, our data demonstrated that uptake of radiolabeled acetate is a useful predictor of FASN-targeted therapy outcome. This suggests that [1-(11C]acetate positron emission tomography (PET could be a powerful tool to accomplish personalized FASN-targeted therapy by non

  18. Vesicle-associated membrane protein 7 (VAMP-7) is essential for target cell killing in a natural killer cell line

    International Nuclear Information System (INIS)

    Marcet-Palacios, Marcelo; Odemuyiwa, Solomon O.; Coughlin, Jason J.; Garofoli, Daniella; Ewen, Catherine; Davidson, Courtney E.; Ghaffari, Mazyar; Kane, Kevin P.; Lacy, Paige; Logan, Michael R.; Befus, A. Dean; Bleackley, R. Chris; Moqbel, Redwan

    2008-01-01

    Natural killer cells recognize and induce apoptosis in foreign, transformed or virus-infected cells through the release of perforin and granzymes from secretory lysosomes. Clinically, NK-cell mediated killing is a major limitation to successful allo- and xenotransplantation. The molecular mechanisms that regulate the fusion of granzyme B-containing secretory lysosomes to the plasma membrane in activated NK cells, prior to target cell killing, are not fully understood. Using the NK cell line YT-Indy as a model, we have investigated the expression of SNAP REceptors (SNAREs), both target (t-) and vesicular (v-) SNAREs, and their function in granzyme B-mediated target cell killing. Our data showed that YT-Indy cells express VAMP-7 and SNAP-23, but not VAMP-2. VAMP-7 was associated with granzyme B-containing lysosomal granules. Using VAMP-7 small interfering RNA (siRNA), we successfully knocked down the expression of VAMP-7 protein in YT-Indy to less than 10% of untreated cells in 24 h. VAMP7-deficient YT-Indy cells activated via co-culture with Jurkat cells released <1 ng/mL of granzyme B, compared to 1.5-2.5 μg/mL from controls. Using Jurkat cells as targets, we showed a 7-fold reduction in NK cell-mediated killing by VAMP-7 deficient YT-Indy cells. Our results show that VAMP-7 is a crucial component of granzyme B release and target cell killing in the NK cell line YT-Indy. Thus, targeting VAMP-7 expression specifically with siRNA, following transplantation, may be a viable strategy for preventing NK cell-mediated transplant rejection, in vivo

  19. Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration

    NARCIS (Netherlands)

    Emran, S.; Yang, M.Y.; He, X.L.; Zandveld, J.; Piper, M.D.W.

    2014-01-01

    Dietary restriction (DR), defined as a moderate reduction in food intake short of malnutrition, has been shown to extend healthy lifespan in a diverse range of organisms, from yeast to primates. Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways

  20. DARHT-II Downstream Transport Beamline

    International Nuclear Information System (INIS)

    Westenskow, G A; Bertolini, L R; Duffy, P T; Paul, A C

    2001-01-01

    This paper describes the mechanical design of the downstream beam transport line for the second axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT II) Facility. The DARHT-II project is a collaboration between LANL, LBNL and LLNL. DARHT II is a 18.4-MeV, 2000-Amperes, 2-(micro)sec linear induction accelerator designed to generate short bursts of x-rays for the purpose of radiographing dense objects. The downstream beam transport line is approximately 22-meter long region extending from the end of the accelerator to the bremsstrahlung target. Within this proposed transport line there are 12 conventional solenoid, quadrupole and dipole magnets; as well as several specialty magnets, which transport and focus the beam to the target and to the beam dumps. There are two high power beam dumps, which are designed to absorb 80-kJ per pulse during accelerator start-up and operation. Aspects of the mechanical design of these elements are presented

  1. Chitosan encapsulation of essential oil "cocktails" with well-defined binary Zn(II)-Schiff base species targeting antibacterial medicinal nanotechnology.

    Science.gov (United States)

    Halevas, Eleftherios; Nday, Christiane M; Chatzigeorgiou, Evanthia; Varsamis, Vasileios; Eleftheriadou, Despoina; Jackson, Graham E; Litsardakis, Georgios; Lazari, Diamanto; Ypsilantis, Konstantinos; Salifoglou, Athanasios

    2017-11-01

    The advent of biodegradable nanomaterials with enhanced antibacterial activity stands as a challenge to the global research community. In an attempt to pursue the development of novel antibacterial medicinal nanotechnology, we herein a) synthesized ionic-gelated chitosan nanoparticles, b) compared and evaluated the antibacterial activity of essential oils extracted from nine different herbs (Greek origin) and their combinations with a well-defined antibacterial Zn(II)-Schiff base compound, and c) encapsulated the most effective hybrid combination of Zn(II)-essential oils inside the chitosan matrix, thereby targeting well-formulated nanoparticles of distinct biological impact. The empty and loaded chitosan nanoparticles were physicochemically characterized by FT-IR, Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), with the entrapment and drug release studies being conducted through UV-Visible and atomic absorption techniques. The antimicrobial properties of the novel hybrid materials were demonstrated against Gram positive (S. aureus, B. subtilis, and B. cereus) and Gram negative (E. coli and X. campestris) bacteria using modified agar diffusion methods. The collective physicochemical profile of the hybrid Zn(II)-essential oil cocktails, formulated so as to achieve optimal activity when loaded to chitosan nanoparticles, signifies the importance of design in the development of efficient nanomedicinal pharmaceuticals a) based on both natural products and biogenic metal ionic cofactors, and b) targeting bacterial infections and drug resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Co-development of diagnostic vectors to support targeted therapies and theranostics: Essential tools in Personalized Cancer Therapy.

    Directory of Open Access Journals (Sweden)

    Nicholas C Nicolaides

    2014-06-01

    Full Text Available Novel technologies are being developed to improve patient therapy through the identification of targets and surrogate molecular signatures that can help direct appropriate treatment regimens for efficacy and drug safety. This is particularly the case in oncology whereby patient tumor and biofluids are routinely isolated and analyzed for genetic, immunohistochemical and/or soluble markers to determine if a predictive biomarker signature exists as a means for selecting optimal treatment. Improvements in diagnostics that can prescreen predictive response biomarker profiles will continue to optimize the ability to enhance patient therapy via molecularly defined disease-specific treatment. A goal for drug developers is to identify and implement new strategies that can rapidly enable the development of beneficial disease-specific therapies for broad, patient-specific targeting without the need of tedious predictive biomarker discovery and validation efforts, currently a bottleneck for development timelines. Here we discuss the use of co-developing diagnostic-targeting vectors to identify patients whose malignant tissue can specifically uptake a drug linked vector prior to treatment. Using this system, a patient can be predetermined in real time as to whether or not their tumor(s can uptake a drug-linked diagnostic vector, thus inferring the uptake of a similar vector linked to an anti-cancer agent. If tumor-specific uptake is observed, then the patient may be suitable for drug-linked vector therapy and have a higher likelihood of clinical benefit while patients with no tumor uptake should consider other therapeutic options. This approach offers complementary opportunities to rapidly develop broad tumor-specific agents for use in personalized medicine.

  3. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting.

    Directory of Open Access Journals (Sweden)

    Alyaa M Abdel-Haleem

    2018-01-01

    Full Text Available Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale metabolic models (GeMMs of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1, choline, and pantothenate (vitamin B5 metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  4. Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting

    KAUST Repository

    Abdel-Haleem, Alyaa M.

    2018-01-04

    Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale models (GEMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1), choline, and pantothenate (vitamin B5) metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

  5. Targeted disruption of cubilin reveals essential developmental roles in the structure and function of endoderm and in somite formation

    Directory of Open Access Journals (Sweden)

    Cooley Marion A

    2006-06-01

    Full Text Available Abstract Background Cubilin is a peripheral membrane protein that interacts with the integral membrane proteins megalin and amnionless to mediate ligand endocytosis by absorptive epithelia such as the extraembryonic visceral endoderm (VE. Results Here we report the effects of the genetic deletion of cubilin on mouse embryonic development. Cubilin gene deletion is homozygous embryonic lethal with death occurring between 7.5–13.5 days post coitum (dpc. Cubilin-deficient embryos display developmental retardation and do not advance morphologically beyond the gross appearance of wild-type 8–8.5 dpc embryos. While mesodermal structures such as the allantois and the heart are formed in cubilin mutants, other mesoderm-derived tissues are anomalous or absent. Yolk sac blood islands are formed in cubilin mutants but are unusually large, and the yolk sac blood vessels fail to undergo remodeling. Furthermore, somite formation does not occur in cubilin mutants. Morphological abnormalities of endoderm occur in cubilin mutants and include a stratified epithelium in place of the normally simple columnar VE epithelium and a stratified cuboidal epithelium in place of the normally simple squamous epithelium of the definitive endoderm. Cubilin-deficient VE is also functionally defective, unable to mediate uptake of maternally derived high-density lipoprotein (HDL. Conclusion In summary, cubilin is required for embryonic development and is essential for the formation of somites, definitive endoderm and VE and for the absorptive function of VE including the process of maternal-embryo transport of HDL.

  6. Cathepsin W expressed exclusively in CD8+ T cells and NK cells, is secreted during target cell killing but is not essential for cytotoxicity in human CTLs.

    Science.gov (United States)

    Stoeckle, Christina; Gouttefangeas, Cécile; Hammer, Michael; Weber, Ekkehard; Melms, Arthur; Tolosa, Eva

    2009-02-01

    Cathepsin W (CatW, lymphopain) is a putative cysteine protease with restricted expression to natural killer (NK) cells and CD8(+) T cells and so far unknown function and properties. Here, we characterize in detail, the regulation of human CatW during T-cell development in response to different stimuli and its functional involvement in cytotoxic lymphocyte effector function. Western blots and real time polymerase chain reaction of sorted, unstimulated, and stimulated cell subsets (thymocytes, T cells, NK cells) and their culture supernatants were used to study regulation and expression of CatW. Primary CD8(+) T cells and short-term T-cell lines were transfected with small interfering RNA to study the involvement of CatW in effector function such as target cell killing and interferon-gamma production. Levels of CatW expression correlate closely with cytotoxic capacity both during development and in response to factors influencing cytotoxicity. Furthermore, CatW is secreted during specific target cell killing. However, knockdown of CatW expression by small interfering RNA neither influences target cell killing nor interferon-gamma production. Despite being expressed in the effector subset of CD8(+) and NK cells and of being released during target cell killing, our functional inhibition studies exclude an essential role of CatW in the process of cytotoxicity.

  7. (Un)targeted metabolomics in Asteraceae: probing the applicability of essential-oil profiles of senecio L. (Senecioneae) taxa in chemotaxonomy.

    Science.gov (United States)

    Radulović, Niko S; Mladenović, Marko Z; Blagojević, Polina D

    2014-09-01

    The possible applicability of (un)targeted metabolomics (volatile metabolites) for revealing taxonomic/evolutionary relationships among Senecio L. species (Asteraceae; tribe Senecioneae) was explored. Essential-oil compositional data of selected Senecio/Senecioneae/Asteraceae taxa (93 samples in total) were mutually compared by means of multivariate statistical analysis (MVA), i.e., agglomerative hierarchical clustering and principal component analysis. The MVA input data set included the very first compositional data on the essential oil extracted from the aerial parts of S. viscosus L. as well as on four different Serbian populations of S. vernalis Waldst. & Kit. (oils from aerial parts and roots; eight samples in total). This metabolomic screening of Senecio/Senecioneae/Asteraceae species (herein presented results and data from the literature) pointed to short-chain alk-1-enes (e.g., oct-1-ene, non-1-ene, and undec-1-ene), with up to now restricted general occurrence in Plantae, as characteristic chemotaxonomic markers/targets for future metabolomic studies of Senecio/Senecioneae taxa. The MVA additionally showed that the evolution of the terpene metabolism (volatile mono- and sesquiterpenoids) within the Asteraceae tribe Senecioneae was not genera specific. However, the MVA did confirm plant-organ specific production/accumulation of volatiles within S. vernalis and suggested the existence of at least two volatile chemotypes for this species. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

  8. Operational optimization in the downstream; Otimizacao operacional no downstream

    Energy Technology Data Exchange (ETDEWEB)

    Silberman, Luis; Cunha, Filipe Silveira Ramos da [Petroleo Ipiranga, Porto Alegre, RS (Brazil)

    2004-07-01

    On the present competitive down stream's market, there is a great necessity of optimization aiming to guarantee the best price and quality of our clients. Our goal is to attend these expectations while we guarantee an efficient operation. The greatest question is how far we are from the ideal model. This way, a lot of projects have been executed during the last years aiming the operational optimization of all our activities. We divide the projects in 4 areas: Logistic (new modals distribution), Transport (transport optimization - quality and more deliveries with less trucks), Client Support (Internet Ipiranga and Support Center), Distribution Terminals Productivity (automation and environment). This work intend to present our ideal, perfect and complete Downstream Operation model. We will talk about how close we are of this ideal model and we will present the projects that we had already developed and implanted on the automation of the terminals and the logistics area. (author)

  9. Human Adenovirus Core Protein V Is Targeted by the Host SUMOylation Machinery To Limit Essential Viral Functions.

    Science.gov (United States)

    Freudenberger, Nora; Meyer, Tina; Groitl, Peter; Dobner, Thomas; Schreiner, Sabrina

    2018-02-15

    Human adenoviruses (HAdV) are nonenveloped viruses containing a linear, double-stranded DNA genome surrounded by an icosahedral capsid. To allow proper viral replication, the genome is imported through the nuclear pore complex associated with viral core proteins. Until now, the role of these incoming virion proteins during the early phase of infection was poorly understood. The core protein V is speculated to bridge the core and the surrounding capsid. It binds the genome in a sequence-independent manner and localizes in the nucleus of infected cells, accumulating at nucleoli. Here, we show that protein V contains conserved SUMO conjugation motifs (SCMs). Mutation of these consensus motifs resulted in reduced SUMOylation of the protein; thus, protein V represents a novel target of the host SUMOylation machinery. To understand the role of protein V SUMO posttranslational modification during productive HAdV infection, we generated a replication-competent HAdV with SCM mutations within the protein V coding sequence. Phenotypic analyses revealed that these SCM mutations are beneficial for adenoviral replication. Blocking protein V SUMOylation at specific sites shifts the onset of viral DNA replication to earlier time points during infection and promotes viral gene expression. Simultaneously, the altered kinetics within the viral life cycle are accompanied by more efficient proteasomal degradation of host determinants and increased virus progeny production than that observed during wild-type infection. Taken together, our studies show that protein V SUMOylation reduces virus growth; hence, protein V SUMOylation represents an important novel aspect of the host antiviral strategy to limit virus replication and thereby points to potential intervention strategies. IMPORTANCE Many decades of research have revealed that HAdV structural proteins promote viral entry and mainly physical stability of the viral genome in the capsid. Our work over the last years showed that this

  10. E2F target genes: unraveling the biology

    DEFF Research Database (Denmark)

    Bracken, Adrian P; Ciro, Marco; Cocito, Andrea

    2004-01-01

    The E2F transcription factors are downstream effectors of the retinoblastoma protein (pRB) pathway and are required for the timely regulation of numerous genes essential for DNA replication and cell cycle progression. Several laboratories have used genome-wide approaches to discover novel target...

  11. Assessing the impacts of Three Gorges Dam on lake inundation areas across the downstream Yangtze floodplain

    Science.gov (United States)

    Wang, J.; Sheng, Y.; Wada, Y.

    2013-12-01

    China's Three Gorges Dam (TGD) has received worldwide attention due to its profound impacts on the downstream hydraulic, morphological, and ecological systems. The TGD operation results in direct alternation of the discharge to the middle and lower Yangtze reach, manifested as regulated flow and reduced sediment load. TGD's flow regulation, typically described as water storage in fall while release in winter and spring, interferes with the natural seasonality of downstream Yangtze River levels which are essentially important to the inundation dynamics of surrounding lakes/wetlands in the Yangtze floodplain. Concurrent decrease of sediment load has caused chronic downstream channel erosion which lowers Yangtze level in relation to flow and further affects the sustainability of riparian lakes and the related ecosystems. By integrating satellite observations, in situ measurement, and hydrologic simulations, this study presents a systematic assessment of the TGD impacts on the inundation areas of six major freshwater lakes across the entire Yangtze basin downstream of the TGD, during the time period from TGD's initial impoundment in June 2003 to early 2012. Despite the small number, the six targeted lakes cover a total area of ~5,000 km2 accounting for ~25% of the freshwater lake area in China, and were identified as the only natural lakes that remain in open connection to the Yangtze River across the downstream floodplain. Using daily MODIS imagery from 2000 to 2012, we revealed a significant year-round decline in the aggregated inundation area of the studied lakes by an average of ~580 km2 or 17.7% from the pre-dam to post-dam period (i.e., before and after June, 2003). To diagnose TGD's contribution to such lake area decline, we followed a two-step procedure by first quantifying the TGD impacts on the seasonal level regime along the complete longitudinal range of the Yangtze River downstream from TGD to the estuary [Wang et al., 2013], and then estimating the

  12. A downstream voyage with mercury

    Science.gov (United States)

    Heinz, Gary

    2016-01-01

    Retrospective essay for the Bulletin of Environmental Contamination and Toxicology.As I look back on my paper, “Effects of Low Dietary Levels of Methyl Mercury on Mallard Reproduction,” published in 1974 in the Bulletin of Environmental Contamination and Toxicology, a thought sticks in my mind. I realize just how much my mercury research was not unlike a leaf in a stream, carried this way and that, sometimes stalled in an eddy, restarted, and carried downstream at a pace and path that was not completely under my control. I was hired in 1969 by the Patuxent Wildlife Research Center to study the effects of environmental pollutants on the behavior of wildlife. A colleague was conducting a study on the reproductive effects of methylmercury on mallards (Anas platyrhynchos), and he offered to give me some of the ducklings. I conducted a pilot study, testing how readily ducklings approached a tape-recorded maternal call. Sample sizes were small, but the results suggested that ducklings from mercury-treated parents behaved differently than controls. That’s how I got into mercury research—pretty much by chance.

  13. Rare earth industries: Downstream business

    International Nuclear Information System (INIS)

    2011-01-01

    The value chain of the rare earths business involves mining, extraction, processing, refining and the manufacture of an extensive range of downstream products which find wide applications in such industries including aerospace, consumer electronics, medical, military, automotive, renewable wind and solar energy and telecommunications. In fact the entire gamut of the high-tech industries depends on a sustainable supply of rare earths elements. The explosive demand in mobile phones is an excellent illustration of the massive potential that the rare earths business offers. In a matter of less than 20 years, the number of cell phones worldwide has reached a staggering 5 billion. Soon, going by the report of their growth in sales, the world demand for cell phones may even exceed the global population. Admittedly, the rare earths business does pose certain risks. Top among the risks are the health and safety risks. The mining, extraction and refining of rare earths produce residues and wastes which carry health and safety risks. The residues from the extraction and refining are radioactive, while their effluent waste streams do pose pollution risks to the receiving rivers and waterways. But, as clearly elaborated in a recent report by IAEA experts, there are technologies and systems available to efficiently mitigate such risks. The risks are Rare Earth manageable. However, it is crucial that the risk and waste management procedures are strictly followed and adhered to. This is where effective monitoring and surveillance throughout the life of all such rare earths facilities is crucial. Fortunately, Malaysia's regulatory standards on rare earths follow international standards. In some areas, Malaysia's regulatory regime is even more stringent than the international guidelines. (author)

  14. Coriandrum sativum L. (Coriander) essential oil: antifungal activity and mode of action on Candida spp., and molecular targets affected in human whole-genome expression.

    Science.gov (United States)

    Freires, Irlan de Almeida; Murata, Ramiro Mendonça; Furletti, Vivian Fernandes; Sartoratto, Adilson; Alencar, Severino Matias de; Figueira, Glyn Mara; de Oliveira Rodrigues, Janaina Aparecida; Duarte, Marta Cristina Teixeira; Rosalen, Pedro Luiz

    2014-01-01

    Oral candidiasis is an opportunistic fungal infection of the oral cavity with increasingly worldwide prevalence and incidence rates. Novel specifically-targeted strategies to manage this ailment have been proposed using essential oils (EO) known to have antifungal properties. In this study, we aim to investigate the antifungal activity and mode of action of the EO from Coriandrum sativum L. (coriander) leaves on Candida spp. In addition, we detected the molecular targets affected in whole-genome expression in human cells. The EO phytochemical profile indicates monoterpenes and sesquiterpenes as major components, which are likely to negatively impact the viability of yeast cells. There seems to be a synergistic activity of the EO chemical compounds as their isolation into fractions led to a decreased antimicrobial effect. C. sativum EO may bind to membrane ergosterol, increasing ionic permeability and causing membrane damage leading to cell death, but it does not act on cell wall biosynthesis-related pathways. This mode of action is illustrated by photomicrographs showing disruption in biofilm integrity caused by the EO at varied concentrations. The EO also inhibited Candida biofilm adherence to a polystyrene substrate at low concentrations, and decreased the proteolytic activity of Candida albicans at minimum inhibitory concentration. Finally, the EO and its selected active fraction had low cytotoxicity on human cells, with putative mechanisms affecting gene expression in pathways involving chemokines and MAP-kinase (proliferation/apoptosis), as well as adhesion proteins. These findings highlight the potential antifungal activity of the EO from C. sativum leaves and suggest avenues for future translational toxicological research.

  15. Haploid genetic screens identify an essential role for PLP2 in the downregulation of novel plasma membrane targets by viral E3 ubiquitin ligases.

    Directory of Open Access Journals (Sweden)

    Richard T Timms

    Full Text Available The Kaposi's sarcoma-associated herpesvirus gene products K3 and K5 are viral ubiquitin E3 ligases which downregulate MHC-I and additional cell surface immunoreceptors. To identify novel cellular genes required for K5 function we performed a forward genetic screen in near-haploid human KBM7 cells. The screen identified proteolipid protein 2 (PLP2, a MARVEL domain protein of unknown function, as essential for K5 activity. Genetic loss of PLP2 traps the viral ligase in the endoplasmic reticulum, where it is unable to ubiquitinate and degrade its substrates. Subsequent analysis of the plasma membrane proteome of K5-expressing KBM7 cells in the presence and absence of PLP2 revealed a wide range of novel K5 targets, all of which required PLP2 for their K5-mediated downregulation. This work ascribes a critical function to PLP2 for viral ligase activity and underlines the power of non-lethal haploid genetic screens in human cells to identify the genes involved in pathogen manipulation of the host immune system.

  16. PknB remains an essential and a conserved target for drug development in susceptible and MDR strains of M. Tuberculosis.

    Science.gov (United States)

    Gupta, Anamika; Pal, Sudhir K; Pandey, Divya; Fakir, Najneen A; Rathod, Sunita; Sinha, Dhiraj; SivaKumar, S; Sinha, Pallavi; Periera, Mycal; Balgam, Shilpa; Sekar, Gomathi; UmaDevi, K R; Anupurba, Shampa; Nema, Vijay

    2017-08-18

    The Mycobacterium tuberculosis (M.tb) protein kinase B (PknB) which is now proved to be essential for the growth and survival of M.tb, is a transmembrane protein with a potential to be a good drug target. However it is not known if this target remains conserved in otherwise resistant isolates from clinical origin. The present study describes the conservation analysis of sequences covering the inhibitor binding domain of PknB to assess if it remains conserved in susceptible and resistant clinical strains of mycobacteria picked from three different geographical areas of India. A total of 116 isolates from North, South and West India were used in the study with a variable profile of their susceptibilities towards streptomycin, isoniazid, rifampicin, ethambutol and ofloxacin. Isolates were also spoligotyped in order to find if the conservation pattern of pknB gene remain consistent or differ with different spoligotypes. The impact of variation as found in the study was analyzed using Molecular dynamics simulations. The sequencing results with 115/116 isolates revealed the conserved nature of pknB sequences irrespective of their susceptibility status and spoligotypes. The only variation found was in one strains wherein pnkB sequence had G to A mutation at 664 position translating into a change of amino acid, Valine to Isoleucine. After analyzing the impact of this sequence variation using Molecular dynamics simulations, it was observed that the variation is causing no significant change in protein structure or the inhibitor binding. Hence, the study endorses that PknB is an ideal target for drug development and there is no pre-existing or induced resistance with respect to the sequences involved in inhibitor binding. Also if the mutation that we are reporting for the first time is found again in subsequent work, it should be checked with phenotypic profile before drawing the conclusion that it would affect the activity in any way. Bioinformatics analysis in our study

  17. WA7 - View from downstream

    CERN Multimedia

    1977-01-01

    With this set-up the Annecy (LAPP)-CERN-Copenhagen(Niels Bohr Institute)-Genova-Oslo-University College London Collaboration investigated large-angle elastic scattering of charged mesons and antiprotons on protons, first at 20 and 30 GeV/c, later at 50 GeV/c. The beam H1 (from top) passes two CEDAR counters (centre) before entering the one-metre long liquid hydrogen target, partly inside a magnet of 1.56 T, with a field volume of about 1.50x0.75x1.50 m3. In the foreground one sees on the left the hadron calorimeter of the 'slow' arm; on the right, are scintillation hodoscopes and behind them, a treshold Cerenkov counter of the 'fast' arm.

  18. The Optimedin gene is a downstream target of Pax6

    Czech Academy of Sciences Publication Activity Database

    Grinchuk, O.; Kozmik, Zbyněk; Wu, X.; Tomarev, S.

    2005-01-01

    Roč. 280, č. 42 (2005), s. 35228-35237 ISSN 0021-9258 R&D Projects: GA ČR GA204/04/1358 Institutional research plan: CEZ:AV0Z50520514 Keywords : Pax6 * optimedin * promotor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.854, year: 2005

  19. Surfactant Distribution Measurements Downstream of a Reynolds Ridge

    Science.gov (United States)

    Kelley, J. S.; Korenowski, G. M.; Vogel, M. J.; Hirsa, A. H.

    1999-11-01

    Minuscule amounts of surface-active agents, of the order of 1 mg/m^2, are sufficient to change the characteristics of flow at an air/water interface. Specifically, the intrinsic viscoelastic interfacial properties, which are a strong function of the concentration of the surfactant, appear in essential terms of the boundary conditions of the flow equations. The noninvasive laser-based technique of second harmonic generation (SHG) is used to determine the surfactant concentration profile downstream of a contamination front in real time. In this experiment, a Reynolds ridge marks the leading edge of a contaminated region upstream of a surface barrier. The SHG technique allows for the nonintrusive characterization of the top molecular layer over the subsurface flow. Results include the concentration gradient and surface tension profiles downstream of the Reynolds ridge. The SHG results, along with simultaneous DPIV measurements, will be related to the interfacial viscosities.

  20. Upstream-downstream cooperation approach in Guanting Reservoir watershed.

    Science.gov (United States)

    Yang, Zhi-Feng; Zhang, Wen-Guo

    2005-01-01

    A case study is introduced and discussed concerning water dispute of misuse and pollution between up- and down-stream parts. The relations between water usage and local industrial structures are analyzed. Results show it is important to change industrial structures of the target region along with controlling water pollution by technical and engineering methods. Three manners of upstream-downstream cooperation are presented and discussed based on the actual conditions of Guangting Reservoir watershed. Two typical scenarios are supposed and studied along with the local plan on water resources development. The best solution for this cooperation presents a good way to help the upstream developing in a new pattern of eco-economy.

  1. Essential thrombocythemia

    Science.gov (United States)

    Primary thrombocythemia; Essential thrombocytosis ... the gums Prolonged bleeding from surgical procedures or tooth removal ... 68. Tefferi A. Polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In: Goldman L, Schafer AI, eds. Goldman- ...

  2. Constitutive phosphorylation of ATM in lymphoblastoid cell lines from patients with ICF syndrome without downstream kinase activity.

    Science.gov (United States)

    Goldstine, Jimena V; Nahas, Shareef; Gamo, Kristin; Gartler, Stanley M; Hansen, R Scott; Roelfsema, Jeroen H; Gatti, Richard A; Marahrens, York

    2006-04-08

    Double strand DNA breaks in the genome lead to the activation of the ataxia-telangiectasia mutated (ATM) kinase in a process that requires ATM autophosphorylation at serine-1981. ATM autophosphorylation only occurs if ATM is previously acetylated by Tip60. The activated ATM kinase phosphorylates proteins involved in arresting the cell cycle, including p53, and in repairing the DNA breaks. Chloroquine treatment and other manipulations that produce chromatin defects in the absence of detectable double strand breaks also trigger ATM phosphorylation and the phosphorylation of p53 in primary human fibroblasts, while other downstream substrates of ATM that are involved in the repair of DNA double strand breaks remain unphosphorylated. This raises the issue of whether ATM is constitutively activated in patients with genetic diseases that display chromatin defects. We examined lymphoblastoid cell lines (LCLs) generated from patients with different types of chromatin disorders: Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome, Coffin Lowry syndrome, Rubinstein Taybi syndrome and Fascioscapulohumeral Muscular Dystrophy. We show that ATM is phosphorylated on serine-1981 in LCLs derived from ICF patients but not from the other syndromes. The phosphorylated ATM in ICF cells did not phosphorylate the downstream targets NBS1, SMC1 and H2AX, all of which require the presence of double strand breaks. We demonstrate that ICF cells respond normally to ionizing radiation, ruling out the possibility that genetic deficiency in ICF cells renders activated ATM incapable of phosphorylating its downstream substrates. Surprisingly, p53 was also not phosphorylated in ICF cells or in chloroquine-treated wild type LCLs. In this regard the response to chromatin-altering agents differs between primary fibroblasts and LCLs. Our findings indicate that although phosphorylation at serine-1981 is essential in the activation of the ATM kinase, serine-1981 phosphorylation is

  3. Philippines' downstream sector poised for growth

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    This paper reports that the Philippines' downstream sector is poised for sharp growth. Despite a slip in refined products demand in recent years, Philippines products demand will rebound sharply by 2000, East-West Center (EWC), Honolulu, predicts. Philippines planned refinery expansions are expected to meet that added demand, EWC Director Fereidun Fesharaki says. Like the rest of the Asia-Pacific region, product specifications are changing, but major refiners in the area expect to meet the changes without major case outlays. At the same time, Fesharaki says, push toward deregulation will further bolster the outlook for the Philippines downstream sector

  4. KNIME essentials

    CERN Document Server

    Bakos, Gábor

    2013-01-01

    KNIME Essentials is a practical guide aimed at getting the results you want, as quickly as possible.""Knime Essentials"" is written for data analysts looking to quickly get up to speed using the market leader in data processing tools, KNIME. No knowledge of KNIME is required, but we will assume that you have some background in data processing.

  5. Wake characterization downstream of a fog collector

    Science.gov (United States)

    Bresci, E.

    The problem of wake geometry characterization downstream of a collector for getting water out of advection fog is investigated combining the results coming from wind tunnel trials and an experimental campaign in Peru ( Lomas de Mejia), where a fog collection project was running. Results from a physical model of the fog collector at a 1:100 scale tested in a wind tunnel through anemometer velocity measurements and flow visualization techniques showed, at different heights from the ground, the general direction of the flow in the vicinity of the obstacle and the extension of the downstream-disturbed area. Wind speed data collection in Peru showed the reduction in wind speed depending on its intensity. The preliminary results show the utility of such an approach in order to improve the understanding of the flow motion downstream of permeable surfaces. The possibility of spatially characterizing the wake presence has a practical utilization whenever the knowledge of the geometry of the wake downstream of an obstacle is required.

  6. Scleroglucan: Fermentative Production, Downstream Processing and Applications

    Directory of Open Access Journals (Sweden)

    Shrikant A. Survase

    2007-01-01

    Full Text Available Exopolysaccharides produced by a variety of microorganisms find multifarious industrial applications in foods, pharmaceutical and other industries as emulsifiers, stabilizers, binders, gelling agents, lubricants, and thickening agents. One such exopolysaccharide is scleroglucan, produced by pure culture fermentation from filamentous fungi of genus Sclerotium. The review discusses the properties, fermentative production, downstream processing and applications of scleroglucan.

  7. Downstream bioprocess characterisation within microfluidic devices

    DEFF Research Database (Denmark)

    Marques, Marco; Krühne, Ulrich; Szita, Nicolas

    2016-01-01

    Miniaturising bioprocess unit operation steps is a well-established approach to find novel routes for process intensification and improved process economics. While a number of microbioreactors have been presented over the last 15 years, miniaturised downstream unit operations (mDUO) are less...

  8. Topology essentials

    CERN Document Server

    Milewski, Emil G

    2013-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Topology includes an overview of elementary set theory, relations and functions, ordinals and cardinals, topological spaces, continuous functions, metric spaces and normed spaces, co

  9. Astronomy essentials

    CERN Document Server

    Brass, Charles O

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Astronomy includes the historical perspective of astronomy, sky basics and the celestial coordinate systems, a model and the origin of the solar system, the sun, the planets, Kepler'

  10. Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors.

    Directory of Open Access Journals (Sweden)

    Hannah Karlsson

    Full Text Available CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

  11. Insight into PreImplantation Factor (PIF*) Mechanism for Embryo Protection and Development: Target Oxidative Stress and Protein Misfolding (PDI and HSP) through Essential RIPK Binding Site

    Science.gov (United States)

    Barnea, Eytan R.; Lubman, David M.; Liu, Yan-Hui; Absalon-Medina, Victor; Hayrabedyan, Soren; Todorova, Krassimira; Gilbert, Robert O.; Guingab, Joy; Barder, Timothy J.

    2014-01-01

    Background Endogenous PIF, upon which embryo development is dependent, is secreted only by viable mammalian embryos, and absent in non-viable ones. Synthetic PIF (sPIF) administration promotes singly cultured embryos development and protects against their demise caused by embryo-toxic serum. To identify and characterize critical sPIF-embryo protein interactions novel biochemical and bio-analytical methods were specifically devised. Methods FITC-PIF uptake/binding by cultured murine and equine embryos was examined and compared with scrambled FITC-PIF (control). Murine embryo (d10) lysates were fractionated by reversed-phase HPLC, fractions printed onto microarray slides and probed with Biotin-PIF, IDE and Kv1.3 antibodies, using fluorescence detection. sPIF-based affinity column was developed to extract and identify PIF-protein interactions from lysates using peptide mass spectrometry (LC/MS/MS). In silico evaluation examined binding of PIF to critical targets, using mutation analysis. Results PIF directly targets viable cultured embryos as compared with control peptide, which failed to bind. Multistep Biotin-PIF targets were confirmed by single-step PIF-affinity column based isolation. PIF binds protein disulfide isomerases a prolyl-4-hydroxylase β-subunit, (PDI, PDIA4, PDIA6-like) containing the antioxidant thioredoxin domain. PIF also binds protective heat shock proteins (70&90), co-chaperone, BAG-3. Remarkably, PIF targets a common RIPK site in PDI and HSP proteins. Further, single PIF amino acid mutation significantly reduced peptide-protein target bonding. PIF binds promiscuous tubulins, neuron backbones and ACTA-1,2 visceral proteins. Significant anti-IDE, while limited anti-Kv1.3b antibody-binding to Biotin-PIF positive lysates HPLC fractions were documented. Conclusion Collectively, data identifies PIF shared targets on PDI and HSP in the embryo. Such are known to play a critical role in protecting against oxidative stress and protein misfolding. PIF

  12. India's Downstream Petroleum Sector

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    This study provides a holistic examination of pricing and investment dynamics in India's downstream petroleum sector. It analyses the current pricing practices, highlights the tremendous fiscal cost of current pricing and regulatory arrangements, and examines the sectoral investment dynamics. It also looks at potential paths towards market-based reform along which the Indian government may move, while at the same time protecting energy market access for India's large poor population.

  13. Emory University: MEDICI (Mining Essentiality Data to Identify Critical Interactions) for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at Emory University has developed a computational methodology to combine high-throughput knockdown data with known protein network topologies to infer the importance of protein-protein interactions (PPIs) for the survival of cancer cells.  Applying these data to the Achilles shRNA results, the CCLE cell line characterizations, and known and newly identified PPIs provides novel insights for potential new drug targets for cancer therapies and identifies important PPI hubs.

  14. EphA2 Is a Therapy Target in EphA2-Positive Leukemias but Is Not Essential for Normal Hematopoiesis or Leukemia.

    Science.gov (United States)

    Charmsaz, Sara; Beckett, Kirrilee; Smith, Fiona M; Bruedigam, Claudia; Moore, Andrew S; Al-Ejeh, Fares; Lane, Steven W; Boyd, Andrew W

    2015-01-01

    Members of the Eph family of receptor tyrosine kinases and their membrane bound ephrin ligands have been shown to play critical roles in many developmental processes and more recently have been implicated in both normal and pathological processes in post-embryonic tissues. In particular, expression studies of Eph receptors and limited functional studies have demonstrated a role for the Eph/ephrin system in hematopoiesis and leukemogenesis. In particular, EphA2 was reported on hematopoietic stem cells and stromal cells. There are also reports of EphA2 expression in many different types of malignancies including leukemia, however there is a lack of knowledge in understanding the role of EphA2 in hematopoiesis and leukemogenesis. We explored the role of EphA2 in hematopoiesis by analyzing wild type and EphA2 knockout mice. Mature, differentiated cells, progenitors and hematopoietic stem cells derived from knockout and control mice were analyzed and no significant abnormality was detected. These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis. Comparative studies using EphA2-negative MLL-AF9 leukemias derived from EphA2-knockout animals showed that there was no detectable functional role for EphA2 in the initiation or progression of the leukemic process. However, expression of EphA2 in leukemias initiated by MLL-AF9 suggested that this protein might be a possible therapy target in this type of leukemia. We showed that treatment with EphA2 monoclonal antibody IF7 alone had no effect on tumorigenicity and latency of the MLL-AF9 leukemias, while targeting of EphA2 using EphA2 monoclonal antibody with a radioactive payload significantly impaired the leukemic process. Altogether, these results identify EphA2 as a potential radio-therapeutic target in leukemias with MLL translocation.

  15. Essential Tremor

    Science.gov (United States)

    ... of botulinum toxin as a treatment for a variety of involuntary movement disorders, including essential tremor of the hand. Get information from the National Library of Medicine’s MedlinePlus Tremor Show More Show Less Search Disorders SEARCH SEARCH Definition ...

  16. Highcharts essentials

    CERN Document Server

    Shahid, Bilal

    2014-01-01

    If you are a web developer with a basic knowledge of HTML, CSS, and JavaScript and want to quickly get started with this web charting technology, this is the book for you. This book will also serve as an essential guide to those who have probably used a similar library and are now looking at migrating to Highcharts.

  17. Swift essentials

    CERN Document Server

    Blewitt, Alex

    2014-01-01

    Whether you are a seasoned Objective-C developer or new to the Xcode platform, Swift Essentials will provide you with all you need to know to get started with the language. Prior experience with iOS development is not necessary, but will be helpful to get the most out of the book.

  18. Dart essentials

    CERN Document Server

    Sikora, Martin

    2015-01-01

    This book is targeted at expert programmers in JavaScript who want to learn Dart quickly. Some previous experience with OOP programming in other languages and a good knowledge of JavaScript are assumed.

  19. Co-targeting intracellular pH and essential amino acid uptake cooperates to induce cell death of T-ALL/LL cells.

    Science.gov (United States)

    Imbert, Véronique; Nebout, Marielle; Mary, Didier; Endou, Hitoshi; Wempe, Michael F; Supuran, Claudiu T; Winum, Jean-Yves; Peyron, Jean-François

    2018-02-01

    Cancer cells reprogram their metabolism to optimize their growth and proliferation in the host microenvironment. For this purpose, they enhance the uptake of extracellular nutrients and deal with the metabolic waste products through the overexpression of numerous membrane proteins including amino-acid transporters (LAT1) and acid-base regulating enzymes, such as carbonic anhydrases (CAs). Here we describe the anti-tumoral effects of a new class of CAXII inhibitors, the glycosyl coumarins on T-ALL/LL cells. These effects appeared to be mediated through inhibition of mTOR/Akt pathway and c-myc downregulation. Interestingly, we show that the combined targeting of amino acid fluxes and pH regulators provides a promising therapeutic strategy in the future of T-ALL/LL management.

  20. Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis

    Directory of Open Access Journals (Sweden)

    Vincent van den Boom

    2016-01-01

    Full Text Available Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here, we find that the non-canonical PRC1.1 complex, as identified by mass-spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3, suggesting a gene-regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls specific genes involved in unique cell biological processes required for leukemic cell viability.

  1. Cerebral Targeting of Acupuncture at Combined Acupoints in Treating Essential Hypertension: An Rs-fMRI Study and Curative Effect Evidence

    Directory of Open Access Journals (Sweden)

    Yanjie Wang

    2016-01-01

    Full Text Available The study attempted to explore that the synergistic effect of acupoints combination is not a simple superposition of single acupoint’s effect by comparing and analyzing the changes of blood pressure (BP, SF-36, and brain regions after acupuncture treatment. 47 patients were randomly divided into LR3+KI3 group, LR3 group, and KI3 group. Subjects received Rs-fMRI scan, BP measurement, and SF-36 questionnaires before and after treatment and short-term acupuncture treatment. After treatment, there were no significant differences in BP and SF-36 among 3 groups, compared to the case before treatment, SBP of 3 groups decreased, and DBP significantly decreased while vitality and mental health significantly increased in LR3+KI3 group. Both number and scopes of changes of brain regions in LR3+KI3 group were the largest, which mainly included BAs 3, 4, 8, 19, 21, 24, 32, 44, and 45. In conclusion, acupuncture at LR3+KI3 may auxiliarily reduce BP and improve the vitality and mental health of patients, and the changes of brain regions were related to somatesthesia, movement, vision, audition, emotion and mood, language, memory, etc. BAs 4, 9, 10, 24, 31, 32, and 46 may be the targeting brain areas of acupuncture in assisting hypotension. It is suggested that acupoints combination of LR3+KI3 maybe generates a synergistic effect, and it is not simple sum of single acupoint effect.

  2. Inhibition of BmNPV replication in silkworm cells using inducible and regulated artificial microRNA precursors targeting the essential viral gene lef-11.

    Science.gov (United States)

    Zhang, Jun; He, Qian; Zhang, Chun-Dong; Chen, Xiang-Yun; Chen, Xue-Mei; Dong, Zhan-Qi; Li, Na; Kuang, Xiu-Xiu; Cao, Ming-Ya; Lu, Cheng; Pan, Min-Hui

    2014-04-01

    Bombyx mori nucleopolyhedrovirus (BmNPV) is a major silkworm pathogen, causing substantial economic losses to the sericulture industry annually. We demonstrate a novel anti-BmNPV system expressing mature artificial microRNAs (amiRNAs) targeting the viral lef-11 gene. The mature amiRNAs inhibited the lef-11 gene in silkworm BmN-SWU1 cells. Antiviral assays demonstrated that mature amiRNAs silenced the gene and inhibited BmNPV proliferation efficiently. As constitutive overexpression of mature amiRNAs may induce acute cellular toxicity, we further developed a novel virus-induced amiRNA expression system. The amiRNA cassette is regulated by a baculovirus-induced fusion promoter. This baculovirus-induced RNA interference system is strictly regulated by virus infection, which functions in a negative feedback loop to activate the expression of mature amiRNAs against lef-11 and subsequently control inhibition of BmNPV replication. Our study advances the use of a regulatable amiRNA cassette as a safe and effective tool for research of basic insect biology and antiviral application. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Essential SQLAlchemy

    CERN Document Server

    Copeland, Rick

    2008-01-01

    Essential SQLAlchemy introduces a high-level open-source code library that makes it easier for Python programmers to access relational databases such as Oracle, DB2, MySQL, PostgreSQL, and SQLite. SQLAlchemy has become increasingly popular since its release, but it still lacks good offline documentation. This practical book fills the gap, and because a developer wrote it, you get an objective look at SQLAlchemy's tools rather than an advocate's description of all the "cool" features. SQLAlchemy includes both a database server-independent SQL expression language and an object-relational mappe

  4. Linux Essentials

    CERN Document Server

    Smith, Roderick W

    2012-01-01

    A unique, full-color introduction to Linux fundamentals Serving as a low-cost, secure alternative to expensive operating systems, Linux is a UNIX-based, open source operating system. Full-color and concise, this beginner's guide takes a learning-by-doing approach to understanding the essentials of Linux. Each chapter begins by clearly identifying what you will learn in the chapter, followed by a straightforward discussion of concepts that leads you right into hands-on tutorials. Chapters conclude with additional exercises and review questions, allowing you to reinforce and measure your underst

  5. Prezi essentials

    CERN Document Server

    Sinclair, Domi

    2014-01-01

    If you want to learn Prezi, and specifically design within Prezi, this is the book for you. Perhaps you already know a bit about Prezi but have never used it, or perhaps you have used Prezi before but want to learn how to incorporate your own custom design elements. In either case, this book will get you up and running quickly. It would be helpful to have a bit of familiarity with basic design concepts and the use of Prezi, but prior experience is not essential.

  6. The jet membrane-experiment: downstream sampling

    International Nuclear Information System (INIS)

    Campargue, R.

    1976-01-01

    The invasion separation effect of the free jet structure was found in 1966 at Saclay. In the Downstream Sampling Configuration patended by Campargue (1967), the light fraction is withdrawn from the supersonic central core, by skimming the separating free jet. From experimental and theoretical results obtained for gas and isotopic mixtures, the following points linked to operation and equipment costs, are considered: system description; influence of mass ratio, expansion ratio, nature of separating gas, ratio of upflow to separating jet flow, rarefaction. Fron an uninteresting aspect of Jet Membrane (elimination of background penetration), a new principle has been discovered to produce nozzle beams which may be of great interest for other separation processes involving free jets and/or molecular beams [fr

  7. Downstream hydraulic geometry and hydraulic similitude

    Science.gov (United States)

    Griffiths, George A.

    2003-04-01

    A theoretical basis is provided for the empirical equations of downstream hydraulic geometry, written as scaling relations, using the equations for momentum, flow resistance, and continuity of gradually varied open channel flow. Width, depth, velocity, and bed slope are expressed as power functions of water discharge and bed sediment size. These theoretical relations apply in alluvial, ice, and bedrock channels and hold for any value of water discharge as opposed to just mean or bank-full values used in empirical equations. A scaling relation for bed load transport rate in alluvial channels is also derived using dimensional analysis. Threshold and regime theories of stable channel design are shown to be consistent with the requirements of hydraulic similitude as defined by the scaling relations. If field measurements confirm that the scaling relations apply in braided alluvial channels, then predictions of a threshold bed slope between states of meandering and braiding will not be valid.

  8. Downstream effects of intermittent power generation

    Energy Technology Data Exchange (ETDEWEB)

    Bretschko, G. (Austrian Academy of Sciences, Lunz (AT). Inst. fuer Limnologie); Moog, O. (Univ. Agric., Vienna (AT). Inst. Water Prov., Water Quality and Fisheries Management)

    1990-01-01

    Intermittent hydro-power generation creates frequent and dramatic discharge peaks combined with intervening extremely low water conditions downstream of the plant. Studies of the two Austrian rivers showed that whereas no alterations were found in the qualitative composition of zoobenthos, the decrease in abundance and biomass may amount up to 95%. The mismatch between the hydrography of surface water and groundwater might well be a cause of the detrimental effects of frequent and artificially created spates. The drastic reduction of zoobenthic biomass affects not only fish production but minimizes self-purification processes as well. Until tributaries diminish the effects of intermittent power generation, the river is reduced to a mere transport vehicle. (author).

  9. Innovation in Downstream Fashion Retail Networks

    DEFF Research Database (Denmark)

    Tambo, Torben

    2012-01-01

    While product marketers and brand owners struggle to make new products, manufacturing processes and inbound logistics, innovation taking place in retail networks is often overlooked. Networks in retailing are comprised by varieties of single- and multi-brand stores, chains and departments stores......, technology and service providers, ownership structures and local level supply chain facilities. This paper analyses theoretical and empirical views of innovation in international retail networks using the fashion industry as a case because this industry better than other industries maintain branded stores......-depth studies of the biggest Danish fashion brand owners and their respective retail networks. The study shows how brand owners can emphasise change by shifting from a passive and narrow observation of its downstream retail network to an active and broad observation, or at least develop a conscious approach...

  10. Essential astrophysics

    CERN Document Server

    Lang, Kenneth R

    2013-01-01

    Essential Astrophysics is a book to learn or teach from, as well as a fundamental reference volume for anyone interested in astronomy and astrophysics. It presents astrophysics from basic principles without requiring any previous study of astronomy or astrophysics. It serves as a comprehensive introductory text, which takes the student through the field of astrophysics in lecture-sized chapters of basic physical principles applied to the cosmos. This one-semester overview will be enjoyed by undergraduate students with an interest in the physical sciences, such as astronomy, chemistry, engineering or physics, as well as by any curious student interested in learning about our celestial science. The mathematics required for understanding the text is on the level of simple algebra, for that is all that is needed to describe the fundamental principles. The text is of sufficient breadth and depth to prepare the interested student for more advanced specialized courses in the future. Astronomical examples are provide...

  11. Downstream Processing of Synechocystis for Biofuel Production

    Science.gov (United States)

    Sheng, Jie

    Lipids and free fatty acids (FFA) from cyanobacterium Synechocystis can be used for biofuel (e.g. biodiesel or renewable diesel) production. In order to utilize and scale up this technique, downstream processes including culturing and harvest, cell disruption, and extraction were studied. Several solvents/solvent systems were screened for lipid extraction from Synechocystis. Chloroform + methanol-based Folch and Bligh & Dyer methods were proved to be "gold standard" for small-scale analysis due to their highest lipid recoveries that were confirmed by their penetration of the cell membranes, higher polarity, and stronger interaction with hydrogen bonds. Less toxic solvents, such as methanol and MTBE, or direct transesterification of biomass (without preextraction step) gave only slightly lower lipid-extraction yields and can be considered for large-scale application. Sustained exposure to high and low temperature extremes severely lowered the biomass and lipid productivity. Temperature stress also triggered changes of lipid quality such as the degree of unsaturation; thus, it affected the productivities and quality of Synechocystis-derived biofuel. Pulsed electric field (PEF) was evaluated for cell disruption prior to lipid extraction. A treatment intensity > 35 kWh/m3 caused significant damage to the plasma membrane, cell wall, and thylakoid membrane, and it even led to complete disruption of some cells into fragments. Treatment by PEF enhanced the potential for the low-toxicity solvent isopropanol to access lipid molecules during subsequent solvent extraction, leading to lower usage of isopropanol for the same extraction efficiency. Other cell-disruption methods also were tested. Distinct disruption effects to the cell envelope, plasma membrane, and thylakoid membranes were observed that were related to extraction efficiency. Microwave and ultrasound had significant enhancement of lipid extraction. Autoclaving, ultrasound, and French press caused significant

  12. Downstream fish passage on Black River system

    International Nuclear Information System (INIS)

    Downstream fish passage of juvenile alewife at the Black River hydroelectric system has traditionally been directed by a major screen assembly to a route avoiding altogether four out of five small hydroelectric power plants. This system includes retention of larvae/juveniles in a lake until mid July, diversion of fish via a major screen assembly and by-passing of a station using a fish ladder. However, difficulties with the arrangement have resulted in increasing numbers of fish passing by all five stations. A second option which reduces labour and maintenance activities and promotes increased growth of fish as they pass from reservoir to reservoir involves use of simple fishways coupled with fish pulsers to deflect fish from the station intakes. The fish pulsers use 100 Hz frequency at 20 pulses per minute placed directly in front of the station intake at a depth of 3 m. Both strategies have contributed to increased fish production and migration such that the present run is 5 million to 8 million fish. 4 refs., 4 figs

  13. Microbial production of scleroglucan and downstream processing

    Directory of Open Access Journals (Sweden)

    Natalia Alejandra Castillo

    2015-10-01

    Full Text Available Synthetic petroleum-based polymers and natural plant polymers have the disadvantage of restricted sources, in addition to the non-biodegradability of the former ones. In contrast, eco-sustainable microbial polysaccharides, of low-cost and standardized production, represent an alternative to address this situation. With a strong global market, they attracted worldwide attention because of their novel and unique physico-chemical properties as well as varied industrial applications, and many of them are promptly becoming economically competitive. Scleroglucan, a beta-1,3-beta-1,6-glucan secreted by Sclerotium fungi, exhibits high potential for commercialization and may show different branching frequency, side-chain length and/or molecular weight depending on the producing strain or culture conditions. Water-solubility, viscosifying ability and wide stability over temperature, pH and salinity make scleroglucan useful for different biotechnological (enhanced oil recovery, food additives, drug delivery, cosmetic and pharmaceutical products, biocompatible materials, etc., and biomedical (immunoceutical, antitumor, etc. applications. It can be copiously produced at bioreactor scale under standardized conditions, where a high EPS concentration normally governs the process optimization. Operative and nutritional conditions, as well as the incidence of scleroglucan downstream processing will be discussed in this chapter. The relevance of using standardized inocula from selected strains and experiences concerning the intricate scleroglucan scaling-up will be also herein outlined.

  14. RFX2 is a candidate downstream amplifier of A-MYB regulation in mouse spermatogenesis

    Directory of Open Access Journals (Sweden)

    Kistler Malathi K

    2009-12-01

    Full Text Available Abstract Background Mammalian spermatogenesis involves formation of haploid cells from the male germline and then a complex morphological transformation to generate motile sperm. Focusing on meiotic prophase, some tissue-specific transcription factors are known (A-MYB or suspected (RFX2 to play important roles in modulating gene expression in pachytene spermatocytes. The current work was initiated to identify both downstream and upstream regulatory connections for Rfx2. Results Searches of pachytene up-regulated genes identified high affinity RFX binding sites (X boxes in promoter regions of several new genes: Adam5, Pdcl2, and Spag6. We confirmed a strong promoter-region X-box for Alf, a germ cell-specific variant of general transcription factor TFIIA. Using Alf as an example of a target gene, we showed that its promoter is stimulated by RFX2 in transfected cells and used ChIP analysis to show that the promoter is occupied by RFX2 in vivo. Turning to upstream regulation of the Rfx2 promoter, we identified a cluster of three binding sites (MBS for the MYB family of transcription factors. Because testis is one of the few sites of A-myb expression, and because spermatogenesis arrests in pachytene in A-myb knockout mice, the MBS cluster implicates Rfx2 as an A-myb target. Electrophoretic gel-shift, ChIP, and co-transfection assays all support a role for these MYB sites in Rfx2 expression. Further, Rfx2 expression was virtually eliminated in A-myb knockout testes. Immunohistology on testis sections showed that A-MYB expression is up-regulated only after pachytene spermatocytes have clearly moved away from the tubule wall, which correlates with onset of RFX2 expression, whereas B-MYB expression, by contrast, is prevalent only in earlier spermatocytes and spermatogonia. Conclusion With an expanding list of likely target genes, RFX2 is potentially an important transcriptional regulator in pachytene spermatocytes. Rfx2 itself is a good candidate to be

  15. Hydroeconomic optimization of reservoir management under downstream water quality constraints

    Science.gov (United States)

    Davidsen, Claus; Liu, Suxia; Mo, Xingguo; Holm, Peter E.; Trapp, Stefan; Rosbjerg, Dan; Bauer-Gottwein, Peter

    2015-10-01

    A hydroeconomic optimization approach is used to guide water management in a Chinese river basin with the objectives of meeting water quantity and water quality constraints, in line with the China 2011 No. 1 Policy Document and 2015 Ten-point Water Plan. The proposed modeling framework couples water quantity and water quality management and minimizes the total costs over a planning period assuming stochastic future runoff. The outcome includes cost-optimal reservoir releases, groundwater pumping, water allocation, wastewater treatments and water curtailments. The optimization model uses a variant of stochastic dynamic programming known as the water value method. Nonlinearity arising from the water quality constraints is handled with an effective hybrid method combining genetic algorithms and linear programming. Untreated pollutant loads are represented by biochemical oxygen demand (BOD), and the resulting minimum dissolved oxygen (DO) concentration is computed with the Streeter-Phelps equation and constrained to match Chinese water quality targets. The baseline water scarcity and operational costs are estimated to 15.6 billion CNY/year. Compliance to water quality grade III causes a relatively low increase to 16.4 billion CNY/year. Dilution plays an important role and increases the share of surface water allocations to users situated furthest downstream in the system. The modeling framework generates decision rules that result in the economically efficient strategy for complying with both water quantity and water quality constraints.

  16. A floating trap for sampling downstream migrant fishes.

    Science.gov (United States)

    Carl E. McLemore; Fred H. Everest; William R. Humphreys; Mario F. Solazzi

    1989-01-01

    Fishery scientists and managers are interested in obtaining information about downstream movements of fish species for biological and economic reasons. Different types of nets and traps have been used for this purpose with only partial success. The floating, self-cleaning downstream migrant trap described here proved successful for sampling several salmoniform and...

  17. Molecular and functional analysis of a conserved CTL epitope in HIV-1 p24 recognized from a long-term nonprogressor: constraints on immune escape associated with targeting a sequence essential for viral replication.

    Science.gov (United States)

    Wagner, R; Leschonsky, B; Harrer, E; Paulus, C; Weber, C; Walker, B D; Buchbinder, S; Wolf, H; Kalden, J R; Harrer, T

    1999-03-15

    It has been hypothesized that sequence variation within CTL epitopes leading to immune escape plays a role in the progression of HIV-1 infection. Only very limited data exist that address the influence of biologic characteristics of CTL epitopes on the emergence of immune escape variants and the efficiency of suppression HIV-1 by CTL. In this report, we studied the effects of HIV-1 CTL epitope sequence variation on HIV-1 replication. The highly conserved HLA-B14-restricted CTL epitope DRFYKTLRAE in HIV-1 p24 was examined, which had been defined as the immunodominant CTL epitope in a long-term nonprogressing individual. We generated a set of viral mutants on an HX10 background differing by a single conservative or nonconservative amino acid substitution at each of the P1 to P9 amino acid residues of the epitope. All of the nonconservative amino acid substitutions abolished viral infectivity and only 5 of 10 conservative changes yielded replication-competent virus. Recognition of these epitope sequence variants by CTL was tested using synthetic peptides. All mutations that abrogated CTL recognition strongly impaired viral replication, and all replication-competent viral variants were recognized by CTL, although some variants with a lower efficiency. Our data indicate that this CTL epitope is located within a viral sequence essential for viral replication. Targeting CTL epitopes within functionally important regions of the HIV-1 genome could limit the chance of immune evasion.

  18. The iPhone Goes Downstream: Mandatory Universal Distribution∗

    OpenAIRE

    Karp, Larry; Perloff, Jeffrey

    2011-01-01

    Apple’s original decision to market iPhones using a single downstream vendor prompted calls for mandatory universal distribution (MUD), whereby all downstream vendors would sell the iPhone under the same contract terms. The upstream monopoly may want either one or more downstream vendors, and, in either case, consumer welfare may be higher with either one or more firms. If the income elasticity of demand for the new good is greater than the income elasticity of the existing generic good, the ...

  19. Transgenic plants for therapeutic proteins: linking upstream and downstream strategies.

    Science.gov (United States)

    Cramer, C L; Boothe, J G; Oishi, K K

    1999-01-01

    We have described two very different and innovative plant-based production systems--postharvest production and recovery of recombinant product from tobacco leaves using an inducible promoter and oleosin-mediated recovery of recombinant product from oilseeds using a seed-specific promoter. Both base technologies are broadly applicable to numerous classes of pharmaceutical and industrial proteins. As with any emerging technology, the key to success may lie in identifying those products and applications that would most benefit from the unique advantages offered by each system. The postharvest tobacco leaf system appears effective for proteins requiring complex posttranslational processing and endomembrane targeting. Because of the remarkable fecundity and biomass production capacity of tobacco, biomass scale-up is very rapid and production costs are low. Clearly the development of equally cost-effective extraction and purification technologies will be critical for full realization of the commercial opportunities afforded by transgenic plant-based bioproduction. The recovery of protein from tobacco leaves or oleosin-partitioned proteins by oil-body separations represent significant break-throughs for cost-effective commercialization strategies. Additional low-cost, high-affinity separation technologies need to be developed for effective scale-up purification of plant-synthesized recombinant proteins. Clearly successful commercialization of plant-synthesized biopharmaceuticals must effectively link upstream strategies involving gene and protein design with downstream strategies for reproducible GMP-level recovery of bioactive recombinant protein. Both the tobacco and oilseed systems are uniquely designed to address issues of biomass storage, product recovery, quality assurance, and regulatory scrutiny in addition to issues of transgene expression and protein processing.

  20. Downstream-based Scheduling for Energy Conservation in Green EPONs

    KAUST Repository

    Chen, Shen

    2012-05-01

    Maximizing the optical network unit’s (ONU) sleep time is an effective approach for achieving maximum energy conservation in green Ethernet passive optical networks (EPONs). While overlapping downstream and upstream ONU transmissions can maximize the ONU sleep time, it jeopardizes the quality of service (QoS) performance of the network, especially for downstream traffic in case the overlapping is based on the upstream time slot. In this paper, we study the downstream traffic performance in green EPONs under the limited service discipline and the upstream-based overlapped time window. Specifically, we first derive the expected mean packet delay, and then present a closed-form expression of the ONU sleep time, setting identical upstream/downstream transmission cycle times based on a maximum downstream traffic delay re-quirement. With the proposed system model, we present a novel downstream bandwidth allocation scheme for energy conservation in green EPONs. Simulation results verify the proposed model and highlight the advantages of our scheme over conventional approaches.

  1. Control of Delta Avulsion by Downstream Sediment Sinks

    Science.gov (United States)

    Salter, Gerard; Paola, Chris; Voller, Vaughan R.

    2018-01-01

    Understanding how fluxes are partitioned at delta bifurcations is critical for predicting patterns of land loss and gain in deltas worldwide. Although the dynamics of river deltas are influenced from both upstream and downstream, previous studies of bifurcations have focused on upstream controls. Using a quasi-1-D bifurcation model, we show that flow switching in bifurcations is strongly influenced by downstream sediment sinks. We find that coupling between upstream and downstream feedbacks can lead to oscillations in water and sediment flux partitioning. The frequency and initial rate of growth/decay of the oscillations depend on both upstream and downstream conditions, with dimensionless bifurcate length and bypass fraction emerging as key downstream parameters. With a strong offshore sink, causing bypass in the bifurcate branches, we find that bifurcation dynamics become "frozen"; that is, the bifurcation settles on a permanent discharge ratio. In contrast, under depositional conditions, we identify three dynamical regimes: symmetric; soft avulsion, where both branches remain open but the dominant branch switches; and full avulsion. Finally, we show that differential subsidence alters these regimes, with the difference in average sediment supply to each branch exactly compensating for the difference in accommodation generation. Additionally, the model predicts that bifurcations with shorter branches are less asymmetric than bifurcations with longer branches, all else equal, providing a possible explanation for the difference between backwater length distributaries, which tend to be avulsive, and relatively stable mouth-bar-scale networks. We conclude that bifurcations are sensitive both quantitatively and qualitatively to downstream sinks.

  2. Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

    Directory of Open Access Journals (Sweden)

    I. van der Pluijm, PhD

    2016-10-01

    Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-β signaling, immune suppression may be more beneficial.

  3. Rapid Downstream Discharge Attenuation During Recent Icelandic Jokulhlaups

    Science.gov (United States)

    Russell, A. J.; Roberts, M. J.; Tweed, F. S.; Knudsen, O.; Harris, T. D.; Rushmer, E. L.; Marren, P. M.; Carrivick, J. L.

    2002-12-01

    Little attention has been paid to downstream discharge attenuation during glacier outburst floods (jokulhlaups). In non-glacial environments, floods resulting from dam failure exhibit major downstream reduction of peak discharge. Transmission losses within ephemeral rivers are also well-known for generating large reductions in peak discharge. We report on three recent jokulhlaups associated with major downstream discharge attenuation: (1) Solheimajokull July 1999; (2) Kverkjokull January 2002; and (3) Tungnaarjokull July 2002. Peak discharges calculated using slope area techniques showed that the 1999 Solheimahlaup decreased in discharge from 4400 m3s-1 to 1700 m3s-1 over a downstream distance of less than 7 km. The Kverkhlaup was gauged at 400 m3s-1, 40 km downstream of the glacier snout. By contrast, less than 1 km from the glacier snouta peak discharge of 2000 m3s-1 was reconstructed using slope-area techniques. The July 2002 jokulhlaup from Tungnaarjokull had a gauged peak discharge of 600 m3s-1 23 km downstream of the glacier snout. Discharge reconstructed at the glacier snout was ~2-3 times greater than the downstream gauged value. The degree of downstream attenuation of these jokulhlaups reflects a number of factors. The rapidity of rising stage water release. The drainage of warm water during these three jokulhlaups is thought to have resulted in a characteristic sudden, short-lived, rise to peak discharge. In the case of the 1999 Solheimahlaup the hydrograph peak was enhanced by a wave-like burst from a flood-filled ice-dammed lake basin. Flow through high resistance complex bedrock (lava) and braided channels is effective in damping j”kulhlaup peak discharge. Transmission loss into highly permeable substrate materials such as lava flows and alluvium visibly reduce peak discharge under normal flow conditions will also be significant during jokulhlaups which flow through wide reaches. Our study of three recent Icelandic jokulhlaups illustrates the

  4. Evidence of Mercurial Contamination and Denundation Downstream of New Idria Mercury Mine, San Benito County, California

    Science.gov (United States)

    Letsinger, H. E.; Sharma, R. K.; Weinman, B.

    2014-12-01

    California's Central Valley water quality and soils are essential to the survival of the valley's communities and agriculture. Therefore, detection of possible contaminants within the valley streams and soils are paramount to the protection of this land and the people that depend upon it. Here we explore the impact of the contaminated stream beds near the New Idria Mercury Mine site, San Benito County, California. Previous work by Ganguli et al. (2000) has been done in this area to determine the mercury levels associated with the water that flows near the ghost town of New Idria. We performed geochemical analyses on the finer bed sediments from channels draining the area, as well as the coarser sediments taken from along the channel banks, to determine mercury transport downriver from the source. Using a novel application of tau, a mass transfer coefficient typically used in critical zone studies or soil production and weathering rates, we determine downstream weathering, accumulation, and transport of mercury. Our initial geochemical data showed higher tau values upstream as well as within the banks of the contaminated streambed and a greater accumulation of mercury near the pollution source (i.e., mine tailings, (τ ~ 103)). Tau results also show elevated mercurial levels existing downstream, with accumulations in mid- (τ ~ 102) and down-stream (τ ~ 10) reaches. Combining tau results with more traditional indices of chemical weathering (CIA) support consistent overall Hg-weathering processes with low levels of chemical weathering and higher dominance of coupled physical-anthropogenic weathering.

  5. Downstream Yangtze River levels impacted by Three Gorges Dam

    International Nuclear Information System (INIS)

    Wang, Jida; Sheng, Yongwei; Gleason, Colin J; Wada, Yoshihide

    2013-01-01

    Changes in the Yangtze River level induced by large-scale human water regulation have profound implications on the inundation dynamics of surrounding lakes/wetlands and the integrity of related ecosystems. Using in situ measurements and hydrological simulation, this study reveals an altered Yangtze level regime downstream from the Three Gorges Dam (TGD) to the Yangtze estuary in the East China Sea as a combined result of (i) TGD’s flow regulation and (ii) Yangtze channel erosion due to reduced sediment load. During the average annual cycle of TGD’s regular flow control in 2009–2012, downstream Yangtze level variations were estimated to have been reduced by 3.9–13.5% at 15 studied gauging stations, manifested as evident level decrease in fall and increase in winter and spring. The impacts on Yangtze levels generally diminished in a longitudinal direction from the TGD to the estuary, with a total time lag of ∼9–12 days. Chronic Yangtze channel erosion since the TGD closure has lowered water levels in relation to flows at most downstream stations, which in turn counteracts the anticipated level increase by nearly or over 50% in winter and spring while reinforcing the anticipated level decrease by over 20% in fall. Continuous downstream channel erosion in the near future may further counteract the benefit of increased Yangtze levels during TGD’s water supplement in winter and accelerate the receding of inundation areas/levels of downstream lakes in fall. (letter)

  6. Mortality of zebra mussel, Dreissena polymorpha, veligers during downstream transport

    Science.gov (United States)

    Horvath, T.G.; Lamberti, G.A.

    1999-01-01

    1. Streams flowing from lakes which contain zebra mussels, Dreissena polymorpha, provide apparently suitable habitats for mussel colonization and downstream range expansion, yet most such streams contain few adult mussels. We postulated that mussel veligers experience high mortality during dispersal via downstream transport. They tested this hypothesis in Christiana Creek, a lake-outlet stream in south-western Michigan, U.S.A., in which adult mussel density declined exponentially with distance downstream. 2. A staining technique using neutral red was developed and tested to distinguish quickly live and dead veligers. Live and dead veligers were distinguishable after an exposure of fresh samples to 13.3 mg L-1 of neutral red for 3 h. 3. Neutral red was used to determine the proportion of live veligers in samples taken longitudinally along Christiana Creek. The proportion of live veligers (mean ?? SE) declined from 90 ?? 3% at the lake outlet to 40 ?? 8% 18 km downstream. 4. Veligers appear to be highly susceptible to damage by physical forces (e.g. shear), and therefore, mortality in turbulent streams could be an important mechanism limiting zebra mussel dispersal to downstream reaches. Predictions of zebra mussel spread and population growth should consider lake-stream linkages and high mortality in running waters.

  7. The effect of feeding a commercial essential oil product on Clostridium perfringens numbers in the intestine of broiler chickens measured by real-time PCR targeting the α-toxin-encoding gene (plc)

    DEFF Research Database (Denmark)

    Abildgaard, Lone; Højberg, Ole; Schramm, Andreas

    2010-01-01

    was to investigate the influence of a commercial essential oil blend, CRINA® Poultry, on the intestinal C. perfringens population in broilers vaccinated against coccidiosis. The observed C. perfringens levels were relatively high in general and peaked at 27 days of bird age with numbers ranging from 7 to 8 log cells...... concentrations of 100 and 200 mg/kg feed of the essential oil blend did not reduce the intestinal numbers of C. perfringens compared to a non-supplemented control group (P>0.05). Further, the essential oil blend failed to improve (P>0.05) both the growth and feed conversion ratio of the broilers. For rapid...

  8. Critical effects of downstream boundary conditions on vortex breakdown

    Science.gov (United States)

    Kandil, Osama; Kandil, Hamdy A.; Liu, C. H.

    1992-01-01

    The unsteady, compressible, full Navier-Stokes (NS) equations are used to study the critical effects of the downstream boundary conditions on the supersonic vortex breakdown. The present study is applied to two supersonic vortex breakdown cases. In the first case, quasi-axisymmetric supersonic swirling flow is considered in a configured circular duct, and in the second case, quasi-axisymmetric supersonic swirling jet, that is issued from a nozzle into a supersonic jet of lower Mach number, is considered. For the configured duct flow, four different types of downstream boundary conditions are used, and for the swirling jet flow from the nozzle, two types of downstream boundary conditions are used. The solutions are time accurate which are obtained using an implicit, upwind, flux-difference splitting, finite-volume scheme.

  9. Transition duct with divided upstream and downstream portions

    Energy Technology Data Exchange (ETDEWEB)

    McMahan, Kevin Weston; LeBegue, Jeffrey Scott; Maldonado, Jaime Javier; Dillard, Daniel Jackson; Flanagan, James Scott

    2015-07-14

    Turbine systems are provided. In one embodiment, a turbine system includes a transition duct comprising an inlet, an outlet, and a duct passage extending between the inlet and the outlet and defining a longitudinal axis, a radial axis, and a tangential axis. The outlet of the transition duct is offset from the inlet along the longitudinal axis and the tangential axis. The duct passage includes an upstream portion extending from the inlet and a downstream portion extending from the outlet. The turbine system further includes a rib extending from an outer surface of the duct passage, the rib dividing the upstream portion and the downstream portion.

  10. Patents and Downstream Innovation Suppression - Facts or Fiction?

    DEFF Research Database (Denmark)

    Howells, John

    Merges and Nelson have proposed that pioneer patents have enabled their owners to 'block' or 'hold-up' downstream innovation in cases as important as the car, radio, aircraft and electric lighting (Merges and Nelson 1990, ; Merges and Nelson 1994). Merges and Nelson use their work to question...... the value of Kitch's prospect theory of patents, a theory that the social value of patents is that they enable the efficient coordination of technological development.    I re-examine history and legal sources bearing on Merges and Nelson's illustrative cases and find no case to illustrate downstream...

  11. Downstream Processability of Crystal Habit-Modified Active Pharmaceutical Ingredient

    DEFF Research Database (Denmark)

    Pudasaini, Nawin; Upadhyay, Pratik Pankaj; Parker, Christian Richard

    2017-01-01

    Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability...... and tabletability, creating significant processability difficulties on a production scale. However, such a habit can be adapted to the needs of downstream processing. To this end, we modified the needle-like crystal habit of the model API 5-aminosalicylic acid (5-ASA). This study reports processability assessment...

  12. DNA Source Selection for Downstream Applications Based on DNA Quality Indicators Analysis

    Science.gov (United States)

    Lucena-Aguilar, Gema; Sánchez-López, Ana María; Barberán-Aceituno, Cristina; Carrillo-Ávila, José Antonio; López-Guerrero, José Antonio

    2016-01-01

    High-quality human DNA samples and associated information of individuals are necessary for biomedical research. Biobanks act as a support infrastructure for the scientific community by providing a large number of high-quality biological samples for specific downstream applications. For this purpose, biobank methods for sample preparation must ensure the usefulness and long-term functionality of the products obtained. Quality indicators are the tool to measure these parameters, the purity and integrity determination being those specifically used for DNA. This study analyzes the quality indicators in DNA samples derived from 118 frozen human tissues in optimal cutting temperature (OCT) reactive, 68 formalin-fixed paraffin-embedded (FFPE) tissues, 119 frozen blood samples, and 26 saliva samples. The results obtained for DNA quality are discussed in association with the usefulness for downstream applications and availability of the DNA source in the target study. In brief, if any material is valid, blood is the most approachable option of prospective collection of samples providing high-quality DNA. However, if diseased tissue is a requisite or samples are available, the recommended source of DNA would be frozen tissue. These conclusions will determine the best source of DNA, according to the planned downstream application. Furthermore our results support the conclusion that a complete procedure of DNA quantification and qualification is necessary to guarantee the appropriate management of the samples, avoiding low confidence results, high costs, and a waste of samples. PMID:27158753

  13. DNA Source Selection for Downstream Applications Based on DNA Quality Indicators Analysis.

    Science.gov (United States)

    Lucena-Aguilar, Gema; Sánchez-López, Ana María; Barberán-Aceituno, Cristina; Carrillo-Ávila, José Antonio; López-Guerrero, José Antonio; Aguilar-Quesada, Rocío

    2016-08-01

    High-quality human DNA samples and associated information of individuals are necessary for biomedical research. Biobanks act as a support infrastructure for the scientific community by providing a large number of high-quality biological samples for specific downstream applications. For this purpose, biobank methods for sample preparation must ensure the usefulness and long-term functionality of the products obtained. Quality indicators are the tool to measure these parameters, the purity and integrity determination being those specifically used for DNA. This study analyzes the quality indicators in DNA samples derived from 118 frozen human tissues in optimal cutting temperature (OCT) reactive, 68 formalin-fixed paraffin-embedded (FFPE) tissues, 119 frozen blood samples, and 26 saliva samples. The results obtained for DNA quality are discussed in association with the usefulness for downstream applications and availability of the DNA source in the target study. In brief, if any material is valid, blood is the most approachable option of prospective collection of samples providing high-quality DNA. However, if diseased tissue is a requisite or samples are available, the recommended source of DNA would be frozen tissue. These conclusions will determine the best source of DNA, according to the planned downstream application. Furthermore our results support the conclusion that a complete procedure of DNA quantification and qualification is necessary to guarantee the appropriate management of the samples, avoiding low confidence results, high costs, and a waste of samples.

  14. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Palomero, Teresa; Odom, Duncan T.; O'Neil, Jennifer; Ferrando, Adolfo A.; Margolin, Adam; Neuberg, Donna S.; Winter, Stuart S.; Larson, Richard S.; Li, Wei; Liu, X. Shirley; Young, Richard A.; Look, A. Thomas

    2006-01-01

    Aberrant expression of 1 or more transcription factor oncogenes is a critical component of the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL); however, oncogenic transcriptional programs downstream of T-ALL oncogenes are mostly unknown. TAL1/SCL is a basic helix-loop-helix (bHLH) transcription factor oncogene aberrantly expressed in 60% of human T-ALLs. We used chromatin immunoprecipitation (ChIP) on chip to identify 71 direct transcriptional targets of TAL1/SCL. ...

  15. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells

    Science.gov (United States)

    Yi, Tingfang; Zhai, Bo; Yu, Yonghao; Kiyotsugu, Yoshikawa; Raschle, Thomas; Etzkorn, Manuel; Seo, Hee-Chan; Nagiec, Michal; Luna, Rafael E.; Reinherz, Ellis L.; Blenis, John; Gygi, Steven P.; Wagner, Gerhard

    2014-01-01

    Breast cancer is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Cancer stem cells (CSCs) are essential for tumor reoccurrence and metastasis which is the major source of cancer lethality. G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is critical for tumor metastasis. However, stromal cell-derived factor 1 (SDF-1)/CXCR4–mediated signaling pathways in breast CSCs are largely unknown. Using isotope reductive dimethylation and large-scale MS-based quantitative phosphoproteome analysis, we examined protein phosphorylation induced by SDF-1/CXCR4 signaling in breast CSCs. We quantified more than 11,000 phosphorylation sites in 2,500 phosphoproteins. Of these phosphosites, 87% were statistically unchanged in abundance in response to SDF-1/CXCR4 stimulation. In contrast, 545 phosphosites in 266 phosphoproteins were significantly increased, whereas 113 phosphosites in 74 phosphoproteins were significantly decreased. SDF-1/CXCR4 increases phosphorylation in 60 cell migration- and invasion-related proteins, of them 43 (>70%) phosphoproteins are unrecognized. In addition, SDF-1/CXCR4 upregulates the phosphorylation of 44 previously uncharacterized kinases, 8 phosphatases, and 1 endogenous phosphatase inhibitor. Using computational approaches, we performed system-based analyses examining SDF-1/CXCR4–mediated phosphoproteome, including construction of kinase–substrate network and feedback regulation loops downstream of SDF-1/CXCR4 signaling in breast CSCs. We identified a previously unidentified SDF-1/CXCR4-PKA-MAP2K2-ERK signaling pathway and demonstrated the feedback regulation on MEK, ERK1/2, δ-catenin, and PPP1Cα in SDF-1/CXCR4 signaling in breast CSCs. This study gives a system-wide view of phosphorylation events downstream of SDF-1/CXCR4 signaling in breast CSCs, providing a resource for the study of CSC-targeted cancer therapy. PMID

  16. Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer

    Science.gov (United States)

    Oran, Amanda R.; Adams, Clare M.; Zhang, Xiao-yong; Gennaro, Victoria J.; Pfeiffer, Harla K.; Mellert, Hestia S.; Seidel, Hans E.; Mascioli, Kirsten; Kaplan, Jordan; Gaballa, Mahmoud R.; Shen, Chen; Rigoutsos, Isidore; King, Michael P.; Cotney, Justin L.; Arnold, Jamie J.; Sharma, Suresh D.; Martinez, Ubaldo E.; Vakoc, Christopher R.; Chodosh, Lewis A.; Thompson, James E.; Bradner, James E.; Cameron, Craig E.; Shadel, Gerald S.; Eischen, Christine M.; McMahon, Steven B.

    2016-01-01

    Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors. PMID:27590350

  17. Optogenetic analysis of a nociceptor neuron and network reveals ion channels acting downstream of primary sensors

    Science.gov (United States)

    Husson, Steven J.; Costa, Wagner Steuer; Wabnig, Sebastian; Stirman, Jeffrey N.; Watson, Joseph D.; Spencer, W. Clay; Akerboom, Jasper; Looger, Loren L.; Treinin, Millet; Miller, David M.; Lu, Hang; Gottschalk, Alexander

    2012-01-01

    Summary Background Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single neuron mRNA profiling of PVD. Results Selectively photoactivating PVD, FLP and downstream interneurons using Channelrhodopsin-2 (ChR2) enabled functionally dissecting this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca2+-channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD’s dynamic range and that GTL-1 may amplify its signals. These channels act cell-autonomously in PVD, downstream of primary mechanosensory molecules. Conclusions Our work implicates TRPM channels in modifying excitability of, and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologues, if functionally conserved, may denote valid targets for novel analgesics. PMID:22483941

  18. Downstream processing of Isochrysis galbana: a step towards microalgal biorefinery

    NARCIS (Netherlands)

    Gilbert-López, B.; Mendiola, J.A.; Fontecha, J.; Broek, van den L.A.M.; Sijtsma, L.; Cifuentes, A.; Herrero, M.; Ibáñez, E.

    2015-01-01

    An algae-based biorefinery relies on the efficient use of algae biomass through its fractionation of several valuable/bioactive compounds that can be used in industry. If this biorefinery includes green platforms as downstream processing technologies able to fulfill the requirements of green

  19. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects

    DEFF Research Database (Denmark)

    Sharpe, R.M.; Skakkebæk, Niels Erik

    2008-01-01

    Reproductive disorders of newborn (cryptorchidism, hypospadias) and young adult males (low sperm counts, testicular germ cell cancer) are common and/or increasing in incidence. It has been hypothesized that these disorders may comprise a testicular dysgenesis syndrome (TDS) with a common origin...... androgen production/action during fetal testis development, may play in the origin of downstream disorders Udgivelsesdato: 2008/2...

  20. Downstream flow top width prediction in a river system | Choudhury ...

    African Journals Online (AJOL)

    ANFIS, ARIMA and Hybrid Multiple Inflows Muskingum models (HMIM) were applied to simulate and forecast downstream discharge and flow top widths in a river system. The ANFIS model works on a set of linguistic rules while the ARIMA model uses a set of past values to predict the next value in a time series. The HMIM ...

  1. The Nigerian petroleum downstream sector and product pricing ...

    African Journals Online (AJOL)

    This research has been designed to explore critically the history of the downstream petroleum sector and the trend of pricing of Nigeria's petroleum products - looking closely at the contentious issue of subsidy and formulate a statistical model for the appropriate pricing of locally produced petroleum products.

  2. Connectivity of Streams and Wetlands to Downstream Waters ...

    Science.gov (United States)

    The U.S. Environmental Protection Agency's (USEPA) Office of Research and Development has finalized the report Connectivity of Streams and Wetlands to Downstream Waters: A Review and Synthesis of the Scientific Evidence. The report reviews more than 1,200 peer-reviewed publications and summarizes current scientific understanding about the connectivity and mechanisms by which streams and wetlands, singly or in aggregate, affect the physical, chemical, and biological integrity of downstream waters. The focus of the report is on surface and shallow subsurface connections by which small or temporary streams, nontidal wetlands, and open waters affect larger waters such as rivers, lakes, reservoirs, and estuaries. This report represents the state-of-the-science on the connectivity and isolation of waters in the United States. It makes five major conclusions, summarized below, that are drawn from a broad range of peer reviewed scientific literature. The scientific literature unequivocally demonstrates that streams, regardless of their size or frequency of flow, are connected to downstream waters and strongly influence their function. The scientific literature clearly shows that wetlands and open waters in riparian areas (transitional areas between terrestrial and aquatic ecosystems) and floodplains are physically, chemically, and biologically integrated with rivers via functions that improve downstream water quality. These system

  3. Flow diagnostics downstream of a tribladed rotor model

    DEFF Research Database (Denmark)

    Naumov, I. V.; Rahmanov, V. V.; Okulov, Valery

    2012-01-01

    This paper presents results of a study of vortex wake structures and measurements of instantaneous 3D velocity fields downstream of a triblade turbine model. Two operation modes of flow around the rotor with different tip speed ratios were tested. Initially the wake structures were visualized and...

  4. Extreme wave phenomena in down-stream running modulated waves

    NARCIS (Netherlands)

    Andonowati, A.; Karjanto, N.; van Groesen, Embrecht W.C.

    Modulational, Benjamin-Feir, instability is studied for the down-stream evolution of surface gravity waves. An explicit solution, the soliton on finite background, of the NLS equation in physical space is used to study various phenomena in detail. It is shown that for sufficiently long modulation

  5. Using stable isotopes to examine watershed connectivity to downstream waters

    Science.gov (United States)

    Water bodies within the USA are protected by the US Clean Water Act when they have a significant nexus to downstream navigable waters. As a research scientist with the US Environmental Protection Agency, I have used water stable isotopes to examine hydrologic connectivity dynami...

  6. Peru's Downstream Natural Gas Sector : A Preliminary Assessment

    OpenAIRE

    David Reinstein; Daniel A. Benítez Benítez; Todd M. Johnson

    2011-01-01

    This study assesses the natural gas market in Peru. In the process of evaluating the downstream market, the study identifies opportunities for meeting the Government s aspirational goals with respect to energy and natural gas development, including the efficient use of natural gas in the power and other sectors, strengthening and coordinating national energy planning for the gas sector, in...

  7. Imaging for monitoring downstream processing of fermentation broths

    DEFF Research Database (Denmark)

    Moiseyenko, Rayisa; Baum, Andreas; Jørgensen, Thomas Martini

    In relation to downstream processing of a fermentation broth coagulation/flocculation is a typical pretreatment method for separating undesirable particles/impurities from the wanted product. In the coagulation process the negatively charged impurities are destabilized by adding of a clarifying...

  8. A novel virtual hub approach for multisource downstream service integration

    Science.gov (United States)

    Previtali, Mattia; Cuca, Branka; Barazzetti, Luigi

    2016-08-01

    A large development of downstream services is expected to be stimulated starting from earth observations (EO) datasets acquired by Copernicus satellites. An important challenge connected with the availability of downstream services is the possibility for their integration in order to create innovative applications with added values for users of different categories level. At the moment, the world of geo-information (GI) is extremely heterogeneous in terms of standards and formats used, thus preventing a facilitated access and integration of downstream services. Indeed, different users and data providers have also different requirements in terms of communication protocols and technology advancement. In recent years, many important programs and initiatives have tried to address this issue even on trans-regional and international level (e.g. INSPIRE Directive, GEOSS, Eye on Earth and SEIS). However, a lack of interoperability between systems and services still exists. In order to facilitate the interaction between different downstream services, a new architectural approach (developed within the European project ENERGIC OD) is proposed in this paper. The brokering-oriented architecture introduces a new mediation layer (the Virtual Hub) which works as an intermediary to bridge the gaps linked to interoperability issues. This intermediation layer de-couples the server and the client allowing a facilitated access to multiple downstream services and also Open Data provided by national and local SDIs. In particular, in this paper an application is presented integrating four services on the topic of agriculture: (i) the service given by Space4Agri (providing services based on MODIS and Landsat data); (ii) Gicarus Lab (providing sample services based on Landsat datasets) and (iii) FRESHMON (providing sample services for water quality) and services from a several regional SDIs.

  9. Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas†

    Science.gov (United States)

    Tamborini, Elena; Virdis, Emanuela; Negri, Tiziana; Orsenigo, Marta; Brich, Silvia; Conca, Elena; Gronchi, Alessandro; Stacchiotti, Silvia; Manenti, Giacomo; Casali, Paolo G.; Pierotti, Marco A.; Pilotti, Silvana

    2010-01-01

    We have previously demonstrated that chordomas express activated platelet-derived growth factor receptor (PDGFRB) and that treatment with imatinib, which is capable of switching off the activation of various receptor tyrosine kinases (RTKs) including PDGFRB, benefits a number of patients. The aim of this study was to identify the possible presence of other activated RTKs and their downstream signaling effectors. Cryopreserved material from 22 naïve sporadic chordomas was investigated for the presence of activated RTKs and their cognate ligands and downstream signaling effectors by means of human phospho-RTK antibody arrays, Western blotting, and molecular analysis; immunohistochemistry and fluorescence in situ hybridization were used to analyze the corresponding formalin-fixed and paraffin-embedded samples. We detected activated PDGFRB, FLT3, and colony stimulating factor 1 receptor (CSF1R) of the PDGFR family and highly phosphorylated EGFR, HER2/neu, and (to a lesser extent) HER4 of the EGFR family. The detection of PDGFRB/PDGFB confirmed our previous data. The presence of activated EGFR was paralleled by the finding of high levels of epidermal growth factor (EGF) and transforming growth factor α (TGFα) and PDGFB co-expression and PDGFRB co-immunoprecipitation. Of the downstream effectors, the PI3K/AKT and RAS/MAPK pathways were both activated, thus leading to the phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 among the regulators involved in translational control. Taken together, our results (i) provide a rationale for tailored treatments targeting upstream activated receptors, including the PDGFR and EGFR families; (ii) support the idea that a combination of upstream antagonists and mTOR inhibitors enhances the control of tumor growth; and (iii) indicate that the 4E-BP1/eIF4E pathway is a major regulator of protein synthesis in chordoma. PMID:20164240

  10. Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas.

    Science.gov (United States)

    Tamborini, Elena; Virdis, Emanuela; Negri, Tiziana; Orsenigo, Marta; Brich, Silvia; Conca, Elena; Gronchi, Alessandro; Stacchiotti, Silvia; Manenti, Giacomo; Casali, Paolo G; Pierotti, Marco A; Pilotti, Silvana

    2010-08-01

    We have previously demonstrated that chordomas express activated platelet-derived growth factor receptor (PDGFRB) and that treatment with imatinib, which is capable of switching off the activation of various receptor tyrosine kinases (RTKs) including PDGFRB, benefits a number of patients. The aim of this study was to identify the possible presence of other activated RTKs and their downstream signaling effectors. Cryopreserved material from 22 naïve sporadic chordomas was investigated for the presence of activated RTKs and their cognate ligands and downstream signaling effectors by means of human phospho-RTK antibody arrays, Western blotting, and molecular analysis; immunohistochemistry and fluorescence in situ hybridization were used to analyze the corresponding formalin-fixed and paraffin-embedded samples. We detected activated PDGFRB, FLT3, and colony stimulating factor 1 receptor (CSF1R) of the PDGFR family and highly phosphorylated EGFR, HER2/neu, and (to a lesser extent) HER4 of the EGFR family. The detection of PDGFRB/PDGFB confirmed our previous data. The presence of activated EGFR was paralleled by the finding of high levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) and PDGFB co-expression and PDGFRB co-immunoprecipitation. Of the downstream effectors, the PI3K/AKT and RAS/MAPK pathways were both activated, thus leading to the phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 among the regulators involved in translational control. Taken together, our results (i) provide a rationale for tailored treatments targeting upstream activated receptors, including the PDGFR and EGFR families; (ii) support the idea that a combination of upstream antagonists and mTOR inhibitors enhances the control of tumor growth; and (iii) indicate that the 4E-BP1/eIF4E pathway is a major regulator of protein synthesis in chordoma.

  11. Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.

    Science.gov (United States)

    Korkut, Anil; Wang, Weiqing; Demir, Emek; Aksoy, Bülent Arman; Jing, Xiaohong; Molinelli, Evan J; Babur, Özgün; Bemis, Debra L; Onur Sumer, Selcuk; Solit, David B; Pratilas, Christine A; Sander, Chris

    2015-08-18

    Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.

  12. Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin.

    Science.gov (United States)

    Campbell, Marcia R; Zhang, Hui; Ziaee, Shabnam; Ruiz-Saenz, Ana; Gulizia, Nathaniel; Oeffinger, Julie; Amin, Dhara N; Ahuja, Deepika; Moasser, Mark M; Park, Catherine C

    2016-02-01

    The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2. There is also potential in lateral combinations based on evidence implicating cross-talk with other membrane receptor systems, particularly integrins, and such lateral combinations can potentially involve either HER2 or HER3. We established a preclinical model of targeting HER3 using doxycycline-inducible shRNA and determined the efficacy of a β1 integrin inhibitor in combination with targeting HER3. We report that targeting HER3 and β1 integrin provides a particularly effective combination therapy approach for HER2-amplified cancers, surpassing the combination of HER2 and β1 integrin targeting, and evading some of the safety concerns associated with direct HER2-targeting. This further validates HER3 as a major hub mediating the tumorigenic functions of HER2 and identifies it as a high value target for lateral combination therapy strategies.

  13. Dead zone area at the downstream flow of barrages

    Directory of Open Access Journals (Sweden)

    Mohamed F. Sauida

    2016-12-01

    Full Text Available Flow separation is a natural phenomenon encountered at some cases downstream of barrages. The main flow is divided into current and dead zone flows. The percentage area of dead zone flow must be taken into consideration downstream of barrages, due to its negative effect on flow characteristics. Experimental studies were conducted in the Hydraulic Research Institute (HRI, on a physical regulator model with five vents. Theoretically the separation zone is described as a part of an ellipse which is practically verified by plotting velocity vectors. The results show that the percentage area of dead zone to the area through length of separation depends mainly on the expansion ratio [channel width to width of opened vents], with maximum value of 81% for operated side gates. A statistical analysis was derived, to predict the percentage area of dead zone flow to the area through length of separation.

  14. International Retailing Operations: Downstream Entry and Expansion via Franchising

    OpenAIRE

    Petersen, Bent; Welch, Lawrence S.

    1999-01-01

    In this article, the shift into international franchising from other forms of operation, rather than the typical home market franchising base is explored. The focus is international retail franchising, based on a study of the Danish clothing and footwear industry. In this study it was found that Danish companies were moving into international franchising as an outcome of a more general shift from upstream wholesaling and subcontracting activities to downstream involvement in retailing activit...

  15. Demand Forecasting in Downstream Supply Chain Telco Product

    OpenAIRE

    Ratih Hendayani; Adrian Darmanda

    2014-01-01

    This study aims is to manage the uncertainty demand in the downstream supply chain for a starter pack Telco product by measuring demand forecasting in one area of West Sumatra at PT. Pioneering Citra Pratama and its outlets as a distributor of PT. Indosat, one of the biggest operational cellular in Indonesia. With demand forecasting, the operator cellular can avoid a big gap between orders and demand and lower their lost opportunity. This research is a descriptive study and data collection te...

  16. Focal Adhesion Kinase functions as an Akt downstream target in migration of colorectal cancer cells

    Czech Academy of Sciences Publication Activity Database

    Turečková, Jolana; Vojtěchová, Martina; Krausová, Michaela; Šloncová, Eva; Kořínek, Vladimír

    2009-01-01

    Roč. 2, č. 4 (2009), s. 281-290 ISSN 1936-5233 R&D Projects: GA ČR GA204/06/1658; GA MŠk 2B06077 Institutional research plan: CEZ:AV0Z50520514 Keywords : FAK * migration * invasion Subject RIV: EB - Genetics ; Molecular Biology

  17. Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction

    NARCIS (Netherlands)

    Mansvelder, H.D.; de Rover, M.; McGehee, D.S.; Brussaard, A.B.

    2003-01-01

    Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses

  18. TBX3, a downstream target of TGF-β1, inhibits mesangial cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Wensing, Lislaine A. [Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, Morumbi, 2SS/Bloco A., São Paulo, São Paulo CEP 05651-901 (Brazil); Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo (Brazil); Campos, Alexandre H., E-mail: alexandre.campos@einstein.br [Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, Morumbi, 2SS/Bloco A., São Paulo, São Paulo CEP 05651-901 (Brazil)

    2014-11-01

    Chronic kidney disease (CKD) is an increasingly common condition characterized by progressive loss of functional nephrons leading to renal failure. TGF-β1-induced mesangial cell (MC) phenotype alterations have been linked to the genesis of CKD. Here we show that TGF-β1 regulates TBX3 gene expression in MC. This gene encodes for two main isoforms, TBX3.1 and TBX3+2α. TBX3.1 has been implicated in cell immortalization, proliferation and apoptosis by inhibiting p14{sup ARF}-Mdm2-p53 pathway, while TBX3+2α role has not been defined. We demonstrated that TBX3 overexpression abrogated MC apoptosis induced by serum deprivation. Moreover, we observed an enhancement in TBX3 protein expression both in glomerular and tubular regions in the model of 5/6 nephrectomy, temporally related to increased expression of TGF-β1, type IV collagen and fibronectin. Our results indicate that TBX3 acts as an anti-apoptotic factor in MC in vitro and may be involved in the mechanism by which TGF-β1 induces glomerulosclerosis and tubular fibrosis during the progression of nephropathies. - Highlights: • TBX3 isoforms are upregulated by TGF-b1 in mesangial cells. • TBX3 isoforms have different subcellular distribution profile in mesangial cells. • TBX3 isoforms exhibit antiapoptotic action in mesangial cells. • TBX3 protein is overexpressed in a model of nephropathy (5/6 nephrectomy)

  19. Genome-wide identification of GLABRA3 downstream genes for anthocyanin biosynthesis and trichome formation in Arabidopsis.

    Science.gov (United States)

    Gao, Chenhao; Li, Dong; Jin, Changyu; Duan, Shaowei; Qi, Shuanghui; Liu, Kaige; Wang, Hanchen; Ma, Haoli; Hai, Jiangbo; Chen, Mingxun

    2017-04-01

    GLABRA3 (GL3), a bHLH transcription factor, has previously proved to be involved in anthocyanin biosynthesis and trichome formation in Arabidopsis, however, its downstream targeted genes are still largely unknown. Here, we found that GL3 was widely present in Arabidopsis vegetative and reproductive organs. New downstream targeted genes of GL3 for anthocyanin biosynthesis and trichome formation were identified in young shoots and expanding true leaves by RNA sequencing. GL3-mediated gene expression was tissue specific in the two biological processes. This study provides new clues to further understand the GL3-mediated regulatory network of anthocyanin biosynthesis and trichome formation in Arabidopsis. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Analysis of Petroleum Downstream Industry Potential in Riau Province

    Directory of Open Access Journals (Sweden)

    Tomi Erfando

    2017-06-01

    Full Text Available Petroleum downstream industry in Riau Province is still not optimal. The data shows that from 98,892,755 barrels lifting oil each year only 62,050,000 barrels could be processed in refinery unit II Dumai operated by PT Pertamina. There is a potential of 35-40% of downstream industry. Indonesian Government through The Ministry of Energy and Mineral Resources declared the construction of a mini refinery to boost oil processing output in the downstream sector. A feasibility study of development plan mini refinery is needed. The study includes production capacity analysis, product analysis, development & operational refinery  analysis and economic analysis. The results obtained by the mini refinery capacity is planned to process crude oil 6000 BOPD with the products produced are gasoline, kerosene, diesel and oil. Investment cost consist of is capital cost US $ 104419784 and operating cost US $ 13766734 each year with net profit earned US $ 12330063/year and rate of return from investment 11.63%

  1. Human gene essentiality.

    Science.gov (United States)

    Bartha, István; di Iulio, Julia; Venter, J Craig; Telenti, Amalio

    2018-01-01

    A gene can be defined as essential when loss of its function compromises viability of the individual (for example, embryonic lethality) or results in profound loss of fitness. At the population level, identification of essential genes is accomplished by observing intolerance to loss-of-function variants. Several computational methods are available to score gene essentiality, and recent progress has been made in defining essentiality in the non-coding genome. Haploinsufficiency is emerging as a critical aspect of gene essentiality: approximately 3,000 human genes cannot tolerate loss of one of the two alleles. Genes identified as essential in human cell lines or knockout mice may be distinct from those in living humans. Reconciling these discrepancies in how we evaluate gene essentiality has applications in clinical genetics and may offer insights for drug development.

  2. Discovery and characterization of novel vascular and hematopoietic genes downstream of etsrp in zebrafish.

    Directory of Open Access Journals (Sweden)

    Gustavo A Gomez

    Full Text Available The transcription factor Etsrp is required for vasculogenesis and primitive myelopoiesis in zebrafish. When ectopically expressed, etsrp is sufficient to induce the expression of many vascular and myeloid genes in zebrafish. The mammalian homolog of etsrp, ER71/Etv2, is also essential for vascular and hematopoietic development. To identify genes downstream of etsrp, gain-of-function experiments were performed for etsrp in zebrafish embryos followed by transcription profile analysis by microarray. Subsequent in vivo expression studies resulted in the identification of fourteen genes with blood and/or vascular expression, six of these being completely novel. Regulation of these genes by etsrp was confirmed by ectopic induction in etsrp overexpressing embryos and decreased expression in etsrp deficient embryos. Additional functional analysis of two newly discovered genes, hapln1b and sh3gl3, demonstrates their importance in embryonic vascular development. The results described here identify a group of genes downstream of etsrp likely to be critical for vascular and/or myeloid development.

  3. Highly resolved numerical simulation of combustion downstream of a rocket engine igniter

    Science.gov (United States)

    Buttay, R.; Gomet, L.; Lehnasch, G.; Mura, A.

    2017-07-01

    We study ignition processes in the turbulent reactive flow established downstream of highly under-expanded coflowing jets. The corresponding configuration is typical of a rocket engine igniter, and to the best knowledge of the authors, this study is the first that documents highly resolved numerical simulations of such a reactive flowfield. Considering the discharge of axisymmetric coaxial under-expanded jets, various morphologies are expected, depending on the value of the nozzle pressure ratio, a key parameter used to classify them. The present computations are conducted with a value of this ratio set to fifteen. The simulations are performed with the massively parallel CREAMS solver on a grid featuring approximately 440,000,000 computational nodes. In the main zone of interest, the level of spatial resolution is D/74, with D the central inlet stream diameter. The computational results reveal the complex topology of the compressible flowfield. The obtained results also bring new and useful insights into the development of ignition processes. In particular, ignition is found to take place rather far downstream of the shock barrel, a conclusion that contrasts with early computational studies conducted within the unsteady RANS computational framework. Consideration of detailed chemistry confirms the essential role of hydroperoxyl radicals, while the analysis of the Takeno index reveals the predominance of a non-premixed combustion mode.

  4. Trehalose-6-phosphate synthesis controls yeast gluconeogenesis downstream and independent of SNF1.

    Science.gov (United States)

    Deroover, Sofie; Ghillebert, Ruben; Broeckx, Tom; Winderickx, Joris; Rolland, Filip

    2016-06-01

    Trehalose-6-P (T6P), an intermediate of trehalose biosynthesis, was identified as an important regulator of yeast sugar metabolism and signaling. tps1Δ mutants, deficient in T6P synthesis (TPS), are unable to grow on rapidly fermentable medium with uncontrolled influx in glycolysis, depletion of ATP and accumulation of sugar phosphates. However, the exact molecular mechanisms involved are not fully understood. We show that SNF1 deletion restores the tps1Δ growth defect on glucose, suggesting that lack of TPS hampers inactivation of SNF1 or SNF1-regulated processes. In addition to alternative, non-fermentable carbon metabolism, SNF1 controls two major processes: respiration and gluconeogenesis. The tps1Δ defect appears to be specifically associated with deficient inhibition of gluconeogenesis, indicating more downstream effects. Consistently, Snf1 dephosphorylation and inactivation on glucose medium are not affected, as confirmed with an in vivo Snf1 activity reporter. Detailed analysis shows that gluconeogenic Pck1 and Fbp1 expression, protein levels and activity are not repressed upon glucose addition to tps1Δ cells, suggesting a link between the metabolic defect and persistent gluconeogenesis. While SNF1 is essential for induction of gluconeogenesis, T6P/TPS is required for inactivation of gluconeogenesis in the presence of glucose, downstream and independent of SNF1 activity and the Cat8 and Sip4 transcription factors. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Δ9-Tetrahydrocannabinol Experience Influences ΔFosB and Downstream Gene Expression in Prefrontal Cortex.

    Science.gov (United States)

    Lazenka, Matthew F; Kang, Minho; De, Dipanjana Datta; Selley, Dana E; Sim-Selley, Laura J

    2017-01-01

    Introduction: Repeated administration of abused drugs, including Δ 9 -tetrahydrocannabinol (THC), induces the stable transcription factor ΔFosB in dopaminergic terminal field regions of the mesolimbic system. These studies investigated the effect of prior repeated THC treatment on THC-induced ΔFosB expression and regulation of downstream targets in the forebrain. Methods: Mice received THC (10 mg/kg) or vehicle twice daily for 13 days, and then half of each group received a single injection of THC or vehicle 45 min before brain collection. ΔFosB messenger RNA (mRNA) and protein were measured by polymerase chain reaction and immunoblotting, respectively. Potential downstream targets of ΔFosB induction were measured by immunoblot. Results: THC injection in mice with a history of repeated THC treatment enhanced ΔFosB expression as compared with vehicle in the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. This change occurred concomitantly with an increase in ΔFosB mRNA in the PFC and NAc. THC injection in mice with a history of repeated THC treatment increased expression of cyclin-dependent kinase 5 (Cdk5) and its regulatory protein p35 only in the PFC. This increase in Cdk5 and p35 expression in PFC was also found in mice that had only received repeated THC administration, suggesting that this effect might be due to induction of ΔFosB. Extracellular signal-regulated kinase (ERK) phosphorylation was increased in PFC after THC injection in repeated THC-treated mice. Phosphorylation of glycogen synthase kinase-3β (GSK3β), a Cdk5 target, was reduced in PFC after repeated THC treatment regardless of THC history, and phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the Cdk5-regulated threonine 75 site was unchanged. Conclusion: These results suggest that a history of repeated THC administration primes THC-mediated induction of ΔFosB in the NAc and PFC, and that expression of both downstream targets of

  6. Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

    DEFF Research Database (Denmark)

    Satpathy, Shankha; Wagner, Sebastian A; Beli, Petra

    2015-01-01

    B-cell receptor (BCR) signaling is essential for the development and function of B cells; however, the spectrum of proteins involved in BCR signaling is not fully known. Here we used quantitative mass spectrometry-based proteomics to monitor the dynamics of BCR signaling complexes (signalosomes......) and to investigate the dynamics of downstream phosphorylation and ubiquitylation signaling. We identify most of the previously known components of BCR signaling, as well as many proteins that have not yet been implicated in this system. BCR activation leads to rapid tyrosine phosphorylation and ubiquitylation...... of the receptor-proximal signaling components, many of which are co-regulated by both the modifications. We illustrate the power of multilayered proteomic analyses for discovering novel BCR signaling components by demonstrating that BCR-induced phosphorylation of RAB7A at S72 prevents its association...

  7. Sox2 Is Essential for Oligodendroglial Proliferation and Differentiation during Postnatal Brain Myelination and CNS Remyelination.

    Science.gov (United States)

    Zhang, Sheng; Zhu, Xiaoqing; Gui, Xuehong; Croteau, Christopher; Song, Lanying; Xu, Jie; Wang, Aijun; Bannerman, Peter; Guo, Fuzheng

    2018-02-14

    In the CNS, myelination and remyelination depend on the successful progression and maturation of oligodendroglial lineage cells, including proliferation and differentiation of oligodendroglial progenitor cells (OPCs). Previous studies have reported that Sox2 transiently regulates oligodendrocyte (OL) differentiation in the embryonic and perinatal spinal cord and appears dispensable for myelination in the postnatal spinal cord. However, the role of Sox2 in OL development in the brain has yet to be defined. We now report that Sox2 is an essential positive regulator of developmental myelination in the postnatal murine brain of both sexes. Stage-specific paradigms of genetic disruption demonstrated that Sox2 regulated brain myelination by coordinating upstream OPC population supply and downstream OL differentiation. Transcriptomic analyses further supported a crucial role of Sox2 in brain developmental myelination. Consistently, oligodendroglial Sox2-deficient mice developed severe tremors and ataxia, typical phenotypes indicative of hypomyelination, and displayed severe impairment of motor function and prominent deficits of brain OL differentiation and myelination persisting into the later CNS developmental stages. We also found that Sox2 was required for efficient OPC proliferation and expansion and OL regeneration during remyelination in the adult brain and spinal cord. Together, our genetic evidence reveals an essential role of Sox2 in brain myelination and CNS remyelination, and suggests that manipulation of Sox2 and/or Sox2-mediated downstream pathways may be therapeutic in promoting CNS myelin repair. SIGNIFICANCE STATEMENT Promoting myelin formation and repair has translational significance in treating myelin-related neurological disorders, such as periventricular leukomalacia and multiple sclerosis in which brain developmental myelin formation and myelin repair are severely affected, respectively. In this report, analyses of a series of genetic conditional

  8. Minimizing Residual Pressure within a Windowless Gas Target System - JENSA

    Science.gov (United States)

    Gomez, Orlando; Browne, Justin; Kontos, Antonios; Montes, Fernando; Jensa Collaboration

    2015-04-01

    Nuclear reactions between light gases and radioactive isotope beams are essential to address open questions in nuclear structure and astrophysics. Pure light gas targets are critical for the measurements of proton- and alpha-induced reactions. J _ et E _ xperiments in N _ uclear S _ tructure and A _ strophysics (JENSA) is the world's most dense (~ 1019 atoms/cm2) windowless gas target system. Most of the gas flow is localized; however, escaping gas creates a pressure gradient which degrades experimental measurements and contaminates the beam line. JENSA contains a differential pumping system to maintain a vacuum. The previous design configuration was not optimized for experiments (pressure measurements 70 cm downstream from the jet were ~ 10-3 torr; optimal is less than 10-4 torr). We have altered the current differential pumping system to minimize the residual pressure profile. Several configurations of two gas-receiving catchers were tested, and the most efficient ones identified using Enhanced Pirani and Cold Cathode gauges. We have determined the 30 mm outer and 20 mm inner gas-receiving cones minimize JENSA central chamber pressure to 200 millitorr at 16,000 torr of discharge pressure. Altering the tubing configuration has additionally lowered the pressure 70 cm downstream to 10-5 torr. The new residual pressure allows operation of JENSA with planned expansion of a recoil mass separator SECAR.

  9. Electric circuits essentials

    CERN Document Server

    REA, Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Electric Circuits I includes units, notation, resistive circuits, experimental laws, transient circuits, network theorems, techniques of circuit analysis, sinusoidal analysis, polyph

  10. Business statistics I essentials

    CERN Document Server

    Clark, Louise

    2014-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Business Statistics I includes descriptive statistics, introduction to probability, probability distributions, sampling and sampling distributions, interval estimation, and hypothesis t

  11. Heat transfer II essentials

    CERN Document Server

    REA, The Editors of

    1988-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Heat Transfer II reviews correlations for forced convection, free convection, heat exchangers, radiation heat transfer, and boiling and condensation.

  12. Statistics I essentials

    CERN Document Server

    Milewski, Emil G

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Statistics I covers include frequency distributions, numerical methods of describing data, measures of variability, parameters of distributions, probability theory, and distributions.

  13. Calculus III essentials

    CERN Document Server

    REA, Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Calculus III includes vector analysis, real valued functions, partial differentiation, multiple integrations, vector fields, and infinite series.

  14. Computer science I essentials

    CERN Document Server

    Raus, Randall

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Computer Science I includes fundamental computer concepts, number representations, Boolean algebra, switching circuits, and computer architecture.

  15. Calculus I essentials

    CERN Document Server

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Calculus I covers functions, limits, basic derivatives, and integrals.

  16. Modern algebra essentials

    CERN Document Server

    Lutfiyya, Lutfi A

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Modern Algebra includes set theory, operations, relations, basic properties of the integers, group theory, and ring theory.

  17. Pre-calculus essentials

    CERN Document Server

    Woodward, Ernest

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Pre-Calculus reviews sets, numbers, operations and properties, coordinate geometry, fundamental algebraic topics, solving equations and inequalities, functions, trigonometry, exponents

  18. Differential equations I essentials

    CERN Document Server

    REA, Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Differential Equations I covers first- and second-order equations, series solutions, higher-order linear equations, and the Laplace transform.

  19. Algebra & trigonometry II essentials

    CERN Document Server

    REA, Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Algebra & Trigonometry II includes logarithms, sequences and series, permutations, combinations and probability, vectors, matrices, determinants and systems of equations, mathematica

  20. Transport phenomena II essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Transport Phenomena II covers forced convention, temperature distribution, free convection, diffusitivity and the mechanism of mass transfer, convective mass transfer, concentration

  1. Numerical analysis II essentials

    CERN Document Server

    REA, The Editors of; Staff of Research Education Association

    1989-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Numerical Analysis II covers simultaneous linear systems and matrix methods, differential equations, Fourier transformations, partial differential equations, and Monte Carlo methods.

  2. The transformation of rivers’ temperature regime downstream of reservoirs

    Directory of Open Access Journals (Sweden)

    Kirvel Ivan

    2015-12-01

    Full Text Available The article is dedicated to the problem of the transformation of rivers’ temperature conditions influenced by artificial reservoirs. A quantitative estimation of average water temperatures over ten days, and maximum and average annual water temperatures of regulated rivers downstream of reservoirs was made on the basis of the data analysis of a complete period of instrumental observations of the Republican Hydrometeorological Centre of the Republic of Belarus. It is established that the character and the parameters of the transformation of temperature conditions of the regulated rivers along with morphometric features of the reservoirs are determined by the meteorological conditions of the year and the operating conditions of the water-engineering system. The length of the cooling period effect varies from 20 days downstream of small reservoirs to 50-70 days downstream of small and average size reservoirs. The warming effect is less significant by temperature, but lasts longer and is appreciable around 200-240 days in a year. An increase in the average annual water temperature up to 0.5°C and a decrease in maximum temperature down to 1.1°C are observed in the tail-water of average size storage pools. Small size storage pools demonstrate an annual increase in annual water temperature up to 0.3°C and a decrease in maximum temperature down to 0.3°C. Small size water pools show an increase both in annual water temperature up to 0.5°C and maximum water temperature up to 0.3°C. Typical changes in temperature conditions of rivers are observed for a distance of 130 kilometres below the dam of average size water pools, along 70 kilometres in small water pools and along 30 kilometres in tiny ones.

  3. Recent Molecular Advances on Downstream Plant Responses to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Cláudia Regina Batista de Souza

    2012-07-01

    Full Text Available Abiotic stresses such as extremes of temperature and pH, high salinity and drought, comprise some of the major factors causing extensive losses to crop production worldwide. Understanding how plants respond and adapt at cellular and molecular levels to continuous environmental changes is a pre-requisite for the generation of resistant or tolerant plants to abiotic stresses. In this review we aimed to present the recent advances on mechanisms of downstream plant responses to abiotic stresses and the use of stress-related genes in the development of genetically engineered crops.

  4. Patents and Downstream Innovation Suppresion - Facts or Fiction?

    DEFF Research Database (Denmark)

    Howells, John

    Merges and Nelson have proposed that pioneer patents of "broad" scope (where the claimed scope is typically broader than that strictly justified by the invention) enable their owners to "block" or "hold-up" downstream innovation.[1] They claim to have illustrated this thesis in such important cases...... of development as aircraft, the car, radio and electric lighting. Merges and Nelson quite logically use their work to question the value of Kitch's prospect theory of patents,[2] a theory that emphasises that the social value of patents is that they enable the coordination of technological development...

  5. Enhanced mixing downstream of a pile in an estuarine flow

    Science.gov (United States)

    Lass, H. U.; Mohrholz, V.; Knoll, M.; Prandke, H.

    2008-11-01

    We studied the impact on stratification and mixing of a bridge pile in a stratified shear flow at the Western Bridge of the Great Belt Fixed Link, Denmark, in January and April 2006. Stratification was measured with high horizontal resolution by towed CTD chains and dissipation of turbulent kinetic energy was measured by a free-falling MSS 90 microstructure profiler equipped with shear probes. Background stratification and current were measured by standard CTD and a bottom-mounted ADCP, respectively. The spatial and temporal variability of the flow field close behind a single pile was measured by an ADCP mounted on a small catamaran tethered to this pile. A shear background flow of varying strength was observed with an inflow of up to 80 cm s - 1 in the surface layer and an outflow of 10 cm s - 1 in the bottom layer. The brackish surface layer was separated from the saline Kattegat water in the bottom layer by an intermediate layer resulting in a Brunt-Väisälä frequency of up to 100 cycles per hour (cph). The maximum Reynolds number ( Re) and internal Froude number ( Fr) were 4.6 × 10 6 and 1.3, respectively. Eddies occurred downstream of a pile with a characteristic diameter of the pile and a frequency corresponding to a von Kármán vortex street when near-surface Fr > 0.7. Enhanced mixing was observed in the von Kármán vortex streets, which caused an increase in salinity by a few psu in the surface mixed layer of the eddy up to 400 m downstream of the piles. Differential advection by cross-channel circulation smeared out laterally from the wakes' salinity anomalies and turbulence. The dissipation of turbulent kinetic energy in the intermediate layer increased by an order of magnitude downstream of the piles as a function of Fr when Fr > 0.7. This enhanced mixing reduced the mean potential energy anomaly downstream by some 10 Jm - 3 in the upper 15 m depth and caused an upstream-directed baroclinic pressure gradient of the same order as the barotropic

  6. The Integrin-Regulated Kinase PYK-2: A Therapeutic Target for Prostate Cancer

    National Research Council Canada - National Science Library

    Edlund, Magnus

    2001-01-01

    ...) . A number of promising therapeutic targets for androgen-independent and metastatic prostate cancers are contained within the signaling cascades downstream of the ECM-binding Integrin molecules...

  7. Integrity of XIAP is essential for effective activity recovery of apoptosome and its downstream caspases by Smac/Diablo.

    Science.gov (United States)

    Attaran-Bandarabadi, Faezeh; Abhari, Behnaz Ahangarian; Neishabouri, Shima Hallaj; Davoodi, Jamshid

    2017-08-01

    Contribution of individual BIR domains to Smac antagonism is investigated. Ammonium citrate was used to activate caspase-9 and pro-caspase-9 (D315, D330/A). However, the presence of citrate resulted in autoproteolysis of pro-caspase-9 and its inhibition by XIAP BIR3, which was not observed for apoptosome activated pro-caspase-9 indicating abnormal behavior of pro-caspase-9 in kosmotropic citrate salt. Thus, we used Apaf-1(residues 1-591) to activate caspase-9 through the formation of mini-apoptosome instead. Inhibition of apoptosome by XIAP BIR-1-2-3 was observed to be similar to that of BIR3 indicating that the cleavage of XIAP does not affect its potency. However, BIR1-2-3 was more prone to Smac antagonism due to simultaneous interaction of two BIR domains from XIAP with two N-terminal binding sites of Smac. Therefore, despite the role in caspase-9 activation, Apaf-1 does not influence caspase-9 inhibition by XIAP. In addition, caspase-3, -7 and -9 activity recovery by Smac protein and peptide were more efficient for BIR1-2-3 than for BIR1-2. Consequently, it can be proposed that the presence of multiple BIR domains for XIAP among different species along with dimeric nature of Smac are evolutionary designed to strengthen the antagonistic activity of Smac culminating in efficient induction of cell death. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Drosophila CHIP protects against mitochondrial dysfunction by acting downstream of Pink1 in parallel with Parkin.

    Science.gov (United States)

    Chen, Jia; Xue, Jin; Ruan, Jingsong; Zhao, Juan; Tang, Beisha; Duan, Ranhui

    2017-12-01

    Mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin function in a common pathway to regulate mitochondrial homeostasis contributing to the pathogenesis of Parkinson disease. The carboxyl terminus of Hsc70-interacting protein (CHIP) acts as a heat shock protein 70/heat shock protein 90 cochaperone to mediate protein folding or as an E3 ubiquitin ligase to target proteins for degradation. In this study, overexpression of Drosophila CHIP suppressed a range of Pink1 mutant phenotypes in flies, including abnormal wing posture, thoracic indentation, locomotion defects, muscle degeneration, and loss of dopaminergic neurons. Mitochondrial defects of Pink1 mutant, such as excessive fusion, reduced ATP content, and crista disorganization, were rescued by CHIP but not its ligase-dead mutants. Similar phenotypes and mitochondrial impairment were ameliorated in Parkin mutant flies by wild-type CHIP. Inactivation of CHIP with null fly mutants resulted in mitochondrial defects, such as reduced thoracic ATP content at 3 d old, decreased thoracic mitochondrial DNA content, and defective mitochondrial morphology at 60 d old. CHIP mutants did not exacerbate the phenotypes of Pink1 mutant flies but markedly shortened the life span of Parkin mutant flies. These results indicate that CHIP is involved in mitochondrial integrity and may act downstream of Pink1 in parallel with Parkin.-Chen, J., Xue, J., Ruan, J., Zhao, J., Tang, B., Duan, R. Drosophila CHIP protects against mitochondrial dysfunction by acting downstream of Pink1 in parallel with Parkin. © FASEB.

  9. Downstream processing of biopharmaceutical proteins produced in plants: the pros and cons of flocculants.

    Science.gov (United States)

    Buyel, Johannes Felix; Fischer, Rainer

    2014-01-01

    All biological platforms for the manufacture of biopharmaceutical proteins produce an initially turbid extract that must be clarified to avoid fouling sensitive media such as chromatography resins. Clarification is more challenging if the feed stream contains large amounts of dispersed particles, because these rapidly clog the filter media typically used to remove suspended solids. Charged polymers (flocculants) can increase the apparent size of the dispersed particles by aggregation, facilitating the separation of solids and liquids, and thus reducing process costs. However, many different factors can affect the behavior of flocculants, including the pH and conductivity of the medium, the size and charge distribution of the particulates, and the charge density and molecular mass of the polymer. Importantly, these properties can also affect the recovery of the target protein and the overall safety profile of the process. We therefore used a design of experiments approach to establish reliable predictive models that characterize the impact of flocculants during the downstream processing of biopharmaceutical proteins. We highlight strategies for the selection of flocculants during process optimization. These strategies will contribute to the quality by design aspects of process development and facilitate the development of safe and efficient downstream processes for plant-derived pharmaceutical proteins.

  10. Essential Bacillus subtilis genes

    DEFF Research Database (Denmark)

    Kobayashi, K.; Ehrlich, S.D.; Albertini, A.

    2003-01-01

    To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among approximate to4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were...... predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related...... to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from...

  11. Tidal Influence on Water Quality of Kapuas Kecil River Downstream

    Science.gov (United States)

    Purnaini, Rizki; Sudarmadji; Purwono, Suryo

    2018-02-01

    The Kapuas Kecil River is strongly influenced by tidal, in the dry season the intrusion of surface water is often a problem for the WTP because it causes the change of raw water quality to be processed. The purpose of this study was to examine the effect of sea tides on water quality of the Kapuas Kecil River. The study was conducted in Kapuas River downstream along ± 30 km from the upper boundary to the estuary. Water sampling is carried out during the dry and rainy season, when the tidal conditions at 7 (seven) locations of the monitoring station. Descriptive analysis methods and regression-correlation statistics are used to determine the effect of tides on water quality in Kapuas River downstream. In general, the water quality of the Kapuas Kecil River has exceeded the criteria of first class water quality, ie water that can be used for drinking water. The status of water quality of the Kapuas Kecil River based on the pollution index calculation shows the condition of the river is "mild to medium pollutants". The result of multiple linear regression analysis got the value of coefficient of determination (adjusted R square) = 0,760, which in whole show that independent variable (tidal and distance) influence to dependent variable (value of TDS) equal to 76%.

  12. Kappa-Electrons Downstream of the Solar Wind Termination Shock

    Science.gov (United States)

    Fahr, H. J.

    2017-12-01

    A theoretical description of the solar wind electron distribution function downstream of the termination shock under the influence of the shock-induced injection of overshooting KeV-energetic electrons will be presented. A kinetic phasespace transport equation in the bulk frame of the heliosheath plasma flow is developed for the solar wind electrons, taking into account shock-induced electron injection, convective changes, magnetic cooling processes and whistler wave-induced energy diffusion. Assuming that the local electron distribution under the prevailing Non-LTE conditions can be represented by a local kappa function with a local kappa parameter that varies with the streamline coordinates, we determine the parameters of the resulting, initial kappa distribution for the downstream electrons. From this initial function spectral electron fluxes can be derived and can be compared with those measured by the VOYAGER-1 spacecraft in the range between 40 to 70 KeV. It can then be shown that with kappa values around kappa = 6 one can in fact fit these data very satisfactorily. In addition it is shown that for isentropic electron flows kappa-distributed electrons have to undergo simultaneous changes of both parameters, i.e. kappa and theta, of the electron kappa function. It is also shown then that under the influence of energy sinks and sources the electron flux becomes non-isentropic with electron entropies changing along the streamline.

  13. LHC Asynchronous Beam Dump: Study of new TCDQ model and effects on downstream magnets

    CERN Document Server

    Versaci, R; Vlachoudis, V

    2012-01-01

    An asynchronous beam dump is one of the most critical accidents the LHC could face. In the effort to have a better protection of the machine, and to increase the robustness of the protection device itself, new models for the TCDQ (Target Collimator Dump Quadrupole) have been proposed and are under evaluation. Within this frame we have performed FLUKA evaluation of the energy deposition on one of the proposed models and on the downstream quadrupoles, MQY.4R6 and MQY.5R6, in order to evaluate the protection provided by the proposed model. The results of our study are compared to a similar one for a different proposed model and are input for the evaluation of the heat load on the proposed collimator.

  14. C programming language essentials

    CERN Document Server

    Ackermann, Ernest C

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. C Programming Language discusses fundamental notions, data types and objects, expressions, statements, declarations, function and program structure, the preprocessor, and the standar

  15. Electronics I essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Electronics I covers fundamentals of semiconductor devices, junction diodes, bipolar junction transistors, power supplies, multitransistor circuits, small signals, low-frequency anal

  16. Electronics II essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Electronics II covers operational amplifiers, feedback and frequency compensation of OP amps, multivibrators, logic gates and families, Boolean algebra, registers, counters, arithmet

  17. Boolean algebra essentials

    CERN Document Server

    Solomon, Alan D

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Boolean Algebra includes set theory, sentential calculus, fundamental ideas of Boolean algebras, lattices, rings and Boolean algebras, the structure of a Boolean algebra, and Boolean

  18. Group theory I essentials

    CERN Document Server

    Milewski, Emil G

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Group Theory I includes sets and mapping, groupoids and semi-groups, groups, isomorphisms and homomorphisms, cyclic groups, the Sylow theorems, and finite p-groups.

  19. Computer science II essentials

    CERN Document Server

    Raus, Randall

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Computer Science II includes organization of a computer, memory and input/output, coding, data structures, and program development. Also included is an overview of the most commonly

  20. Set theory essentials

    CERN Document Server

    Milewski, Emil G

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Set Theory includes elementary logic, sets, relations, functions, denumerable and non-denumerable sets, cardinal numbers, Cantor's theorem, axiom of choice, and order relations.

  1. Complex variables I essentials

    CERN Document Server

    Solomon, Alan D

    2013-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Complex Variables I includes functions of a complex variable, elementary complex functions, integrals of complex functions in the complex plane, sequences and series, and poles and r

  2. Transport phenomena I essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Transport Phenomena I includes viscosity, flow of Newtonian fluids, velocity distribution in laminar flow, velocity distributions with more than one independent variable, thermal con

  3. Algebra & trigonometry I essentials

    CERN Document Server

    REA, Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Algebra & Trigonometry I includes sets and set operations, number systems and fundamental algebraic laws and operations, exponents and radicals, polynomials and rational expressions, eq

  4. Geometry I essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Geometry I includes methods of proof, points, lines, planes, angles, congruent angles and line segments, triangles, parallelism, quadrilaterals, geometric inequalities, and geometric

  5. Complex variables II essentials

    CERN Document Server

    Solomon, Alan D

    2013-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Complex Variables II includes elementary mappings and Mobius transformation, mappings by general functions, conformal mappings and harmonic functions, applying complex functions to a

  6. Data structures II essentials

    CERN Document Server

    Smolarski, Dennis C

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Data Structures II includes sets, trees, advanced sorting, elementary graph theory, hashing, memory management and garbage collection, and appendices on recursion vs. iteration, alge

  7. Data structures I essentials

    CERN Document Server

    Smolarski, Dennis C

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Data Structures I includes scalar variables, arrays and records, elementary sorting, searching, linked lists, queues, and appendices of binary notation and subprogram parameter passi

  8. Thermodynamics I essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Thermodynamics I includes review of properties and states of a pure substance, work and heat, energy and the first law of thermodynamics, entropy and the second law of thermodynamics

  9. Physics I essentials

    CERN Document Server

    REA, The Editors of

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Physics I includes vectors and scalars, one-dimensional motion, plane motion, dynamics of a particle, work and energy, conservation of energy, dynamics of systems of particles, rotation

  10. Thermodynamics II essentials

    CERN Document Server

    REA, The Editors of

    2013-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Thermodynamics II includes review of thermodynamic relations, power and refrigeration cycles, mixtures and solutions, chemical reactions, chemical equilibrium, and flow through nozzl

  11. Physical chemistry II essentials

    CERN Document Server

    REA, The Editors of

    1992-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Physical Chemistry II includes reaction mechanisms, theoretical approaches to chemical kinetics, gravitational work, electrical and magnetic work, surface work, kinetic theory, collisional and transport properties of gases, statistical mechanics, matter and waves, quantum mechanics, and rotations and vibrations of atoms and molecules.

  12. Laplace transforms essentials

    CERN Document Server

    Shafii-Mousavi, Morteza

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Laplace Transforms includes the Laplace transform, the inverse Laplace transform, special functions and properties, applications to ordinary linear differential equations, Fourier tr

  13. Statistics II essentials

    CERN Document Server

    Milewski, Emil G

    2012-01-01

    REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Statistics II discusses sampling theory, statistical inference, independent and dependent variables, correlation theory, experimental design, count data, chi-square test, and time se

  14. Roitt's essential immunology

    National Research Council Canada - National Science Library

    Delves, Peter J; Roitt, Ivan M

    2011-01-01

    ... of the immune system, the hallmark easy-reading style of Roitt's Essential Immunology clearly explains the key principles needed by medical and health sciences students, from the basis of immunity to clinical applications...

  15. Treatment of Essential Tremor

    Science.gov (United States)

    ... essential tremor. Neurologists from the American Academy of Neurology are doctors who identify and treat diseases of ... an educational service of the American Academy of Neurology. It is based on an assessment of current ...

  16. Marketingmanagement : De essentie

    NARCIS (Netherlands)

    Kotler, P.J.; Keller, K.; Robben, H.S.J.

    2007-01-01

    'Marketingmanagement, de essentie' biedt een volledige introductie in modern marketingmanagement. De nieuwste concepten en onderzoeksresultaten komen aan bod. Zo wordt veel aandacht besteed aan holistische marketing en is de impact van technologische ontwikkelingen op hedendaagse marketing in deze

  17. Marketing management : De essentie

    NARCIS (Netherlands)

    Kotler, P.J.; Keller, K.; Robben, H.S.J.

    2010-01-01

    'Marketingmanagement, de essentie' biedt een volledige introductie in modern marketingmanagement. De nieuwste concepten en onderzoeksresultaten komen aan bod. Zo wordt veel aandacht besteed aan holistische marketing en is de impact van technologische ontwikkelingen op hedendaagse marketing in deze

  18. Essential software architecture

    CERN Document Server

    Gorton, Ian

    2011-01-01

    Job titles like ""Technical Architect"" and ""Chief Architect"" nowadays abound in software industry, yet many people suspect that ""architecture"" is one of the most overused and least understood terms in professional software development. Gorton's book tries to resolve this dilemma. It concisely describes the essential elements of knowledge and key skills required to be a software architect. The explanations encompass the essentials of architecture thinking, practices, and supporting technologies. They range from a general understanding of structure and quality attributes through technical i

  19. The downstream externalities of harvesting rainwater in semi-arid watersheds: an Indian case study

    NARCIS (Netherlands)

    Bouma, J.A.; Biggs, T.W.; Bouwer, L.M.

    2011-01-01

    Water-related investment projects affect downstream water availability, and therefore should account for these externalities. Few projects do, however, owing to lack of awareness, lack of data and difficulty in linking upstream investments to downstream effects. This article assesses the downstream

  20. Exploring the optimal strategy to predict essential genes in microbes.

    Science.gov (United States)

    Deng, Jingyuan; Tan, Lirong; Lin, Xiaodong; Lu, Yao; Lu, Long J

    2011-12-27

    Accurately predicting essential genes is important in many aspects of biology, medicine and bioengineering. In previous research, we have developed a machine learning based integrative algorithm to predict essential genes in bacterial species. This algorithm lends itself to two approaches for predicting essential genes: learning the traits from known essential genes in the target organism, or transferring essential gene annotations from a closely related model organism. However, for an understudied microbe, each approach has its potential limitations. The first is constricted by the often small number of known essential genes. The second is limited by the availability of model organisms and by evolutionary distance. In this study, we aim to determine the optimal strategy for predicting essential genes by examining four microbes with well-characterized essential genes. Our results suggest that, unless the known essential genes are few, learning from the known essential genes in the target organism usually outperforms transferring essential gene annotations from a related model organism. In fact, the required number of known essential genes is surprisingly small to make accurate predictions. In prokaryotes, when the number of known essential genes is greater than 2% of total genes, this approach already comes close to its optimal performance. In eukaryotes, achieving the same best performance requires over 4% of total genes, reflecting the increased complexity of eukaryotic organisms. Combining the two approaches resulted in an increased performance when the known essential genes are few. Our investigation thus provides key information on accurately predicting essential genes and will greatly facilitate annotations of microbial genomes.

  1. Allogeneic cell therapy bioprocess economics and optimization: downstream processing decisions.

    Science.gov (United States)

    Hassan, Sally; Simaria, Ana S; Varadaraju, Hemanthram; Gupta, Siddharth; Warren, Kim; Farid, Suzanne S

    2015-01-01

    To develop a decisional tool to identify the most cost effective process flowsheets for allogeneic cell therapies across a range of production scales. A bioprocess economics and optimization tool was built to assess competing cell expansion and downstream processing (DSP) technologies. Tangential flow filtration was generally more cost-effective for the lower cells/lot achieved in planar technologies and fluidized bed centrifugation became the only feasible option for handling large bioreactor outputs. DSP bottlenecks were observed at large commercial lot sizes requiring multiple large bioreactors. The DSP contribution to the cost of goods/dose ranged between 20-55%, and 50-80% for planar and bioreactor flowsheets, respectively. This analysis can facilitate early decision-making during process development.

  2. 'Patents and Downstream Innovation Suppression - Fact or Fiction?'

    DEFF Research Database (Denmark)

    Howells, John

    1977), a theory that is a version of the classic justification for the award of the exclusive right - that it should protect the incentive to develop property. Merges and Nelson insist that their thesis should be supported by empirical evidence and they turn to historical accounts as an important form......Merges and Nelson have provided an empirically grounded argument that firms use pioneer patents of 'broad' scope to block downstream technological development (Merges and Nelson 1990). If this is a regular occurrence then, as they claim, they have faulted Kitch's 'prospect theory' of patents (Kitch....... This interpretation restores the credibility of Kitch's prospect theory of patent function and emphasises that maintenance of the prospect function should be an object of patent policy....

  3. Upstream and downstream strategies to economize biodiesel production.

    Science.gov (United States)

    Hasheminejad, Meisam; Tabatabaei, Meisam; Mansourpanah, Yaghoub; Khatami far, Mahdi; Javani, Azita

    2011-01-01

    In recent years biodiesel has drawn considerable amount of attention as a clean and renewable fuel. Biodiesel is produced from renewable sources such as vegetable oils and animal fat mainly through catalytic or non-catalytic transesterification method as well as supercritical method. However, as a consequence of disadvantages of these methods, the production cost increases dramatically. This article summarizes different biodiesel production methods with a focus on their advantages and disadvantages. The downstream and upstream strategies such as using waste cooking oils, application of non-edible plant oils, plant genetic engineering, using membrane separation technology for biodiesel production, separation and purification, application of crude glycerin as an energy supplement for ruminants, glycerin ultra-purification and their consequent roles in economizing the production process are fully discussed in this article. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. A Copernicus downstream service for surface displacement monitoring in Germany

    Science.gov (United States)

    Cahyadi Kalia, Andre; Frei, Michaela; Lege, Thomas

    2016-04-01

    SAR Interferometry is a powerful technique able to detect and monitor various surface displacements caused by e.g. gravitative mass movement, subrosion, groundwater extraction, fluid injection, natural gas extraction. These processes can e.g. cause damage to buildings, infrastructure, affect ecosystems, agriculture and the economic use of the geological underground by influencing the hydro(geo)logical setting. Advanced techniques of interferometric processing (Persistent Scatterer Interferometry, PSI) allow highly precise displacement measurements (mm precision) by analyzing stacks of SAR imagery. The PSI mapping coverage can be increased to entire nations by using several adjacent satellite tracks. In order to assist the operational use of this technique a German-wide, officially approved, PSI dataset is under development. The intention of this presentation is to show i) the concept of the Copernicus downstream service for surface displacement monitoring in Germany and ii) a pilot study to exemplarily demonstrate the workflow and potential products from the Copernicus downstream service. The pilot study is focusing on the built up of an officially approved wide-area PSI dataset. The study area covers an area of more than 30.000 km² and is located in the Northwest German Basin. Several natural processes (e.g. compaction of marine sediments, peat loss) and anthropogenic activities (e.g. natural gas extraction, rock salt mining) are causing surface displacements in the study area. The PSI analysis is based on six ERS-1/-2 data stacks covering the timespan from 1992 until 2001. Each data stack consists of 49 to 73 ERS-1/-2 SAR images. A comparison of the PSI results with thematic data (e.g. volume and location of extracted natural gas) strongly indicates that a part of the detected land subsidence is caused by natural gas extraction. Furthermore, land subsidence caused by e.g. fluid injection and rock salt mining were successfully detected by the PSI analysis.

  5. Python essential reference

    CERN Document Server

    Beazley, David M

    2009-01-01

    Python Essential Reference is the definitive reference guide to the Python programming language — the one authoritative handbook that reliably untangles and explains both the core Python language and the most essential parts of the Python library. Designed for the professional programmer, the book is concise, to the point, and highly accessible. It also includes detailed information on the Python library and many advanced subjects that is not available in either the official Python documentation or any other single reference source. Thoroughly updated to reflect the significant new programming language features and library modules that have been introduced in Python 2.6 and Python 3, the fourth edition of Python Essential Reference is the definitive guide for programmers who need to modernize existing Python code or who are planning an eventual migration to Python 3. Programmers starting a new Python project will find detailed coverage of contemporary Python programming idioms.

  6. Essential travel medicine

    CERN Document Server

    Zuckerman, Jane N; Leggat, Peter

    2015-01-01

    This 1st edition of Essential Travel Medicine provides an excellent concise introduction to the specialty of Travel Medicine. This core text will enable health care practitioners particularly those new to the clinical practice of Travel Medicine, to gain a fundamental understanding of the diverse and complex issues which can potentially affect the health of the many millions of people who undertake international travel. Jane N Zuckerman is joined by Gary W Brunette from CDC and Peter A Leggat from Australia as Editors. Leading international specialists in their fields have contributed authoritative chapters reflecting current knowledge to facilitate best clinical practice in the different aspects of travel medicine. The aim of Essential Travel Medicine is to provide a comprehensive guide to Travel Medicine as well as a fundamental knowledge base to support international undergraduate and postgraduate specialty training programmes in the discipline of Travel Medicine. The 1st edition of Essential Travel ...

  7. Physics Essentials For Dummies

    CERN Document Server

    Holzner, Steven

    2010-01-01

    For students who just need to know the vital concepts of physics, whether as a refresher, for exam prep, or as a reference, Physics Essentials For Dummies is a must-have guide. Free of ramp-up and ancillary material, Physics Essentials For Dummies contains content focused on key topics only. It provides discrete explanations of critical concepts taught in an introductory physics course, from force and motion to momentum and kinetics. This guide is also a perfect reference for parents who need to review critical physics concepts as they help high school students with homework assignments, as we

  8. Essentials of Computational Electromagnetics

    CERN Document Server

    Sheng, Xin-Qing

    2012-01-01

    Essentials of Computational Electromagnetics provides an in-depth introduction of the three main full-wave numerical methods in computational electromagnetics (CEM); namely, the method of moment (MoM), the finite element method (FEM), and the finite-difference time-domain (FDTD) method. Numerous monographs can be found addressing one of the above three methods. However, few give a broad general overview of essentials embodied in these methods, or were published too early to include recent advances. Furthermore, many existing monographs only present the final numerical results without specifyin

  9. Corrosion impact of reductant on DWPF and downstream facilities

    Energy Technology Data Exchange (ETDEWEB)

    Mickalonis, J. I. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Imrich, K. J. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Jantzen, C. M. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Murphy, T. H. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Wilderman, J. E. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2014-12-01

    Glycolic acid is being evaluated as an alternate reductant in the preparation of high level waste for the Defense Waste Processing Facility (DWPF) at the Savannah River Site (SRS). During processing, the glycolic acid is not completely consumed and small quantities of the glycolate anion are carried forward to other high level waste (HLW) facilities. The impact of the glycolate anion on the corrosion of the materials of construction throughout the waste processing system has not been previously evaluated. A literature review had revealed that corrosion data in glycolate-bearing solution applicable to SRS systems were not available. Therefore, testing was recommended to evaluate the materials of construction of vessels, piping and components within DWPF and downstream facilities. The testing, conducted in non-radioactive simulants, consisted of both accelerated tests (electrochemical and hot-wall) with coupons in laboratory vessels and prototypical tests with coupons immersed in scale-up and mock-up test systems. Eight waste or process streams were identified in which the glycolate anion might impact the performance of the materials of construction. These streams were 70% glycolic acid (DWPF feed vessels and piping), SRAT/SME supernate (Chemical Processing Cell (CPC) vessels and piping), DWPF acidic recycle (DWPF condenser and recycle tanks and piping), basic concentrated recycle (HLW tanks, evaporators, and transfer lines), salt processing (ARP, MCU, and Saltstone tanks and piping), boric acid (MCU separators), and dilute waste (HLW evaporator condensate tanks and transfer line and ETF components). For each stream, high temperature limits and worst-case glycolate concentrations were identified for performing the recommended tests. Test solution chemistries were generally based on analytical results of actual waste samples taken from the various process facilities or of prototypical simulants produced in the laboratory. The materials of construction for most vessels

  10. Essential Palatal Myoclonus

    Directory of Open Access Journals (Sweden)

    Bhuwan Raj Pandey

    2017-06-01

    Full Text Available Introduction: Palatal myoclonus is a rare condition presenting with clicking sound in ear or muscle tremor in pharynx. There are two varieties: essential and symptomatic. Various treatment options exists ranging from watchful observation to botulinum toxin injection. We have not found any reported case of palatal myoclonus from our country. Here we present a case of essential palatal myoclonus managed with clonazepam. Case report: A young female presented in Ear Nose and Throat clinic with complain of auditory click and spontaneous rhythmic movement of throat muscles for eight months. On examination, there was involuntary, rhythmic contraction of bilateral soft-palate, uvula, and base of tongue. Neurological, eye, and peripheral examination were normal. A diagnosis of essential palatal myoclonus was made. It was managed successfully with clonazepam; patient was still on low dose clonazepam at the time of making this report. Conclusion: Essential palatal myoclonus can be clinically diagnosed and managed even in settings where MRI is not available or affordable.

  11. Essential trichomegaly: case report

    Directory of Open Access Journals (Sweden)

    Julia Dutra Rossetto

    2013-02-01

    Full Text Available The present study reports two cases of symptomatic essential trichomegaly. Trichomegaly may develop in various diseases, including anorexia nervosa, hypothyroidism, pregnancy, pretibial myxedema, systemic lupus erythematosus, vernal keratoconjunctivitis, and uveitis. The exact incidence trichomegaly is unknown, and the condition remains sporadically reported. Two cases of symptomatic trichomegaly without any associated systemic disorder are presented in this paper.

  12. The 2003 essential. AREVA

    International Nuclear Information System (INIS)

    2004-07-01

    This document presents the essential activities of the Areva Group, a world nuclear industry leader. This group proposes technological solutions to produce the nuclear energy and to transport the electric power. It develops connection systems for the telecommunication, the computers and the automotive industry. Key data on the program management, the sustainable development activities and the different divisions are provided. (A.L.B.)

  13. The Maternal Obesity Management (MOM) Trial Protocol: a lifestyle intervention during pregnancy to minimize downstream obesity.

    Science.gov (United States)

    Adamo, Kristi B; Ferraro, Zachary M; Goldfield, Gary; Keely, Erin; Stacey, Dawn; Hadjiyannakis, Stasia; Jean-Philippe, Sonia; Walker, Mark; Barrowman, Nicholas J

    2013-05-01

    Maternal obesity and/or high gestational weight gain (GWG) are associated with downstream child obesity. Pregnancy represents a critical period for prevention as women are highly motivated and more receptive to behavior change. This pilot study was developed to test the feasibility of intervening with the mother, specifically keeping her GWG within the Institute of Medicine (IOM) limits, with the intended target of preventing obesity in her child downstream. We are testing the practicality of delivering a structured physical activity and nutrition intervention to pregnant women during gestation and then following mom and baby to 24 months of age. This study is a two-arm, parallel group, randomized controlled trial being conducted in Ottawa. Pregnant women, with pregravid BMI >18.5, between 12 and 20 weeks gestation are randomized to one of two groups: intervention (n=30) who receive the MOM trial Handbook (guide to healthy gestation) plus a structured physical activity and nutrition program, or a standard clinical care control group (n=30). The intervention lasts 25-28 weeks (6 months) depending on anticipated delivery date, with follow-up assessment on mother and child at 3, 6, 12 and 24 months post-delivery. Pregnancy, a critical time of growth, development and physiological change, provides an opportunity for early lifestyle intervention. The goal of identifying an effective lifestyle program for the gestational period that leads to healthy fetal development and subsequently normal weight offspring, less likely to develop obesity and its co-morbidities, is unique and could possibly attenuate the inter-generational cycle of obesity. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Occurrence and removal of antibiotics and the corresponding resistance genes in wastewater treatment plants: effluents' influence to downstream water environment.

    Science.gov (United States)

    Li, Jianan; Cheng, Weixiao; Xu, Like; Jiao, Yanan; Baig, Shams Ali; Chen, Hong

    2016-04-01

    In this study, the occurrence of 8 antibiotics [3 tetracyclines (TCs), 4 sulfonamides, and 1 trimethoprim (TMP)], 12 antibiotic resistance genes (ARGs) (10 tet, 2 sul), 4 types of bacteria [no antibiotics, anti-TC, anti-sulfamethoxazole (SMX), and anti-double], and intI1 in two wastewater treatment plants (WWTPs) were assessed and their influences in downstream lake were investigated. Both WWTPs' effluent demonstrated some similarities, but the abundance and removal rate varied significantly. Results revealed that biological treatment mainly removed antibiotics and ARGs, whereas physical techniques were found to eliminate antibiotic resistance bacteria (ARBs) abundance (about 1 log for each one). UV disinfection did not significantly enhance the removal efficiency, and the release of the abundantly available target contaminants from the excess sludge may pose threats to human and the environment. Different antibiotics showed diverse influences on the downstream lake, and the concentrations of sulfamethazine (SM2) and SMX were observed to increase enormously. The total ARG abundance ascended about 0.1 log and some ARGs (e.g., tetC, intI1, tetA) increased due to the high input of the effluent. In addition, the abundance of ARB variation in the lake also changed, but the abundance of four types of bacteria remained stable in the downstream sampling sites.

  15. Energy taxes and subsidies downstream: transparency and dissemination

    International Nuclear Information System (INIS)

    Aissaour, A.

    2001-01-01

    The reasons why governments levy taxes are discussed with special reference to the energy sector. The article focuses on the quantitative aspect of policies and gives a guide to the relevant statistical sources. It summarises the basis of taxes and subsidies and discusses the incidence of energy taxation together with the structure of taxes and subsidies in energy downstream. It reviews the main sources of data and issues highlighted by published statistics and the impact of taxes levied on the consumption of energy products and other taxes (e.g. VAT) which directly affect end-user prices. Production-based levies such as royalties, petroleum revenue taxes, windfall taxes and import and export taxes on fuels are not discussed. The paper is presented under the sub-headings of (i) theoretical foundations in a nutshell; (ii) the incidence of taxation; (iii) the structure and main features of energy taxation (iv) base rate and level of taxation (v) sources of data and methods and (vi) observability and comparability

  16. Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts

    Science.gov (United States)

    Shim, Jae-Hyuck; Greenblatt, Matthew B.; Zou, Weiguo; Huang, Zhiwei; Wein, Marc N.; Brady, Nicholas; Hu, Dorothy; Charron, Jean; Brodkin, Heather R.; Petsko, Gregory A.; Zaller, Dennis; Zhai, Bo; Gygi, Steven; Glimcher, Laurie H.; Jones, Dallas C.

    2013-01-01

    Mice deficient in Schnurri-3 (SHN3; also known as HIVEP3) display increased bone formation, but harnessing this observation for therapeutic benefit requires an improved understanding of how SHN3 functions in osteoblasts. Here we identified SHN3 as a dampener of ERK activity that functions in part downstream of WNT signaling in osteoblasts. A D-domain motif within SHN3 mediated the interaction with and inhibition of ERK activity and osteoblast differentiation, and knockin of a mutation in Shn3 that abolishes this interaction resulted in aberrant ERK activation and consequent osteoblast hyperactivity in vivo. Additionally, in vivo genetic interaction studies demonstrated that crossing to Lrp5–/– mice partially rescued the osteosclerotic phenotype of Shn3–/– mice; mechanistically, this corresponded to the ability of SHN3 to inhibit ERK-mediated suppression of GSK3β. Inducible knockdown of Shn3 in adult mice resulted in a high–bone mass phenotype, providing evidence that transient blockade of these pathways in adults holds promise as a therapy for osteoporosis. PMID:23945236

  17. Gellan Gum: Fermentative Production, Downstream Processing and Applications

    Directory of Open Access Journals (Sweden)

    Ishwar B. Bajaj

    2007-01-01

    Full Text Available The microbial exopolysaccharides are water-soluble polymers secreted by microorganisms during fermentation. The biopolymer gellan gum is a relatively recent addition to the family of microbial polysaccharides that is gaining much importance in food, pharmaceutical and chemical industries due to its novel properties. It is commercially produced by C. P. Kelco in Japan and the USA. Further research and development in biopolymer technology is expected to expand its use. This article presents a critical review of the available information on the gellan gum synthesized by Sphingomonas paucimobilis with special emphasis on its fermentative production and downstream processing. Rheological behaviour of fermentation broth during fermentative production of gellan gum and problems associated with mass transfer have been addressed. Information on the biosynthetic pathway of gellan gum, enzymes and precursors involved in gellan gum production and application of metabolic engineering for enhancement of yield of gellan gum has been specified. Characteristics of gellan gum with respect to its structure, physicochemical properties, rheology of its solutions and gel formation behaviour are discussed. An attempt has also been made to review the current and potential applications of gellan gum in food, pharmaceutical and other industries.

  18. Flume experiments on scour downstream of wood stream restoration structures

    Science.gov (United States)

    Pagliara, Stefano; Kurdistani, Sahameddin Mahmoudi

    2017-02-01

    River restoration aims to improve physical natural form and processes of a river. Techniques to control the riverbed, stabilize channel alignment, protect stream banks, and rebuild the natural habitat are an important part of river restoration projects. Rivers can be stabilized and habitat restored through techniques such as rebuilding meanders and pool-riffle sequences and managing large wood. Structures that limit channel width to accelerate the normal flows through the constricted section are referred to as stream deflectors. Single-wing, double-wing and triangular deflectors are the most commonly used types of this measure. Log-frame deflectors consist of a triangular log frame filled with rock. Deflector constructions singly or in series in low gradient meandering streams, divert base flows toward the center of the channel and, under certain conditions, increase the depth and velocity of flow thereby creating scour pools and enhancing fish habitat. Scour characteristics and morphologies downstream of log-frame deflectors have been analyzed at the hydraulic laboratory of the University of Pisa. All experiments have been carried out in clear water conditions. The results showed that the tailwater depth plays an important role on scour characteristics. In addition, it was experimentally proven that using log-frame deflectors instead of log-deflectors result in a better river bank protection. In this case, for all the tested hydraulic conditions, the scour hole never occurred close to the channel bank. Useful empirical relationships have been proposed in order to evaluate the main features of the scour geometry.

  19. Generic chromatography-based purification strategies accelerate the development of downstream processes for biopharmaceutical proteins produced in plants.

    Science.gov (United States)

    Buyel, Johannes F; Fischer, Rainer

    2014-04-01

    Plants offer a valuable alternative to cultured mammalian cells for the production of recombinant biopharmaceutical proteins. However, the target protein typically represents only a minor fraction of the total protein in the initial plant extract, which means that the development of product-specific chromatography-based purification strategies is often laborious and expensive. To address this challenge, we designed a generic downstream process that is suitable for the purification of recombinant proteins with diverse properties from plant production platforms. This was achieved by focusing on the binding behavior of tobacco host cell proteins (HCPs) to a broad set of chromatography resins under different pH and conductivity conditions. Strong cation exchanger and salt-tolerant anion exchanger resins exhibited the best resolution of tobacco HCPs among the 13 tested resins, and their selectivity was easy to manipulate through the adjustment of pH and conductivity. The advantages, such as direct capture of a target protein from leaf extract, and limitations, such as low binding capacity, of various chromatography ligands and resins are discussed. We also address the most useful applications of the chromatography ligands, namely recovery of proteins with a certain pI, in a downstream process that aims to purify diverse plant-derived biopharmaceutical proteins. Based on these results, we describe generic purification schemes that are suitable for acidic, neutral, and basic target proteins, as a first step toward the development of industrial platform processes. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. OCT4 and downstream factors are expressed in human somatic urogenital epithelia and in culture of epididymal spheres

    DEFF Research Database (Denmark)

    Audouze, Karine Marie Laure; Brunak, Søren; Kristensen, DM

    2010-01-01

    and microdissected tissues, in situ hybridisation, immunohistochemistry, and Western blotting to show that OCT4 and SOX2 together with downstream targets, UTF1 and REX1, are expressed in the human male urogenital tract. We further supported these results by analysis of DNA methylation of a region in the OCT4...... promoter. In culture, human primary epididymis cells formed spheres that continued to express the investigated genes for at least 20 days. Transcriptomic analysis of cultured cells showed up-regulation of CD29, CD44, and CD133 that are normally associated with sphere-forming cancer stem cells. Furthermore...

  1. Simulating potential structural and operational changes for Detroit Dam on the North Santiam River, Oregon, for downstream temperature management

    Science.gov (United States)

    Buccola, Norman L.; Rounds, Stewart A.; Sullivan, Annett B.; Risley, John C.

    2012-01-01

    structural options were explored with the model scenarios. Multiple downstream temperature targets were used along with three sets of environmental forcing conditions representing cool/wet, normal, and hot/dry conditions. Five structural options at Detroit Dam were modeled, including the use of existing outlets, one hypothetical variable-elevation outlet such as a sliding gate, a hypothetical combination of a floating outlet and a fixed-elevation outlet, and a hypothetical combination of a floating outlet and a sliding gate. Finally, 14 sets of operational guidelines for Detroit Dam were explored to gain an understanding of the effects of imposing different downstream minimum streamflows, imposing minimum outflow rules to specific outlets, and managing the level of the lake with different timelines through the year. Selected subsets of these combinations of operational and structural scenarios were run through the downstream models of Big Cliff Reservoir and the North Santiam and Santiam Rivers to explore how hypothetical changes at Detroit Dam might provide improved temperatures for endangered salmonids downstream of the Detroit-Big Cliff Dam complex. Conclusions that can be drawn from these model scenarios include: *The water-temperature targets set by the U.S. Army Corps of Engineers for releases from Detroit Dam can be met through a combination of new dam outlets or a delayed drawdown of the lake in autumn. *Spring and summer dam operations greatly affect the available release temperatures and operational flexibility later in the autumn. Releasing warm water during midsummer tends to keep more cool water available for release in autumn. *The ability to meet downstream temperature targets during spring depends on the characteristics of the available outlets. Under existing conditions, although warm water sometimes is present at the lake surface in spring and early summer, such water may not be available for release if the lake level is either well below or well above the

  2. Efficient expression of cyclodextrin glycosyltransferase from Geobacillus stearothermophilus in Escherichia coli by promoter engineering and downstream box evolution.

    Science.gov (United States)

    Deng, Chen; Li, Jianghua; Shin, Hyun-Dong; Du, Guocheng; Chen, Jian; Liu, Long

    2018-01-20

    Cyclodextrin glycosyltransferase (CGTase) catalyzes hydrolysis, cyclization, coupling, and disproportionation reactions and is widely used in the starch processing industry. In this work, the expression of CGTase from Geobacillus stearothermophilus in Escherichia coli BL21 (DE3) was significantly improved by promoter engineering and downstream box evolution. Firstly, the effects of the promoter type (P T7 , P trp , P lacUV5 , and the hybrid promoters P tacI and P tacII ) and spacer sequence on the expression of CGTase were examined. P tacI demonstrated the highest rate of transcriptional activity, which was 4.4-, 7.1-, 3.3-, and 1.5-fold greater than that of P T7 , P trp , P lacUV5 , and P tacII , respectively. The spacer sequence of the promoter was optimized using a degenerate base library, and the GC content of the spacer was found to be inversely proportional to CGTase expression. In addition, CGTase expression was higher when TG:CA and TA:TA dimers were present in the spacer sequence. Under the control of the P tacI promoter with an optimized spacer sequence, extracellular CGTase activity reached 170.6 U/mL, which was seven times higher than that of the original strain (25.2 U/mL). Directed evolution of the downstream box sequence was then performed by randomization of the sequence using degenerate codons, similarly as for the optimization of the spacer sequence. After optimizing the downstream box sequence, CGTase activity increased from 170.6 to 214 U/mL. The results obtained here indicate that in addition to promoter type, the spacer sequence of the promoter and the downstream box are important target elements for improved gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. [Treatment of essential thrombocythemia].

    Science.gov (United States)

    Alvarez-Larrán, Alberto; Cervantes, Francisco; Besses, Carlos

    2013-09-21

    Essential thrombocythemia is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis, bone marrow megakaryocytic hyperplasia and an increased risk of thrombosis and hemorrhage. The goal of treatment is to prevent the development of vascular complications without increasing the risk of transformation. Patients aged>60 years or a history of thrombosis have a high risk of thrombosis while those with a platelet count>1,500 x 10(9)/l have a higher risk of hemorrhage. Patients with low-risk essential thrombocythemia can be managed appropriately with low-dose of acetylsalicylic acid or even observation only, while patients with a high-risk disease are candidates to receive cytoreductive treatment, hydroxyurea being the first choice therapy. Anagrelide is the most suitable option for patients with resistance or intolerance to hydroxyurea. All patients must be submitted to a rigorous control of cardiovascular risk factors. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  4. Trombocitemia Essencial Essential thrombocythaemia

    Directory of Open Access Journals (Sweden)

    Andrea B. Leite

    2001-04-01

    Full Text Available Essential thrombocythaemia is a chronic myeloproliferative disorder characterized by the proliferation of megakaryocytes in the bone marrow, leading to a persistent increase in circulating platelets. Apart from this increase (>600 x 10(9/L this disease also exhibits accentuated hyperplasia of the megakaryocytes in the bone marrow, splenomegaly and clinically both thrombotic and haemorrhagic episodes. The etiology of this illness is largely unknown and the clinical manifestations are mostly asymptomatic, thus the diagnostic is often accidentally made. Here the case report of a 71-year-old male patient is discussed, who was admitted into hospital due to occlusion of the femoral artery requiring re-vascularisation. The physical exam showed that the patient suffered several other symptoms related to essential thrombocythaemia. In conclusion, this is a grave, potentially fatal disease which needs further study to determine the etiology. Early diagnosis and treatment are crucial for a good prognosis.

  5. Wind-Driven Ecological Flow Regimes Downstream from Hydropower Dams

    Science.gov (United States)

    Kern, J.; Characklis, G. W.

    2012-12-01

    Conventional hydropower can be turned on and off quicker and less expensively than thermal generation (coal, nuclear, or natural gas). These advantages enable hydropower utilities to respond to rapid fluctuations in energy supply and demand. More recently, a growing renewable energy sector has underlined the need for flexible generation capacity that can complement intermittent renewable resources such as wind power. While wind power entails lower variable costs than other types of generation, incorporating it into electric power systems can be problematic. Due to variable and unpredictable wind speeds, wind power is difficult to schedule and must be used when available. As a result, integrating large amounts of wind power into the grid may result in atypical, swiftly changing demand patterns for other forms of generation, placing a premium on sources that can be rapidly ramped up and down. Moreover, uncertainty in wind power forecasts will stipulate increased levels of 'reserve' generation capacity that can respond quickly if real-time wind supply is less than expected. These changes could create new hourly price dynamics for energy and reserves, altering the short-term financial signals that hydroelectric dam operators use to schedule water releases. Traditionally, hourly stream flow patterns below hydropower dams have corresponded in a very predictable manner to electricity demand, whose primary factors are weather (hourly temperature) and economic activity (workday hours). Wind power integration has the potential to yield more variable, less predictable flows at hydro dams, flows that at times could resemble reciprocal wind patterns. An existing body of research explores the impacts of standard, demand-following hydroelectric dams on downstream ecological flows; but weighing the benefits of increased reliance on wind power against further impacts to ecological flows may be a novel challenge for the environmental community. As a preliminary step in meeting this

  6. Essentials of artificial intelligence

    CERN Document Server

    Ginsberg, Matt

    1993-01-01

    Since its publication, Essentials of Artificial Intelligence has beenadopted at numerous universities and colleges offering introductory AIcourses at the graduate and undergraduate levels. Based on the author'scourse at Stanford University, the book is an integrated, cohesiveintroduction to the field. The author has a fresh, entertaining writingstyle that combines clear presentations with humor and AI anecdotes. At thesame time, as an active AI researcher, he presents the materialauthoritatively and with insight that reflects a contemporary, first hand

  7. Rake task management essentials

    CERN Document Server

    Koleshko, Andrey

    2014-01-01

    A step-by-step and interactive approach explaining the Rake essentials along with code examples and advanced features. If you are a developer who is acquainted with the Ruby language and want to speed up writing the code concerned with files, then this book is for you. To start reading this book, basic Ruby knowledge is required; however, a huge amount of experience with the language is not necessary.

  8. IPv6 Essentials

    CERN Document Server

    Hagen, Silvia

    2006-01-01

    IPv6 Essentials, Second Edition provides a succinct, in-depth tour of all the new features and functions in IPv6. It guides you through everything you need to know to get started, including how to configure IPv6 on hosts and routers and which applications currently support IPv6. Aimed at system and network administrators, engineers, network designers, and IT managers, this book will help you understand, plan for, design, and integrate IPv6 into your current IPv4 infrastructure

  9. Android application security essentials

    CERN Document Server

    Rai, Pragati

    2013-01-01

    Android Application Security Essentials is packed with examples, screenshots, illustrations, and real world use cases to secure your apps the right way.If you are looking for guidance and detailed instructions on how to secure app data, then this book is for you. Developers, architects, managers, and technologists who wish to enhance their knowledge of Android security will find this book interesting. Some prior knowledge of development on the Android stack is desirable but not required.

  10. Moodle administration essentials

    CERN Document Server

    Henrick, Gavin

    2015-01-01

    If you are an experienced system administrator and know how to manage servers and set up web environments but now want to explore Moodle, this book is perfect for you. You'll get to grips with the basics and learn to manage Moodle quickly, focusing on essential tasks. Having prior knowledge of virtual learning environments would be beneficial, but is not mandatory to make the most of this book.

  11. Process Improvement Essentials

    CERN Document Server

    Persse, James R

    2006-01-01

    Process Improvement Essentials combines the foundation needed to understand process improvement theory with the best practices to help individuals implement process improvement initiatives in their organization. The three leading programs: ISO 9001:2000, CMMI, and Six Sigma--amidst the buzz and hype--tend to get lumped together under a common label. This book delivers a combined guide to all three programs, compares their applicability, and then sets the foundation for further exploration.

  12. Which tributaries disrupt downstream fining along gravel-bed rivers?

    Science.gov (United States)

    Rice, Stephen

    1998-02-01

    Tributaries and other lateral sediment sources can have a significant impact on river bed sediment texture and, in turn, on channel form. Sufficiently voluminous or distinct sediment inputs redefine the mainstem grain-size distribution, punctuating downstream maturation and isolating a sequence of discrete sedimentary links. Within these links fining processes usually dominate, such that models of sorting and abrasion, when applied to individual links, provide reasonable predictions of grain-size change. Links represent the fundamental natural unit within which fining models can be tested, developed and applied. Identification of significant lateral sources is therefore important, yet, beyond vague references to relative tributary size, sediment load, and sediment calibre, no criteria exist for the a priori discrimination of such sources. In this paper a procedure for identifying significant lateral (tributary) sources, without the benefit of grain-size information, is outlined. A high-resolution characterisation of bed material texture along two Canadian gravel-bed rivers facilitated classification of all their perennial tributaries as either significant or insignificant. Three absolute tributary basin parameters and their relative counterparts, chosen to reflect the likely controls on tributary significance, are then used to develop a discriminant function which isolates a large proportion of significant tributaries while minimising incorrect classifications. Examination of consistently misclassified (anomalous) tributaries reveals the importance of lateral source spacing and of inconsistencies in the geomorphic history of the contributing basins. In turn, a general tributary categorisation procedure is suggested which includes a logistic regression model for attaching probability statements to individual classifications. The generality of the discriminant and logistic functions cannot be assessed because of the lack of other suitable data sets.

  13. Improved intake design for downstream migrating fish at hydropower plants

    International Nuclear Information System (INIS)

    Mih, W.C.

    1991-01-01

    This paper reports on hydroelectric power projects on the Columbia River which provided low-cost electricity to the Pacific Northwest. However, they are detrimental to anadromous fisheries resources. Anadromous fish are migratory. They begin their life in shallow mountain streams. After several months, they migrate to the ocean, where the fish grow to maturity before their return migration. Remarkably, most anadromous fish return to spawn in their natal streams. At dams, the upstream migration of grown salmon and steelhead is accomplished through fishways. The downstream migration of juveniles remains a serious problem. Juvenile fish follow the water flow during their sea-ward migration. When passing through a turbine, fish can be severely injured due to the sudden pressure drop, high velocity shear zones, and rotating turbine blades. Stunned fish that survive the gauntlet of the turbine are easy prey for sea gulls and squawfish in the tailrace of the powerhouse. Fish mortality per turbine passage is estimated at 15 percent. With nine hydropower projected on the main steam of the Columbia River, their combined mortality is very serious. The historical Columbia River anadromous run of about 12 million fish has declined to 2.5 million in recent years. Modern high-output hydraulic turbines are designed to be placed at a lower elevation to minimize cavitation damage to turbine blades. The modern design trend of deep intake submergence has caused parallel and unsteady vortex flow patterns in the forebay, resulting in a decrease in the guiding efficiency of the screens, such as at Bonneville Second Powerhouse and at Rocky Reach Project

  14. Low cost energy in Canada: The view from downstream

    International Nuclear Information System (INIS)

    Irving, K.

    1993-01-01

    The key cost determinants of energy in Canada are analyzed and recommendations are made to ensure the competitiveness of Canadian energy costs and energy-consuming industries in the North American and world markets. Oil supplies 45% of world energy and has a key role in determining prices of all other energy forms since it serves as an incremental source of energy: its consumption changes according to economic growth, changes in weather patterns, and other factors. North America currently accounts for about a third of world oil consumption. North American oil demand is expected to remain flat over the next few decades. As Canada only produces ca 3% of world oil supply, it cannot determine oil prices. However, with an efficient downstream industry, Canada can influence the end-user price of energy. The cost structure of refined products in Canada is analyzed. The cost of raw materials is the single biggest determinant of the final product cost, followed by taxes, operating costs, and profit margin. For gasoline in Ontario, taxes account for half the retail cost, crude oil prices ca 30%, and refining costs ca 4%. Refining costs comprise about two thirds labor costs and one third energy costs. Refiner margins have not exceeded 2 cents/l since 1981, creating reluctance to invest in the refining sector. By 1994, some 200,000 bbl/d of refining capacity is expected to be shut down in Canada. Compared to refineries in the USA, Canadian refineries are smaller and have a much lower capacity to upgrade residual fuel oil to light products. Future challenges to the industry include a projected need for $5 billion in investment, largely to fund new environmental initiatives. Such an investment cannot be met through current industry profits. 12 figs., 3 tabs

  15. Downstream processing and chromatography based analytical methods for production of vaccines, gene therapy vectors, and bacteriophages

    Science.gov (United States)

    Kramberger, Petra; Urbas, Lidija; Štrancar, Aleš

    2015-01-01

    Downstream processing of nanoplexes (viruses, virus-like particles, bacteriophages) is characterized by complexity of the starting material, number of purification methods to choose from, regulations that are setting the frame for the final product and analytical methods for upstream and downstream monitoring. This review gives an overview on the nanoplex downstream challenges and chromatography based analytical methods for efficient monitoring of the nanoplex production. PMID:25751122

  16. Aberrations and Emittance Growth in the DARHT 2nd Axis Downstream Transport

    Energy Technology Data Exchange (ETDEWEB)

    Schulze, Martin E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-10-24

    The emittance of the DARHT 2nd Axis has been inferred from solenoid scans performed in the downstream transport (DST) region using a short kicked pulse. The beam spot size is measured by viewing optical transition radiation (OTR) in the near field as a function of the field (current) of a solenoid magnet (S4). The imaging station containing the OTR target is located about 100 cm downstream of the solenoid magnet. The emittance is then inferred using a beam optics code such as LAMDA or XTR by fitting the data to initial conditions upstream of the S4 solenoid magnet. The initial conditions are the beam size, beam convergence and emittance. The beam energy and current are measured. In preparation for a solenoid scan, the magnets upstream of the solenoid are adjusted to produce a round beam with no beam losses due to scraping in the beam tube. This is different from the standard tune in which the beam tune is adjusted to suppress the effects of ions and rf in the septum dump. In this standard tune, approximately 10% of the beam is lost due to scraping as the beam enters the small 3.75” ID beam tube after the septum. The normalized emittance inferred from recent solenoid scans typically ranges from 600 to 800 π(mm-mrad). This larger beam size increases the sensitivity to any non-linear fields in the Collins quadrupoles that are mounted along the small diameter beam tube. The primary magnet used to adjust the beam size in this region is the S3 solenoid magnet. Measurements made of the beam shape as the beam size was decreased showed significant structure consistent with non-linear fields. Using the measured magnetic fields in the Collins quadrupoles including higher order multipoles, the beam transport through the Collins quadrupoles is simulated and compared to the observed OTR images. The simulations are performed using the beam optics codes TRANSPORT [1] and TURTLE [2]. Estimates of the emittance growth and beam losses are made as a function of the S3

  17. Enhancing an essential service

    International Nuclear Information System (INIS)

    Konow, H.

    2004-01-01

    An annual review of the activities and accomplishments of the Canadian electrical industry as a whole and those of the Association's member companies is provided. In addition to recording activities of the past year, there is also extended discussion of the strategic issues facing the industry, and the planned responses of the industry as a whole, as well as responses by individual member companies. With regard to a collective response, the Association expects significant advances in the industry's downstream business from automated distribution, which enables utilities to remotely monitor, coordinate and operate distribution components in real-time mode. Beyond that, CEA proposes to deal with the mounting pressures facing the electricity sector on the basis of a five point plan which comprises (1) establishment of an investment climate to ensure future electricity supply; (2) moving government and industry towards smart and effective regulation; (3) working to ensure a sustainable future for the next generation; (4) fostering innovation and accelerating skill development. and (5) building a strong Canadian electricity system while strengthening North American institutional arrangements. With recurring references to the blackout in August 2003, the five point plan stresses mandatory reliability standards as a means to strengthen the electricity grid in the context of North American institutional arrangements, of which the most significant example is CEA's active involvement in the North American Electric Reliability Council (NERC). The extensive discussion of the industry's collective responses to the challenges facing the industry is followed by one-page reviews of the plans and objectives of CEA's 26 member companies representing the industry from coast to coast

  18. Comparison of emerging contaminants in receiving waters downstream of a conventional wastewater treatment plant and a forest-water reuse system.

    Science.gov (United States)

    McEachran, Andrew D; Hedgespeth, Melanie L; Newton, Seth R; McMahen, Rebecca; Strynar, Mark; Shea, Damian; Nichols, Elizabeth Guthrie

    2018-02-19

    Forest-water reuse (FWR) systems treat municipal, industrial, and agricultural wastewaters via land application to forest soils. Previous studies have shown that both large-scale conventional wastewater treatment plants (WWTPs) and FWR systems do not completely remove many contaminants of emerging concern (CECs) before release of treated wastewater. To better characterize CECs and potential for increased implementation of FWR systems, FWR systems need to be directly compared to conventional WWTPs. In this study, both a quantitative, targeted analysis and a nontargeted analysis were utilized to better understand how CECs release to waterways from an FWR system compared to a conventional treatment system. Quantitatively, greater concentrations and total mass load of CECs was exhibited downstream of the conventional WWTP compared to the FWR. Average summed concentrations of 33 targeted CECs downstream of the conventional system were ~ 1000 ng/L and downstream of the FWR were ~ 30 ng/L. From a nontargeted chemical standpoint, more tentatively identified chemicals were present, and at a greater relative abundance, downstream of the conventional system as well. Frequently occurring contaminants included phthalates, pharmaceuticals, and industrial chemicals. These data indicate that FWR systems represent a sustainable wastewater treatment alternative and that emerging contaminant release to waterways was lower at a FWR system than a conventional WWTP.

  19. Play framework essentials

    CERN Document Server

    Richard-Foy, Julien

    2014-01-01

    This book targets Java and Scala developers who already have some experience in web development and who want to master Play framework quickly and efficiently. This book assumes you have a good level of knowledge and understanding of efficient Java and Scala code.

  20. Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells.

    Science.gov (United States)

    Ning, Li; Chen, Herbert; Kunnimalaiyaan, Muthusamy

    2010-05-01

    We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells. (c)2010 AACR.

  1. A Target Repurposing Approach Identifies N-myristoyltransferase as a New Candidate Drug Target in Filarial Nematodes

    Science.gov (United States)

    Villemaine, Estelle; Poole, Catherine B.; Chapman, Melissa S.; Pollastri, Michael P.; Wyatt, Paul G.; Carlow, Clotilde K. S.

    2014-01-01

    Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5–10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis. PMID:25188325

  2. Target Essentiality and Centrality Characterize Drug Side Effects

    OpenAIRE

    Wang, Xiujuan; Thijssen, Bram; Yu, Haiyuan

    2013-01-01

    Author Summary The ultimate goal of medical research is to develop effective treatments for disease with minimal side effects. Currently, about 20% of drug candidates failed at clinical trial phases II and III due to safety issues. Therefore, understanding the determining factors of drug side effects is of paramount importance to human health and the pharmaceutical industry. Here, we present the first systematic study to uncover key factors leading to drug side effects within the framework of...

  3. Essentials and Targets of Water Resources Management in Kenya

    International Nuclear Information System (INIS)

    Mutuku, J. Mutinga

    2006-01-01

    Fresh water comprises of 3% of the global waters and the rest is saline and not suitable for consumption without subjecting it to expensive treatment. Water is associated with development since civilization started in areas where water was easily accessible. However, much of the 3% is locked up in the ice caps. Water scarcity in any community is associated with abject poverty. The ecosystem functions of water and it's interactions with other environmental resources are least appreciated which has contributed to over exploitation, misuse, contamination, impairment and degradation of water bodies and their catchments. Over-exploitation of ground water in some coastal areas has in turn led to of seawater into freshwater aquifers and therefore making the water from aquifers unaccessible due to salinity

  4. [Resistance to target-based therapy and its circumvention].

    Science.gov (United States)

    Nishio, Kazuto

    2004-07-01

    Intrinsic and acquired resistance to molecular target therapy critically limits the outcome of cancer treatments. Target levels including quantitative and gene alteration should be determinants for the resistance. Downstream of the target molecules, drug metabolism, and drug transport influences the tumor sensitivity to molecular target therapy. The mechanisms of resistance to antibody therapy have not been fully clarified. Correlative clinical studies using these biomarkers of resistance are extremely important for circumvention of clinical resistance to target based therapy.

  5. Surface chemistry essentials

    CERN Document Server

    Birdi, K S

    2013-01-01

    Surface chemistry plays an important role in everyday life, as the basis for many phenomena as well as technological applications. Common examples range from soap bubbles, foam, and raindrops to cosmetics, paint, adhesives, and pharmaceuticals. Additional areas that rely on surface chemistry include modern nanotechnology, medical diagnostics, and drug delivery. There is extensive literature on this subject, but most chemistry books only devote one or two chapters to it. Surface Chemistry Essentials fills a need for a reference that brings together the fundamental aspects of surface chemistry w

  6. Geometry essentials for dummies

    CERN Document Server

    Ryan, Mark

    2011-01-01

    Just the critical concepts you need to score high in geometry This practical, friendly guide focuses on critical concepts taught in a typical geometry course, from the properties of triangles, parallelograms, circles, and cylinders, to the skills and strategies you need to write geometry proofs. Geometry Essentials For Dummies is perfect for cramming or doing homework, or as a reference for parents helping kids study for exams. Get down to the basics - get a handle on the basics of geometry, from lines, segments, and angles, to vertices, altitudes, and diagonals Conque

  7. The essential David Bohm

    CERN Document Server

    Nichol, Lee

    2002-01-01

    There are few scientists of the twentieth century whose life's work has created more excitement and controversy than that of physicist David Bohm (1917-1992). For the first time in a single volume, The Essential David Bohm offers a comprehensive overview of Bohm's original works from a non-technical perspective. Including three chapters of previously unpublished material, and a forward by the Dalai Lama, each reading has been selected to highlight some aspect of the implicate order process, and to provide an introduction to one of the most provocative thinkers of our time.

  8. Cisco networking essentials

    CERN Document Server

    McMillan, Troy

    2015-01-01

    Start a career in networking Cisco Networking Essentials, 2nd Edition provides the latest for those beginning a career in networking. This book provides the fundamentals of networking and leads you through the concepts, processes, and skills you need to master fundamental networking concepts. Thinking of taking the CCENT Cisco Certified Entry Networking Technician ICND1 Exam 100-101? This book has you covered! With coverage of important topics and objectives, each chapter outlines main points and provides clear, engaging discussion that will give you a sound understanding of core topics and c

  9. Microsoft Windows networking essentials

    CERN Document Server

    Gibson, Darril

    2011-01-01

    The core concepts and technologies of Windows networking Networking can be a complex topic, especially for those new to the field of IT. This focused, full-color book takes a unique approach to teaching Windows networking to beginners by stripping down a network to its bare basics, thereby making each topic clear and easy to understand. Focusing on the new Microsoft Technology Associate (MTA) program, this book pares down to just the essentials, showing beginners how to gain a solid foundation for understanding networking concepts upon which more advanced topics and technologies can be built.

  10. Autodesk Maya 2014 essentials

    CERN Document Server

    Naas, Paul

    2013-01-01

    The premiere book on getting started with Maya 2014 Whether you're just beginning, or migrating from another 3D application, this step-by-step guide is what you need to get a good working knowledge of Autodesk Maya 2014. Beautifully illustrated with full-color examples and screenshots, Autodesk Maya 2014 Essentials explains the basics of Maya as well as modeling, texturing, animating, setting a scene, and creating visual effects. You'll absorb important concepts and techniques, and learn how to confidently use Maya tools the way professionals do. Each chapter includes fun and cha

  11. RabbitMQ essentials

    CERN Document Server

    Dossot, David

    2014-01-01

    This book is a quick and concise introduction to RabbitMQ. Follow the unique case study of Clever Coney Media as they progressively discover how to fully utilize RabbitMQ, containing clever examples and detailed explanations.Whether you are someone who develops enterprise messaging products professionally or a hobbyist who is already familiar with open source Message Queuing software and you are looking for a new challenge, then this is the book for you. Although you should be familiar with Java, Ruby, and Python to get the most out of the examples, RabbitMQ Essentials will give you the push y

  12. Cisco Networking Essentials

    CERN Document Server

    McMillan, Troy

    2011-01-01

    An engaging approach for anyone beginning a career in networking As the world leader of networking products and services, Cisco products are constantly growing in demand. Yet, few books are aimed at those who are beginning a career in IT--until now. Cisco Networking Essentials provides a solid foundation on the Cisco networking products and services with thorough coverage of fundamental networking concepts. Author Troy McMillan applies his years of classroom instruction to effectively present high-level topics in easy-to-understand terms for beginners. With this indispensable full-color resour

  13. French essentials for dummies

    CERN Document Server

    Lawless, Laura K

    2011-01-01

    Just the core concepts you need to write and speak French correctly If you have some knowledge of French and want to polish your skills, French Essentials For Dummies focuses on just the core concepts you need to communicate effectively. From conjugating verbs to understanding tenses, this easy-to-follow guide lets you skip the suffering and score high at exam time. French 101 - get the lowdown on the basics, from expressing dates and times to identifying parts of speech Gender matters - see how a noun's gender determines the articles, adjectives, and pronouns y

  14. Samii's essentials in neurosurgery

    International Nuclear Information System (INIS)

    Ramina, Ricardo; Pontifical Catholic Univ. of Parana, Curitiba; Pires Aguiar, Paulo Henrique; Sao Paulo Univ.; Hospital Santa Paula, Sao Paulo; Tatagiba, Marcos

    2008-01-01

    'Samii's Essentials in Neurosurgery' contains selected papers written by internationally recognized contributors who were trained by Professor Madjid Samii in Hannover, Germany. The main topics deal with cutting-edge technology in neurosurgery, skull-base surgery, and specific peripheral nerve, spine, and vascular surgeries. The texts and a wealth of illustrations review and reinforce guidelines on the diagnosis and management of situations that readers are likely to encounter in everyday practice. This book will be of great interest to neurosurgeons, neurologists, ENT surgeons, neuroradiologists, and neurophysiotherapists. (orig.)

  15. MooTools essentials

    CERN Document Server

    Newton, Aaron

    2008-01-01

    Mootools is a light, modular JavaScript framework that makes adding Ajax, animations, and interactive elements to your site a breeze. But it's more than fancy effects and shortcuts; Mootools enhances the JavaScript language and makes writing clean, object oriented code almost pleasant. Unlocking the power of Mootools, and therefore JavaScript, isn't that hard, but knowing where to start can be. Mootools Essentials aims to help you accomplish that task with the following: * Illustrations of nearly every class and function in the library * Real world examples of how to use them * Written by Moot

  16. Twisted network programming essentials

    CERN Document Server

    Fettig, Abe

    2005-01-01

    Twisted Network Programming Essentials from O'Reilly is a task-oriented look at this new open source, Python-based technology. The book begins with recommendations for various plug-ins and add-ons to enhance the basic package as installed. It then details Twisted's collection simple network protocols, and helper utilities. The book also includes projects that let you try out the Twisted framework for yourself. For example, you'll find examples of using Twisted to build web services applications using the REST architecture, using XML-RPC, and using SOAP. Written for developers who want to s

  17. Essential dynamics and relativity

    CERN Document Server

    O'Donnell, Peter J

    2014-01-01

    Essential Dynamics & Relativity provides students with an introduction to the core aspects of dynamics and special relativity. The author reiterates important ideas and terms throughout and covers concepts that are often missing from other textbooks at this level. He also places each topic within the wider constructs of the theory, without jumping from topic to topic to illustrate a point.The first section of the book focuses on dynamics, discussing the basic aspects of single particle motion and analyzing the motion of multi-particle systems. The book also explains the dynamical behavior of b

  18. Microsoft Windows Security Essentials

    CERN Document Server

    Gibson, Darril

    2011-01-01

    Windows security concepts and technologies for IT beginners IT security can be a complex topic, especially for those new to the field of IT. This full-color book, with a focus on the Microsoft Technology Associate (MTA) program, offers a clear and easy-to-understand approach to Windows security risks and attacks for newcomers to the world of IT. By paring down to just the essentials, beginners gain a solid foundation of security concepts upon which more advanced topics and technologies can be built. This straightforward guide begins each chapter by laying out a list of topics to be discussed,

  19. 3D Animation Essentials

    CERN Document Server

    Beane, Andy

    2012-01-01

    The essential fundamentals of 3D animation for aspiring 3D artists 3D is everywhere--video games, movie and television special effects, mobile devices, etc. Many aspiring artists and animators have grown up with 3D and computers, and naturally gravitate to this field as their area of interest. Bringing a blend of studio and classroom experience to offer you thorough coverage of the 3D animation industry, this must-have book shows you what it takes to create compelling and realistic 3D imagery. Serves as the first step to understanding the language of 3D and computer graphics (CG)Covers 3D anim

  20. Calcium, essential for health

    Science.gov (United States)

    Martínez de Victoria, Emilio

    2016-07-12

    Calcium (Ca) is the most abundant mineral element in our body. It accounts for about 2% of body weight. The functions of calcium are: a) functions skeletal and b) regulatory functions. Bone consists of a protein matrix that mineralizes mainly with calcium (the most abundant), phosphate and magnesium, for it is essential an adequate dietary intake of Ca, phosphorus and vitamin D. The ionic Ca (Ca2+) is essential to maintain and / or perform different specialized functions of, virtually, all body cells cellular. Because of its important functions Ca2+ must be closely regulated, keeping plasma concentrations within narrow ranges. For this reason there is an accurate response against hypocalcemia or hypercalcemia in which the parathormone, calcitriol, calcitonin and vitamin K are involved. Ca intakes in the Spanish population are low in a significant percentage of the older adult’s population, especially in women. The main source of Ca in the diet is milk and milk derivatives. Green leafy vegetables, fruits and legumes can be important sources of Ca in a Mediterranean dietary pattern. The bioavailability of dietary Ca depends on physiological and dietary factors. Physiological include age, physiological status (gestation and lactation) Ca and vitamin D status and disease. Several studies relate Ca intake in the diet and various diseases, such as osteoporosis, cancer, cardiovascular disease and obesity.

  1. The Botrytis cinerea PAK kinase BcCla4 mediates morphogenesis, growth and cell cycle regulating processes downstream of BcRac.

    Science.gov (United States)

    Minz-Dub, Anna; Sharon, Amir

    2017-05-01

    Rac proteins are involved in a variety of cellular processes. Effector proteins that interact with active Rac convey the GTPase-generated signal to downstream developmental cascades and processes. Here we report on the analysis of the main effector and signal cascade downstream of BcRac, the Rac homolog of the grey mold fungus Botrytis cinerea. Several lines of evidence highlighted the p21-activated kinase Cla4 as an important effector of Rac in fungi. Analysis of Δbccla4 strains revealed that the BcCla4 protein was sufficient to mediate all of the examined BcRac-driven processes, including hyphal growth and morphogenesis, conidia production and pathogenicity. In addition, the Δbccla4 strains had altered nuclei content, a phenomenon that was previously observed in Δbcrac isolates, thus connecting the BcRac/BcCla4 module with cell cycle control. Further analyses revealed that BcRac/BcCla4 control mitotic entry through changes in phosphorylation status of the cyclin dependent kinase BcCdk1. The complete cascade includes the kinase BcWee1, which is downstream of BcCla4 and upstream of BcCdk1. These results provide a mechanistic insight on the connection of cell cycle, morphogenesis and pathogenicity in fungi, and position BcCla4 as the most essential effector and central regulator of all of these processes downstream of BcRac. © 2017 John Wiley & Sons Ltd.

  2. Upstream and downstream relationship in an increasingly competitive environment

    International Nuclear Information System (INIS)

    Bergmann, Burckhard

    1999-01-01

    The electricity industry in some countries in Western Europe is changing faster and more extensively than expected. The same has not been true of multi-energy sales and multi-energy mergers and the question is: Will the gas industry evolve in a similar way? A development for gas similar to that for electricity is not observed, and the author illustrates the differences. There are many uncertainties. A very important factor for developments in Western Europe will be how the major producers, Russia, Norway and the Netherlands, position themselves. But there are also unchanging actions and modes of behaviour which are justified in different market scenarios, and they are discussed. It is concluded that it is essential to ensure that policy-makers allow sufficient latitude for market forces and leave the final decision to the consumer

  3. Target Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — [Part of the ATLAS user facility.] The Physics Division operates a target development laboratory that produces targets and foils of various thickness and substrates,...

  4. Unravelling pathways downstream Sox6 induction in K562 erythroid cells by proteomic analysis

    KAUST Repository

    Barbarani, Gloria

    2017-10-20

    The Sox6 transcription factor is crucial for terminal maturation of definitive red blood cells. Sox6-null mouse fetuses present misshapen and nucleated erythrocytes, due to impaired actin assembly and cytoskeleton stability. These defects are accompanied with a reduced survival of Sox6-/- red blood cells, resulting in a compensated anemia. Sox6-overexpression in K562 cells and in human primary ex vivo erythroid cultures enhances erythroid differentiation and leads to hemoglobinization, the hallmark of erythroid maturation. To obtain an overview on processes downstream to Sox6 expression, we performed a differential proteomic analysis on human erythroid K562 cells overexpressing Sox6. Sox6-overexpression induces dysregulation of 64 proteins, involved in cytoskeleton remodeling and in protein synthesis, folding and trafficking, key processes for erythroid maturation. Moreover, 43 out of 64 genes encoding for differentially expressed proteins contain within their proximal regulatory regions sites that are bound by SOX6 according to ENCODE ChIP-seq datasets and are possible direct SOX6 targets. SAR1B, one of the most induced proteins upon Sox6 overexpression, shares a conserved regulatory module, composed by a double SOX6 binding site and a GATA1 consensus, with the adjacent SEC24 A gene. Since both genes encode for COPII components, this element could concur to the coordinated expression of these proteins during erythropoiesis.

  5. Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma.

    Science.gov (United States)

    de Cristofaro, Tiziana; Di Palma, Tina; Soriano, Amata Amy; Monticelli, Antonella; Affinito, Ornella; Cocozza, Sergio; Zannini, Mariastella

    2016-07-05

    Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma.

  6. CypA, a gene downstream of HIF-1α, promotes the development of PDAC.

    Directory of Open Access Journals (Sweden)

    Huan Zhang

    Full Text Available Hypoxia-inducible factor-1α (HIF-1α is a highly important transcription factor involved in cell metabolism. HIF-1α promotes glycolysis and inhibits of mitochondrial respiration in pancreatic ductal adenocarcinoma (PDAC. In response to tumor hypoxia, cyclophilin A (CypA is over-expressed in various cancer types, and is associated with cell apoptosis, tumor invasion, metastasis, and chemoresistance in PDAC. In this study, we showed that both HIF-1α and CypA expression were significantly associated with lymph node metastasis and tumor stage. The expression of CypA was correlated with HIF-1α. Moreover, the mRNA and protein expression of CypA markedly decreased or increased following the suppression or over-expression of HIF-1α in vitro. Chromatin immunoprecipitation analysis showed that HIF-1α could directly bind to the hypoxia response element (HRE in the CypA promoter regions and regulated CypA expression. Consistent with other studies, HIF-1α and CypA promoted PDAC cell proliferation and invasion, and suppressed apoptosis in vitro. Furthermore, we proved the combination effect of 2-methoxyestradiol and cyclosporin A both in vitro and in vivo. These results suggested that,CypA, a gene downstream of HIF-1α, could promote the development of PDAC. Thus, CypA might serve as a potential therapeutic target for PDAC.

  7. 40 CFR 80.210 - What sulfur standards apply to gasoline downstream from refineries and importers?

    Science.gov (United States)

    2010-07-01

    ... combined with non-S-RGAS for the sole purpose of producing midgrade gasoline. (6) Where S-RGAS is being... of the gasoline. (f) Downstream standards applicable to S-RGAS when produced or imported. (1) The downstream standard applicable to any gasoline classified as S-RGAS when produced or imported shall be...

  8. Hydrodynamic properties and distribution of bait downstream of a zooplankton trap

    DEFF Research Database (Denmark)

    Selander, Erik; Heuschele, Jan; Larsson, Ann I.

    2017-01-01

    The flow regime around a chemically baited trap is crucial for the trapping process and distribution of bait downstream of traps. We measured the flow field downstream of a trap prototype in flume experiments and mapped the distribution of bait using laser induced fluorescence. The trap produced ...

  9. Advanced Targeted Nanomedicine

    Science.gov (United States)

    Arachchige, Mohan C M; Reshetnyak, Yana K.; Andreev, Oleg A.

    2015-01-01

    Targeted drug delivery has been the major topic in drug formulation and delivery. As nanomedicine emerges to create nano scale therapeutics and diagnostics, it is still essential to embed targeting capability to these novel systems to make them useful. Here we discuss various targeting approaches for delivery of therapeutic and diagnostic nano materials in view of search for more universal methods to target diseased tissues. Many diseases are accompanied with hypoxia and acidosis. Coating nanoparticles with pH Low Insertion Peptides (pHLIPs) increases efficiency of targeting acidic diseased tissues. It has been showing promising results to create future nanotheranostics for cancer and other diseases which are dominating in the present world. PMID:25615945

  10. A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Konstantinos Tzelepis

    2016-10-01

    Full Text Available Acute myeloid leukemia (AML is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

  11. The brassinosteroid receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling

    KAUST Repository

    Wheeler, Janet I.

    2017-05-08

    The brassinosteroid receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) is a member of the leucine rich repeat receptor like kinase family. The intracellular kinase domain of BRI1 is an active kinase and also encapsulates a guanylate cyclase catalytic centre. Using liquid chromatography tandem mass spectrometry, we confirmed that the recombinant cytoplasmic domain of BRI1 generates pmol amounts of cGMP per μg protein with a preference for magnesium over manganese as a co-factor. Importantly, a functional BRI1 kinase is essential for optimal cGMP generation. Therefore, the guanylate cyclase activity of BRI1 is modulated by the kinase while cGMP, the product of the guanylate cyclase, in turn inhibits BRI1 kinase activity. Furthermore, we show using Arabidopsis root cell cultures that cGMP rapidly potentiates phosphorylation of the downstream substrate BRASSINOSTEROID SIGNALING KINASE 1 (BSK1). Taken together, our results suggest that cGMP acts as a modulator that enhances downstream signaling while dampening signal generation from the receptor. This article is protected by copyright. All rights reserved.

  12. Target RNA capture and cleavage by the Cmr type III-B CRISPR–Cas effector complex

    Science.gov (United States)

    Hale, Caryn R.; Cocozaki, Alexis; Li, Hong

    2014-01-01

    The effector complex of the Cmr/type III-B CRISPR (clustered regularly interspaced short palindromic repeat)–Cas (CRISPR-associated) system cleaves RNAs recognized by the CRISPR RNA (crRNA) of the complex and includes six protein subunits of unknown functions. Using reconstituted Pyrococcus furiosus Cmr complexes, we found that each of the six Cmr proteins plays a critical role in either crRNA interaction or target RNA capture. Cmr2, Cmr3, Cmr4, and Cmr5 are all required for formation of a crRNA-containing complex detected by native gel electrophoresis, and the conserved 5′ repeat sequence tag and 5′-OH group of the crRNA are essential for the interaction. Interestingly, capture of the complementary target RNA additionally requires both Cmr1 and Cmr6. In detailed functional studies, we determined that P. furiosus Cmr complexes cleave target RNAs at 6-nucleotide (nt) intervals in the region of complementarity, beginning 5 nt downstream from the crRNA tag and continuing to within ∼14 nt of the 3′ end of the crRNA. Our findings indicate that Cmr3 recognizes the signature crRNA tag sequence (and depends on protein–protein interactions with Cmr2, Cmr4, and Cmr5), each Cmr4 subunit mediates a target RNA cleavage, and Cmr1 and Cmr6 mediate an essential interaction between the 3′ region of the crRNA and the target RNA. PMID:25367038

  13. Essential real analysis

    CERN Document Server

    Field, Michael

    2017-01-01

    This book provides a rigorous introduction to the techniques and results of real analysis, metric spaces and multivariate differentiation, suitable for undergraduate courses. Starting from the very foundations of analysis, it offers a complete first course in real analysis, including topics rarely found in such detail in an undergraduate textbook such as the construction of non-analytic smooth functions, applications of the Euler-Maclaurin formula to estimates, and fractal geometry.  Drawing on the author’s extensive teaching and research experience, the exposition is guided by carefully chosen examples and counter-examples, with the emphasis placed on the key ideas underlying the theory. Much of the content is informed by its applicability: Fourier analysis is developed to the point where it can be rigorously applied to partial differential equations or computation, and the theory of metric spaces includes applications to ordinary differential equations and fractals. Essential Real Analysis will appeal t...

  14. Essentials of nonlinear optics

    CERN Document Server

    Murti, Y V G S

    2014-01-01

    Current literature on Nonlinear Optics varies widely in terms of content, style, and coverage of specific topics, relative emphasis of areas and the depth of treatment. While most of these books are excellent resources for the researchers, there is a strong need for books appropriate for presenting the subject at the undergraduate or postgraduate levels in Universities. The need for such a book to serve as a textbook at the level of the bachelors and masters courses was felt by the authors while teaching courses on nonlinear optics to students of both science and engineering during the past two decades. This book has emerged from an attempt to address the requirement of presenting the subject at college level. A one-semester course covering the essentials can effectively be designed based on this.

  15. DSP Architecture Design Essentials

    CERN Document Server

    Marković, Dejan

    2012-01-01

    In DSP Architecture Design Essentials, authors Dejan Marković and Robert W. Brodersen cover a key subject for the successful realization of DSP algorithms for communications, multimedia, and healthcare applications. The book addresses the need for DSP architecture design that maps advanced DSP algorithms to hardware in the most power- and area-efficient way. The key feature of this text is a design methodology based on a high-level design model that leads to hardware implementation with minimum power and area. The methodology includes algorithm-level considerations such as automated word-length reduction and intrinsic data properties that can be leveraged to reduce hardware complexity. From a high-level data-flow graph model, an architecture exploration methodology based on linear programming is used to create an array of architectural solutions tailored to the underlying hardware technology. The book is supplemented with online material: bibliography, design examples, CAD tutorials and custom software.

  16. TQM: the essential concepts.

    Science.gov (United States)

    Chambers, D W

    1998-01-01

    This is an introduction to the major concepts in total quality management, a loose collection of management approaches that focus on continuous improvement of processes, guided by routine data collection and adjustment of the processes. Customer focus and involvement of all members of an organization are also characteristics commonly found in TQM. The seventy-five-year history of the movement is sketched from its beginning in statistical work on quality assurance through the many improvements and redefinitions added by American and Japanese thinkers. Essential concepts covered include: control cycles, focus on the process rather than the defects, the GEAR model, importance of the customer, upstream quality, just-in-time, kaizen, and service quality.

  17. Genetics of essential hypertension.

    Science.gov (United States)

    Mein, Charles A; Caulfield, Mark J; Dobson, Richard J; Munroe, Patricia B

    2004-04-01

    Essential hypertension affects 1 billion people worldwide and its genetic basis is well established. For this review we surveyed the literature on the genetics of hypertension during the past 18 months and we now report the highlights. There has been publication of the two largest genome scans for blood pressure and new loci including significant linkage to chromosome 6q have been reported. The molecular basis of Gordon's syndrome has been partially unravelled with a dual function for WNK4 in ion transport regulation being discovered. There has also been progress in narrowing rodent quantitative trait loci using congenic approaches and several linkage peaks have now been demonstrated to have more than one loci. We also report some of the initial findings from pharmacogenetic studies.

  18. PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease

    Directory of Open Access Journals (Sweden)

    Haghikia Aiden

    2011-05-01

    Full Text Available Abstract Background Huntington disease (HD is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD gene. The primary genetic determinant of the age at onset (AO is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO. Results In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively. Conclusions These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

  19. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

    Science.gov (United States)

    Frost, Julianty; Galdeano, Carles; Soares, Pedro; Gadd, Morgan S.; Grzes, Katarzyna M.; Ellis, Lucy; Epemolu, Ola; Shimamura, Satoko; Bantscheff, Marcus; Grandi, Paola; Read, Kevin D.; Cantrell, Doreen A.; Rocha, Sonia; Ciulli, Alessio

    2016-11-01

    Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

  20. Downstream boundary effects on the frequency of self-excited oscillations in transonic diffuser flows

    Science.gov (United States)

    Hsieh, T.; Coakley, T. J.

    1987-01-01

    An investigation of downstream boundary effects on the frequency of self-excited oscillations in two-dimensional, separated transonic diffuser flows has been conducted numerically by solving the compressible, Reynolds-averaged, thin-layer Navier-Stokes equation with a two-equation turbulence model. It was found that the unsteady diffuser flowfields are very sensitive to the location of the downstream boundary. Extension of the diffuser downstream boundary significantly reduces the frequency and amplitude of oscillations for pressure, velocity and shock. Computational results suggest that the mechanism causing the self-excited oscillation changes from viscous convective wave dominated oscillations to inviscid acoustic wave dominated oscillations when the location of downstream boundary varies from 8.66 to 134.7 throat height. The existence of a suction slot in the experimental setup obscures the physical downstream boundary and, therefore, presents a difficulty for quantitative comparisons between computation and experiment.

  1. Exploring the Optimal Strategy to Predict Essential Genes in Microbes

    Directory of Open Access Journals (Sweden)

    Yao Lu

    2011-12-01

    Full Text Available Accurately predicting essential genes is important in many aspects of biology, medicine and bioengineering. In previous research, we have developed a machine learning based integrative algorithm to predict essential genes in bacterial species. This algorithm lends itself to two approaches for predicting essential genes: learning the traits from known essential genes in the target organism, or transferring essential gene annotations from a closely related model organism. However, for an understudied microbe, each approach has its potential limitations. The first is constricted by the often small number of known essential genes. The second is limited by the availability of model organisms and by evolutionary distance. In this study, we aim to determine the optimal strategy for predicting essential genes by examining four microbes with well-characterized essential genes. Our results suggest that, unless the known essential genes are few, learning from the known essential genes in the target organism usually outperforms transferring essential gene annotations from a related model organism. In fact, the required number of known essential genes is surprisingly small to make accurate predictions. In prokaryotes, when the number of known essential genes is greater than 2% of total genes, this approach already comes close to its optimal performance. In eukaryotes, achieving the same best performance requires over 4% of total genes, reflecting the increased complexity of eukaryotic organisms. Combining the two approaches resulted in an increased performance when the known essential genes are few. Our investigation thus provides key information on accurately predicting essential genes and will greatly facilitate annotations of microbial genomes.

  2. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification

    DEFF Research Database (Denmark)

    Harboe, Morten; Garred, Peter; Karlstrøm, Ellen

    2009-01-01

    was not observed even at high mannan concentrations since addition of the inhibiting anti-MBL mAb 3F8 completely abolished generation of the terminal C5b-9 complex (TCC). However, selective blockade of AP by anti-factor D inhibited more than 80% of TCC release into the fluid phase after LP activation showing...... that AP amplification is quantitatively responsible for the final effect of initial specific LP activation. TCC generation on the solid phase was distinctly but less inhibited by anti-fD. C2 bypass of the LP pathway could be demonstrated, and AP amplification was also essential during C2 bypass in LP...... as shown by complete inhibition of TCC generation in C2-deficient serum by anti-fD and anti-properdin antibodies. In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway....

  3. Development of a new approach for targeted gene editing in primordial germ cells using TALENs in Xenopus

    Directory of Open Access Journals (Sweden)

    Keisuke Nakajima

    2015-02-01

    Full Text Available A gene of interest can be efficiently modified using transcription activator-like effector nucleases (TALENs (Christian et al., 2010;Li et al., 2011. However, if a target gene is essential for development, growth and fertility, use of TALENs with high mutagenic activity in F0 frogs could result in developmental disorders or sterility, which would reduce the number of F1 progeny and make F1 phenotypical analysis difficult. We used the 3′ untranslated region of DEADSouth gene (DS-3′ of Xenopus tropicalis to solve this problem, because the addition of the DS-3′ to mRNA is known to induce primordial germ cell (PGC-specific expression and reduce the stability in somatic cells of mRNA in Xenopus laevis. At first, we inserted the X. tropicalis DS-3′ downstream of the EGFP termination codon and confirmed that the EGFP expression was specifically detected in PGCs for three weeks. Therefore, we inserted the DS-3′ downstream of the termination codon of the TALEN coding sequence. The tyrosinase gene was selected as the target gene for TALEN because the bi-allelic mutation of this gene is easily discernible by the albino phenotype. When fertilized eggs were microinjected with TALEN mRNAs fused to the DS-3′, their sperm and oocytes had a high rate (84–100% of target-gene modification in contrast to the lower rate (0–45% of nucleotide alteration observed in somatic cells.

  4. Fluvial wood function downstream of beaver versus man-made dams in headwater streams in Massachusetts, USA

    Science.gov (United States)

    David, G. C.; DeVito, L. F.; Munz, K. T.; Lisius, G.

    2014-12-01

    Fluvial wood is an essential component of stream ecosystems by providing habitat, increasing accumulation of organic matter, and increasing the processing of nutrients and other materials. However, years of channel alterations in Massachusetts have resulted in low wood loads despite the afforestation that has occurred since the early 1900s. Streams have also been impacted by a large density of dams, built during industrialization, and reduction of the beaver population. Beavers were reintroduced to Massachusetts in the 1940s and they have since migrated throughout the state. Beaver dams impound water, which traps sediment and results in the development of complex channel patterns and more ecologically productive and diverse habitats than those found adjacent to man-made dams. To develop better management practices for dam removal it is essential that we understand the geomorphic and ecologic function of wood in these channels and the interconnections with floodplain dynamics and stream water chemistry. We investigate the connections among fluvial wood, channel morphology, floodplain soil moisture dynamics, and stream water chemistry in six watersheds in Massachusetts that have been impacted by either beaver or man-made dams. We hypothesize that wood load will be significantly higher below beaver dams, subsequently altering channel morphology, water chemistry, and floodplain soil moisture. Reaches are surveyed up- and downstream of each type of dam to better understand the impact dams have on the fluvial system. Surveys include a longitudinal profile, paired with dissolved oxygen and ammonium measurements, cross-section and fluvial wood surveys, hydraulic measurements, and floodplain soil moisture mapping. We found that dissolved oxygen mirrored the channel morphology, but did not vary significantly between reaches. Wood loads were significantly larger downstream of beaver dams, which resulted in significant changes to the ammonium levels. Floodplain soil moisture

  5. Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes.

    Science.gov (United States)

    Taylor, Douglas D; Shah, Sahil

    2015-10-01

    Viable tumor cells actively release vesicles into the peripheral circulation and other biologic fluids, which exhibit proteins and RNAs characteristic of that cell. Our group demonstrated the presence of these extracellular vesicles of tumor origin within the peripheral circulation of cancer patients and proposed their utility for diagnosing the presence of tumors and monitoring their response to therapy in the 1970s. However, it has only been in the past 10 years that these vesicles have garnered interest based on the recognition that they serve as essential vehicles for intercellular communication, are key determinants of the immunosuppressive microenvironment observed in cancer and provide stability to tumor-derived components that can serve as diagnostic biomarkers. To date, the clinical utility of extracellular vesicles has been hampered by issues with nomenclature and methods of isolation. The term "exosomes" was introduced in 1981 to denote any nanometer-sized vesicles released outside the cell and to differentiate them from intracellular vesicles. Based on this original definition, we use "exosomes" as synonymous with "extracellular vesicles." While our original studies used ultracentrifugation to isolate these vesicles, we immediately became aware of the significant impact of the isolation method on the number, type, content and integrity of the vesicles isolated. In this review, we discuss and compare the most commonly utilized methods for purifying exosomes for post-isolation analyses. The exosomes derived from these approaches have been assessed for quantity and quality of specific RNA populations and specific marker proteins. These results suggest that, while each method purifies exosomal material, there are pros and cons of each and there are critical issues linked with centrifugation-based methods, including co-isolation of non-exosomal materials, damage to the vesicle's membrane structure and non-standardized parameters leading to qualitative and

  6. Interplays between Sumoylation, SUMO-Targeted Ubiquitin Ligases, and the Ubiquitin-Adaptor Protein Ufd1 in Fission Yeast

    DEFF Research Database (Denmark)

    Køhler, Julie Bonne

    their conformation or interactions with other macromolecules. Though, whereas the downstream consequence of ubiquitin conjugation is often protein degradation, the functional outcomes of sumoylation are less unifiable. A class of ubiquitin E3 ligases able to target sumoylated proteins for degradation by the 26S...... proteasome mediates direct cross-talk between the two modification systems. By contributing to the dynamic turnover of SUMO conjugated species these SUMO-targeted ubiquitin ligases (STUbLs) fulfills essential roles in both yeast and man. However, the specific sumoylated proteins affected by STUbL activity...... and the specific molecular interactions and sequence of events linking sumoylation, ubiquitylation and substrate degradation, has been largely uncovered. Using the fission yeast model organism I here present evidence for a role of the Ufd1 (ubiquitinfusion degradation 1) protein, and by extension of the Cdc48-Ufd1...

  7. Genetics Home Reference: essential tremor

    Science.gov (United States)

    ... may be aggravated by emotional stress, anxiety, fatigue, hunger, caffeine, cigarette smoking, or temperature extremes. Essential tremor ... 6. Review. Citation on PubMed Testa CM. Key issues in essential tremor genetics research: Where are we ...

  8. Changes in the Mountain Cryosphere and Potential Risks to Downstream Communities: Insights from the Indian Himalayan Region

    Science.gov (United States)

    Allen, Simon; Ballesteros, Juan Antonio; Huggel, Christian; Linsbauer, Andreas; Mal, Suraj; Singh Rana, Ranbir; Singh Randhawa, Surjeet; Ruiz-Villanueva, Virginia; Salzmann, Nadine; Singh Samant, Sher; Stoffel, Markus

    2017-04-01

    Mountain environments around the world are often considered to be amongst the most sensitive to the impacts of climate change. For people living in mountain communities, there are clear challenges to be faced as their livelihoods and subsistence are directly dependent on their surrounding natural environment. But what of the wider implications for societies and large urban settlements living downstream - why should they care about the climate-driven changes occurring potentially hundreds of kilometers away in the snow and ice capped mountains? In this contribution we address this question, drawing on studies and experiences gained within joint Indo-Swiss research collaborations focused on the Indian Himalayan states of Himachal Pradesh and Uttarakhand. With the Intergovernmental Panel on Climate Change currently embarking on the scoping of their 6th Assessment Cycle, which includes a planned Special Report on Oceans and the Cryosphere, this contribution provides a timely reminder of the importance of mountain regions, and potential far-reaching consequences of changes in the mountain cryosphere. Our studies highlight several key themes which link the mountain environment to the lowland populated areas, including the role of the mountain cryosphere as a water source, far-reaching hazards and disasters that can originate from mountain regions, the role of mountains in providing essential ecosystem services, the economic importance of tourism in mountain regions, and the importance of transportation routes which pass through mountain environments. These themes are intricately linked, as for example demonstrated during the 2013 Uttarakhand flood disaster where many of the approximately 6000 fatalities were tourists visiting high mountain pilgrimage sites. As a consequence of the disaster, tourists stayed away during subsequent seasons with significant economic impacts felt across the State. In Himachal Pradesh, a key national transportation corridor is the Rohtang pass

  9. Mercury exposure in terrestrial birds far downstream of an historical point source

    International Nuclear Information System (INIS)

    Jackson, Allyson K.; Evers, David C.; Folsom, Sarah B.; Condon, Anne M.; Diener, John; Goodrick, Lizzie F.; McGann, Andrew J.; Schmerfeld, John; Cristol, Daniel A.

    2011-01-01

    Mercury (Hg) is a persistent environmental contaminant found in many freshwater and marine ecosystems. Historical Hg contamination in rivers can impact the surrounding terrestrial ecosystem, but there is little known about how far downstream this contamination persists. In 2009, we sampled terrestrial forest songbirds at five floodplain sites up to 137 km downstream of an historical source of Hg along the South and South Fork Shenandoah Rivers (Virginia, USA). We found that blood total Hg concentrations remained elevated over the entire sampling area and there was little evidence of decline with distance. While it is well known that Hg is a pervasive and long-lasting aquatic contaminant, it has only been recently recognized that it also biomagnifies effectively in floodplain forest food webs. This study extends the area of concern for terrestrial habitats near contaminated rivers for more than 100 km downstream from a waterborne Hg point source. - Highlights: → We report blood mercury levels for terrestrial songbirds downstream of contamination. → Blood mercury levels remain elevated above reference for at least 137 km downstream. → Trends vary based on foraging guild and migration strategy. → Mercury affects terrestrial biota farther downstream than previously documented. - Blood mercury levels of forest songbirds remain elevated above reference levels for at least 137 km downstream of historical point source.

  10. Downstream fish passage guide walls: A hydraulic scale model analysis

    Science.gov (United States)

    Mulligan, Kevin; Towler, Brett; Haro, Alexander J.; Ahlfeld, David P.

    2018-01-01

    Partial-depth guide walls are used to improve passage efficiency and reduce the delay of out-migrating anadromous fish species by guiding fish to a bypass route (i.e. weir, pipe, sluice gate) that circumvents the turbine intakes, where survival is usually lower. Evaluation and monitoring studies, however, indicate a high propensity for some fish to pass underneath, rather than along, the guide walls, compromising their effectiveness. In the present study we evaluated a range of guide wall structures to identify where/if the flow field shifts from sweeping (i.e. flow direction primarily along the wall and towards the bypass) to downward-dominant. Many migratory fish species, particularly juveniles, are known to drift with the flow and/or exhibit rheotactic behaviour during their migration. When these behaviours are present, fish follow the path of the flow field. Hence, maintaining a strong sweeping velocity in relation to the downward velocity along a guide wall is essential to successful fish guidance. Nine experiments were conducted to measure the three-dimensional velocity components upstream of a scale model guide wall set at a wide range of depths and angles to flow. Results demonstrated how each guide wall configuration affected the three-dimensional velocity components, and hence the downward and sweeping velocity, along the full length of the guide wall. In general, the velocities produced in the scale model were sweeping dominant near the water surface and either downward dominant or close to the transitional depth near the bottom of the guide wall. The primary exception to this shift from sweeping do downward flow was for the minimum guide wall angle tested in this study (15°). At 15° the flow pattern was fully sweeping dominant for every cross-section, indicating that a guide wall with a relatively small angle may be more likely to produce conditions favorable to efficient guidance. A critical next step is to evaluate the behaviour of migratory fish as

  11. FLOW AND HEAT TRANSFER CHARACTERISTICS DOWNSTREAM OF A POROUS SUDDEN EXPANSION: A NUMERICAL STUDY

    Directory of Open Access Journals (Sweden)

    Khalid N Alammar

    2011-01-01

    Full Text Available Incompressible, axisymmetric laminar flow downstream of a porous expansion is simulated. Effect of the Darcy number and inertia coefficient on flow and heat transfer characteristics downstream of the expansion is investigated. The simulation revealed circulation downstream of the expansion. Decreasing the Darcy number is shown to decrease the circulation region. The Nusselt number, friction coefficient, and pressure drop are shown to increase, while reattachment and location of maximum heat transfer move upstream with decreasing Darcy number. Similar effects are observed with increasing inertia coefficient.

  12. Measurement of velocity deficit at the downstream of a 1:10 axial hydrokinetic turbine model

    Energy Technology Data Exchange (ETDEWEB)

    Gunawan, Budi [ORNL; Neary, Vincent S [ORNL; Hill, Craig [St. Anthony Falls Laboratory, 2 Third Avenue SE, Minneapolis, MN 55414; Chamorro, Leonardo [St. Anthony Falls Laboratory, 2 Third Avenue SE, Minneapolis, MN 55414

    2012-01-01

    Wake recovery constrains the downstream spacing and density of turbines that can be deployed in turbine farms and limits the amount of energy that can be produced at a hydrokinetic energy site. This study investigates the wake recovery at the downstream of a 1:10 axial flow turbine model using a pulse-to-pulse coherent Acoustic Doppler Profiler (ADP). In addition, turbine inflow and outflow velocities were measured for calculating the thrust on the turbine. The result shows that the depth-averaged longitudinal velocity recovers to 97% of the inflow velocity at 35 turbine diameter (D) downstream of the turbine.

  13. Ebf1 and c-Myb repress rag transcription downstream of Stat5 during early B cell development.

    Science.gov (United States)

    Timblin, Greg A; Schlissel, Mark S

    2013-11-01

    The temporal control of RAG (Rag) expression in developing lymphocytes prevents DNA breaks during periods of proliferation that could threaten genomic integrity. In developing B cells, the IL-7R and precursor B cell Ag receptor (pre-BCR) synergize to induce proliferation and the repression of Rag at the protein and mRNA levels for a brief period following successful Ig H chain gene rearrangement. Whereas the mechanism of RAG2 protein downregulation is well defined, little is known about the pathways and transcription factors that mediate transcriptional repression of Rag. Using Abelson murine leukemia virus-transformed B cells to model this stage of development, we identified early B cell factor 1 (Ebf1) as a strong repressor of Rag transcription. Short hairpin RNA-mediated knockdown of either Ebf1 or its downstream target c-Myb was sufficient to induce Rag transcription in these highly proliferative cells. Ebf1 and c-Myb antagonize Rag transcription by negatively regulating the binding of Foxo1 to the Rag locus. Ebf1 accomplishes this through both direct negative regulation of Foxo1 expression and direct positive regulation of Gfi1b expression. Ebf1 expression is driven by the IL-7R downstream effector Stat5, providing a link between the negative regulation of Rag transcription by IL-7 and a novel repressive pathway involving Ebf1 and c-Myb.

  14. Knowledge about Essential Tremor: A Study of Essential Tremor Families.

    Science.gov (United States)

    Cristal, Ashley D; Chen, Karen P; Hernandez, Nora Cristina; Factor-Litvak, Pam; Clark, Lorraine N; Ottman, Ruth; Louis, Elan D

    2018-01-01

    Essential tremor (ET) is among the most common neurological diseases and it often runs in families. How knowledgeable ET patients and their families are about their disease has been the subject of surprisingly little scholarship. To fill this gap in knowledge, we administered a comprehensive 32-item survey (i.e., questions about etiology, pathophysiology, symptoms and signs, natural history, and treatments) to 427 participants, including 76 ET probands, 74 affected relatives (AFRs), 238 unaffected relatives, and 39 spouses of unaffected relatives, all of whom were participating in two ET family studies. We hypothesized that there would be gaps in knowledge about ET and furthermore, that probands and AFRs would be the most knowledgeable, followed by unaffected relatives and then spouses of unaffected relatives, who would be the least knowledgeable. Overall, ET patients lacked knowledge about their disease. Nearly one-third of probands answered "yes" or "do not know" to the question, "is ET the same or different from the type of tremor that many normal people can get when they become old and frail?" A similar proportion did not know whether children could get ET or they responded "no." Nearly one-fourth of affecteds (i.e., probands and AFRs) did not know whether or to what degree (e.g., very well, moderately well, not well) the symptoms of ET could be medically controlled, and 38.0% either reported that there was no brain surgery for ET or reported that they did not know. Nearly 17% of affecteds did not endorse genes as a cause for ET, which was surprising given the fact that this was a family study of ET. Probands and AFRs were the most knowledgeable, followed by unaffected relatives. Spouses of unaffected relatives were the least knowledgeable. We targeted a large group of ET patients and their families, as this group is perhaps most likely to be informed about the disease. ET patients and their AFRs were more knowledgeable about the features of ET than their

  15. A CRISPR-Based Screen Identifies Genes Essential for West-Nile-Virus-Induced Cell Death.

    Science.gov (United States)

    Ma, Hongming; Dang, Ying; Wu, Yonggan; Jia, Gengxiang; Anaya, Edgar; Zhang, Junli; Abraham, Sojan; Choi, Jang-Gi; Shi, Guojun; Qi, Ling; Manjunath, N; Wu, Haoquan

    2015-07-28

    West Nile virus (WNV) causes an acute neurological infection attended by massive neuronal cell death. However, the mechanism(s) behind the virus-induced cell death is poorly understood. Using a library containing 77,406 sgRNAs targeting 20,121 genes, we performed a genome-wide screen followed by a second screen with a sub-library. Among the genes identified, seven genes, EMC2, EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1, stood out as having the strongest phenotype, whose knockout conferred strong protection against WNV-induced cell death with two different WNV strains and in three cell lines. Interestingly, knockout of these genes did not block WNV replication. Thus, these appear to be essential genes that link WNV replication to downstream cell death pathway(s). In addition, the fact that all of these genes belong to the ER-associated protein degradation (ERAD) pathway suggests that this might be the primary driver of WNV-induced cell death. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Physical and Chemical Connectivity of Streams and Riparian Wetlands to Downstream Waters: A Synthesis

    Science.gov (United States)

    Streams, riparian areas, floodplains, alluvial aquifers, and downstream waters (e.g., large rivers, lakes, and oceans) are interconnected by longitudinal, lateral, and vertical fluxes of water, other materials, and energy. Collectively, these interconnected waters are called fluv...

  17. Wavelength remodulation scheme using DPSK downstream and upstream for DWDM-PONs.

    Science.gov (United States)

    Deb, Nebras; Anis, Hanan

    2011-08-15

    We propose a novel wavelength-division-multiplexed passive optical network (WDM-PON) architecture with enhanced tolerance toward chromatic dispersion where a DPSK-modulated downstream signal with constant intensity is remodulated at the ONU side with a return to zero (RZ-DPSK). Driving the downstream modulator with a 50% RZ data enabled us to employ the pulse carver at the ONU for both removing downstream data and generating the optical RZ signal for upstream. This offers an attractive alternative to earlier proposed schemes as it allows us to use full modulation depth (FMD) and balanced detection for downstream data restoration. We experimentally demonstrate the system with both balanced and single-ended detection at 2.5 Gb/s. Error-free operation has been achieved along a 20 Km single mode fiber without dispersion compensation. © 2011 Optical Society of America

  18. Evaluation of a Solid Phase DNA Binding Matrix for Downstream PCR Analysis

    National Research Council Canada - National Science Library

    Bader, Douglas E; Fisher, Glen R; Stratilo, Chad W

    2005-01-01

    A commercially available solid-phase DNA binding matrix (FTA cards) was evaluated for its ability to capture and release DNA for downstream gene amplification and detection assays using polymerase chain reaction (PCR...

  19. The dynamics of entrepreneurship in ICT: case of mobile phones downstream services in Kenya

    NARCIS (Netherlands)

    R.N. Kanothi (Raphael)

    2009-01-01

    textabstractThe research paper explores the extent to which mobile phones downstream services, defined here as those provided using the existing connectivity, are generating opportunities for entrepreneurship development in Kenya. After identifying the services of mobile payphones, money transfer

  20. Downstream wind flow path diversion and its effects on the performance of vertical axis wind turbine

    International Nuclear Information System (INIS)

    Maganhar, A.L.

    2015-01-01

    In the present experimental study efforts have been made to analysis path diversion effect of downstream wind flow on performance of vertical axis wind turbine (VAWT). For the blockage of downstream wind flow path at various linear displaced positions, a normal erected flat wall, semi-circular and cylindrical shapes were tested for path diverting geometries. Performance of VAWT in terms of improved rotor speed up to 45% was achieved. (author)

  1. Bioactive Carbohydrates and Peptides in Foods: An Overview of Sources, Downstream Processing Steps and Associated Bioactivities

    Directory of Open Access Journals (Sweden)

    Maria Hayes

    2015-09-01

    Full Text Available Bioactive peptides and carbohydrates are sourced from a myriad of plant, animal and insects and have huge potential for use as food ingredients and pharmaceuticals. However, downstream processing bottlenecks hinder the potential use of these natural bioactive compounds and add cost to production processes. This review discusses the health benefits and bioactivities associated with peptides and carbohydrates of natural origin and downstream processing methodologies and novel processes which may be used to overcome these.

  2. Bioactive Carbohydrates and Peptides in Foods: An Overview of Sources, Downstream Processing Steps and Associated Bioactivities

    OpenAIRE

    Maria Hayes; Brijesh K. Tiwari

    2015-01-01

    Bioactive peptides and carbohydrates are sourced from a myriad of plant, animal and insects and have huge potential for use as food ingredients and pharmaceuticals. However, downstream processing bottlenecks hinder the potential use of these natural bioactive compounds and add cost to production processes. This review discusses the health benefits and bioactivities associated with peptides and carbohydrates of natural origin and downstream processing methodologies and novel processes which ma...

  3. Bioactive Carbohydrates and Peptides in Foods: An Overview of Sources, Downstream Processing Steps and Associated Bioactivities.

    Science.gov (United States)

    Hayes, Maria; Tiwari, Brijesh K

    2015-09-17

    Bioactive peptides and carbohydrates are sourced from a myriad of plant, animal and insects and have huge potential for use as food ingredients and pharmaceuticals. However, downstream processing bottlenecks hinder the potential use of these natural bioactive compounds and add cost to production processes. This review discusses the health benefits and bioactivities associated with peptides and carbohydrates of natural origin and downstream processing methodologies and novel processes which may be used to overcome these.

  4. Downstream Migration of Masu Salmon Smolt at a Diversion Facility of Dam

    Science.gov (United States)

    Hayashida, K.; Nii, H.; Kasuga, K.; Watanabe, K.

    2014-12-01

    A diversion facility was installed on the upstream of Pirika Dam in Northern Japan that produced a downstream flow into the fishway, thus allowing the fish to migrate to the sea. On the other hand, if the flow rate in the river was more than 7.00 m 3/s (design flow rate of diversion facility), masu salmon smolt were concerned about accessing the dam reservoir, because the smolt can't migrate to the sea through the diversion facility unfortunately. Therefore, the downstream migration of smolt was investigated around the diversion facility. The PIT tag system and radio transmitters as the biotelemetry were used to determine 1) whether masu salmon smolt were able to migrate downstream through the diversion facility and fishway at Pirika Dam, 2) when the smolt started to migrate downstream, 3) whether the downstream migration of smolt were affected by the flow increase in the river. It was clarified that 88% of the smolt were able to enter the diversion facility, and then 81% of the smolt were able to access the fishway. It was also clarified that smolt downstream migration had two peaks in a day (5:00 and 18:00). During the study period, although the flow rate was in the 2.21 m3/s to 30.44 m3/s range (average 6.70 m3/s), it was revealed that the diversion facility has a satisfactory function for the downstream migration of smolt as presented above. The survey clarified the downstream migration behavior of masu salmon by using two types of biotelemetry equipment. PIT tag and radio transmitter were found to be very effective in tracking the behavior of small fish such as smolt. PIT tags, in particular, require very little operating cost, because once they are inserted in the fish, they do not need human labor for tracking. It is desirable to actively introduce the biotelemetry as tracking equipment when surveying the fish migration in the river.

  5. Influence of Upstream and Downstream Compressor Stators on Rotor Exit Flow Field

    Directory of Open Access Journals (Sweden)

    Nicole L. Key

    2014-01-01

    Full Text Available Measurements acquired at the rotor exit plane illuminate the interaction of the rotor with the upstream vane row and the downstream vane row. The relative phase of the upstream and downstream vane rows is adjusted using vane clocking so that the effect of the upstream propagating potential field from the downstream stator can be distinguished from the effects associated with the wakes shed from the upstream stator. Unsteady absolute flow angle information shows that the downstream potential field causes the absolute flow angle to increase in the vicinity of the downstream stator leading edge. The presence of Stator 1 wake is also detected at this measurement plane using unsteady total pressure data. The rotor wakes are measured at different circumferential locations across the vane passage, and the influence of Stator 1 wake on the suction side of the rotor wake is evident. Also, the influence of the downstream stator is detected on the pressure side of the rotor wake for a particular clocking configuration. Understanding the role of the surrounding vane rows on rotor wake development will lead to improved comparison between experimental data and results from computational models.

  6. Essential medicines: An Indian perspective

    Directory of Open Access Journals (Sweden)

    Rituparna Maiti

    2015-01-01

    Full Text Available The concept of defining essential medicines and establishing a list of them was aimed to improve the availability of affordable medicines for the world′s poor. Access to essential medicines is a major determinant of health outcomes. Several countries have made substantial progress towards increasing access to essential medicines, but access to essential medicines in developing countries like India is not adequate. In this review we have tried to present the Indian scenario in respect to availability and accessibility of essential medicines over last one decade. To enhance the credibility of Indian healthcare system, procurement and delivery systems of essential medicines have to be strengthened through government commitment, careful selection, adequate public sector financing, efficient distribution systems, control on taxes and duties, and inculcating a culture of rational use of medicines in current and future prescribers.

  7. Essential oils and anxiolytic aromatherapy.

    Science.gov (United States)

    Setzer, William N

    2009-09-01

    A number of essential oils are currently in use as aromatherapy agents to relieve anxiety, stress, and depression. Popular anxiolytic oils include lavender (Lavandula angustifolia), rose (Rosa damascena), orange (Citrus sinensis), bergamot (Citrus aurantium), lemon (Citrus limon), sandalwood (Santalum album), clary sage (Salvia sclarea), Roman chamomile (Anthemis nobilis), and rose-scented geranium (Pelargonium spp.). This review discusses the chemical constituents and CNS effects of these aromatherapeutic essential oils, as well as recent studies on additional essential oils with anxiolytic activities.

  8. Levels of Essential and Non-Essential Elements in Commercially ...

    African Journals Online (AJOL)

    Enebi Jasper

    and quantify the essential and non-essential elements as well as to determine heavy metal accumulation in the herbs tissues of the commercial moringa herb teas as a consequence of environmental pollution. For this reason all elements laying between sodium. (Na) to uranium (U) were analyzed using X-ray fluorescence.

  9. Interactions between Channel Morphology and the Propagation of Coarse Sediment Augmentations Downstream from Dams

    Science.gov (United States)

    Gaeuman, D. A.; Dickenson, S.; Pyles, M.

    2009-12-01

    Gravel augmentations are being implemented in a number of streams where natural recruitment of gravel is impeded by dams. Uncertainties relevant to the management of gravel augmentations include the quantities of gravel needed to achieve habitat benefits at downstream locations and the temporal and spatial scales over which those benefits that will be realized. The solution to such questions depends to a large extent on how gravel slugs evolve as the material is transported downstream, i.e., whether the gravel translates downstream as a coherent wave or whether it tends to disperse. A number of recent studies conducted in laboratory flumes or by numerical simulation that gravels slugs tend to disperse rather than translate. However, these studies do not consider the influence of channel morphology on slug behavior. Initial monitoring results based from 2 California streams suggest that natural channel morphology suppresses slug dispersion because the gravel tends to accumulate in discrete deposition zones. Field mapping and about 200 tracer stones implanted with passive integrated transponder (PIT) tags show that gravel recruitment piles of about 80 tons each placed in Grass Valley Creek in 2007 and 2008 were deposited as 2 new bars immediately downstream. The more upstream of the 2 bars formed during the 2007 winter and spring flood season, whereas the more downstream bar did not appear until the following year. A sharp deposition front and an absence of tracers in the reaches downstream strongly suggest that none of the added gravel was transported downstream beyond the area of bar formation in either year. A relatively small proportion of the mobilized tracer particles (59%) were located following the 2007 flood season, probably due to deep burial in the newly deposited bar and to radio interference caused by the high concentration of tracers in a small area. The proportion of newly introduced or previously-located tracers that were relocated in 2009 was

  10. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor γ, controls hepatitis B virus replication

    International Nuclear Information System (INIS)

    Yoon, Sarah; Jung, Jaesung; Kim, Taeyeung; Park, Sun; Chwae, Yong-Joon; Shin, Ho-Joon; Kim, Kyongmin

    2011-01-01

    In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), adiponectin, liver X receptor α (LXRα), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPARγ and C/EBPα. Conversely, HBV replication was upregulated by adiponectin and PPARγ agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.

  11. CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets

    DEFF Research Database (Denmark)

    Barbagallo, Davide; Condorelli, Angelo Giuseppe; Piro, Salvatore

    2014-01-01

    Transcription factor CEBPA has been widely studied for its involvement in hematopoietic cell differentiation and causal role in hematological malignancies. We demonstrate here that it also performs a causal role in cytokine-induced apoptosis of pancreas β cells. Treatment of two mouse pancreatic ...

  12. Mammary epithelial cell phagocytosis downstream of TGF-β3 is characterized by adherens junction reorganization.

    Science.gov (United States)

    Fornetti, J; Flanders, K C; Henson, P M; Tan, A-C; Borges, V F; Schedin, P

    2016-02-01

    After weaning, during mammary gland involution, milk-producing mammary epithelial cells undergo apoptosis. Effective clearance of these dying cells is essential, as persistent apoptotic cells have a negative impact on gland homeostasis, future lactation and cancer susceptibility. In mice, apoptotic cells are cleared by the neighboring epithelium, yet little is known about how mammary epithelial cells become phagocytic or whether this function is conserved between species. Here we use a rat model of weaning-induced involution and involuting breast tissue from women, to demonstrate apoptotic cells within luminal epithelial cells and epithelial expression of the scavenger mannose receptor, suggesting conservation of phagocytosis by epithelial cells. In the rat, epithelial transforming growth factor-β (TGF-β) signaling is increased during involution, a pathway known to promote phagocytic capability. To test whether TGF-β enhances the phagocytic ability of mammary epithelial cells, non-transformed murine mammary epithelial EpH4 cells were cultured to achieve tight junction impermeability, such as occurs during lactation. TGF-β3 treatment promoted loss of tight junction impermeability, reorganization and cleavage of the adherens junction protein E-cadherin (E-cad), and phagocytosis. Phagocytosis correlated with junction disruption, suggesting junction reorganization is necessary for phagocytosis by epithelial cells. Supporting this hypothesis, epithelial cell E-cad reorganization and cleavage were observed in rat and human involuting mammary glands. Further, in the rat, E-cad cleavage correlated with increased γ-secretase activity and β-catenin nuclear localization. In vitro, pharmacologic inhibitors of γ-secretase or β-catenin reduced the effect of TGF-β3 on phagocytosis to near baseline levels. However, β-catenin signaling through LiCl treatment did not enhance phagocytic capacity, suggesting a model in which both reorganization of cell junctions and

  13. Essentialism, hybridism and cultural critique

    DEFF Research Database (Denmark)

    Frello, Birgitta

    2007-01-01

    In my paper, I suggest that we sharpen our attention towards the complexities of the work of power in transgressions as well as in constructions of essentialist identities. Criticising essentialism is vital for fighting group-based exclusionism. However, criticising essentialism and celebrating h...

  14. Neuroimaging essentials in essential tremor: a systematic review.

    Science.gov (United States)

    Sharifi, Sarvi; Nederveen, Aart J; Booij, Jan; van Rootselaar, Anne-Fleur

    2014-01-01

    Essential tremor is regarded to be a disease of the central nervous system. Neuroimaging is a rapidly growing field with potential benefits to both diagnostics and research. The exact role of imaging techniques with respect to essential tremor in research and clinical practice is not clear. A systematic review of the different imaging techniques in essential tremor is lacking in the literature. We performed a systematic literature search combining the terms essential tremor and familial tremor with the following keywords: imaging, mri, vbm, dwi, fmri, pet and spect, both in abbreviated form as well as in full form. We summarize and discuss the quality and the external validity of each study and place the results in the context of existing knowledge regarding the pathophysiology of essential tremor. A total of 48 neuroimaging studies met our search criteria, roughly divided into 19 structural and 29 functional and metabolic studies. The quality of the studies varied, especially concerning inclusion criteria. Functional imaging studies indicated cerebellar hyperactivity during rest and during tremor. The studies also pointed to the involvement of the thalamus, the inferior olive and the red nucleus. Structural studies showed less consistent results. Neuroimaging techniques in essential tremor give insight into the pathophysiology of essential tremor indicating the involvement of the cerebellum as the most consistent finding. GABAergic dysfunction might be a major premise in the pathophysiological hypotheses. Inconsistencies between studies can be partly explained by the inclusion of heterogeneous patient groups. Improvement of scientific research requires more stringent inclusion criteria and application of advanced analysis techniques. Also, the use of multimodal neuroimaging techniques is a promising development in movement disorders research. Currently, the role of imaging techniques in essential tremor in daily clinical practice is limited.

  15. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  16. Characterization equipment essential drawing plan

    International Nuclear Information System (INIS)

    WILSON, G.W.

    1999-01-01

    The purpose of this document is to list the Characterization equipment drawings that are classified as Essential Drawings. Essential Drawings: Are those drawings identified by the facility staff as necessary to directly support the safe operation of the facility or equipment (HNF 1997a). The Characterization equipment drawings identified in this report are deemed essential drawings as defined in HNF-PRO-242, Engineering Drawing Requirements (HNF 1997a). These drawings will be prepared, revised, and maintained per HNF-PRO-440, Engineering Document Change Control (HNF 1997b). All other Characterization equipment drawings not identified in this document will be considered Support drawings until the Characterization Equipment Drawing Evaluation Report is completed

  17. A dulal-functional medium voltage level DVR to limit downstream fault currents

    DEFF Research Database (Denmark)

    Blaabjerg, Frede; Li, Yun Wei; Vilathgamuwa, D. Mahinda

    2007-01-01

    , the DVR will therefore be tasked to mitigate even more faults involving downstream loads. Large fault currents would flow through the DVR during a downstream fault before the opening of a circuit breaker. This will cause the voltage at point of common coupling (PCC) to drop, which would affect the loads...... on the other parallel feeders connected to PCC. Furthermore, if not controlled properly, the DVR might also contribute to this PCC voltage sag in the process of compensating the missing voltage, thus further worsening the fault situation. To limit the flow of large line currents, and therefore restore the PCC...... voltage as well as protect the DVR system components, a downstream fault limiting function is proposed and integrated in the DVR operation. A flux-charge-model feedback algorithm is implemented so that the DVR would act as a large virtual inductance in series with the distribution feeder in fault...

  18. Full-scale observation of the flow downstream of a suspension bridge deck

    DEFF Research Database (Denmark)

    Cheynet, Etienne; Jakobsen, Jasna Bogunović; Snæbjörnsson, Jónas

    2017-01-01

    The paper presents a full-scale observation of the flow conditions downstream of a suspension bridge by a system of synchronized short-range dual-Doppler wind lidars. The lidar units were deployed directly on the bridge walkway during a four-day pilot experiment. The wind velocity was monitored...... at every meter along a 111 m long vertical line segment 40 m downstream of the deck, with a sampling period of one second. The lidar wind data are studied in terms of the mean wind velocity deficit and turbulence intensity downstream of the bridge deck. They provided a full-scale characterization...... tests. Challenges in the estimation of the wind velocity data related to the variable measurement noise of the individual lidars, as a function of the wind direction, are highlighted. Suggestions for future applications of a similar measurement set-up, based on this unique study performed during...

  19. Downstream lightening and upward heavying, sorting of sediments of uniform grain size but differing in density

    Science.gov (United States)

    Viparelli, E.; Solari, L.; Hill, K. M.

    2014-12-01

    Downstream fining, i.e. the tendency for a gradual decrease in grain size in the downstream direction, has been observed and studied in alluvial rivers and in laboratory flumes. Laboratory experiments and field observations show that the vertical sorting pattern over a small Gilbert delta front is characterized by an upward fining profile, with preferential deposition of coarse particles in the lowermost part of the deposit. The present work is an attempt to answer the following questions. Are there analogous sorting patterns in mixtures of sediment particles having the same grain size but differing density? To investigate this, we performed experiments at the Hydrosystems Laboratory at the University of Illinois at Urbana-Champaign. During the experiments a Gilbert delta formed and migrated downstream allowing for the study of transport and sorting processes on the surface and within the deposit. The experimental results show 1) preferential deposition of heavy particles in the upstream part of the deposit associated with a pattern of "downstream lightening"; and 2) a vertical sorting pattern over the delta front characterized by a pattern of "upward heavying" with preferential deposition of light particles in the lowermost part of the deposit. The observed downstream lightening is analogous of the downstream fining with preferential deposition of heavy (coarse) particles in the upstream part of the deposit. The observed upward heavying was unexpected because, considering the particle mass alone, the heavy (coarse) particles should have been preferentially deposited in the lowermost part of the deposit. Further, the application of classical fractional bedload transport relations suggests that in the case of mixtures of particles of uniform size and different densities equal mobility is not approached. We hypothesize that granular physics mechanisms traditionally associated with sheared granular flows may be responsible for the observed upward heavying and for the

  20. Photoperiod control of downstream movements of Atlantic salmon Salmo salar smolts

    Science.gov (United States)

    Zydlewski, Gayle B.; Stich, Daniel S.; McCormick, Stephen D.

    2014-01-01

    This study provides the first direct observations that photoperiod controls the initiation of downstream movement in Atlantic salmon Salmo salar smolts. Under simulated natural day length (LDN) conditions and seasonal increases in temperature, smolts increased their downstream movements five-fold for a period of 1 month in late spring. Under the same conditions, parr did not show changes in downstream movement behaviour. When given a shortened day length (10L:14D) beginning in late winter, smolts did not increase the number of downstream movements. An early increase in day length (16L:8D) in late winter resulted in earlier initiation and termination of downstream movements compared to the LDN group. Physiological status and behaviour were related but not completely coincident: gill Na+/K+-ATPase activity increased in all treatments and thyroid hormone was elevated prior to movement in 16L:8D treatment. The most parsimonious model describing downstream movement of smolts included synergistic effects of photoperiod treatment and temperature, indicating that peak movements occurred at colder temperatures in the 16L:8D treatment than in LDN, and temperature did not influence movement of smolts in the 10L:14D treatment. The complicated interactions of photoperiod and temperature are not surprising since many organisms have evolved to rely on correlations among environmental cues and windows of opportunity to time behaviours associated with life-history transitions. These complicated interactions, however, have serious implications for phenological adjustments and persistence ofS. salar populations in response to climate change.

  1. Evaluating the Invasion of Red Cedar (Juniperus viriginiana) Downstream of Gavins Point Dam, Missouri National Recreational River

    Science.gov (United States)

    Greene, S.; Knox, J. C.

    2013-12-01

    Gavins Point Dam, the final dam on the main-stem Missouri River, alters downstream river form and function. Throughout a 59-mile downstream reach, the dam reduces overbank flooding and lowers the water surface by 1-3 meters. Under the dam-created hydro-geomorphic conditions, native cottonwood trees are unable to regenerate. The limited regeneration of native riparian cottonwoods, the lowered water surface, and the reduced overbank flooding creates a terrace environment within the riparian habitat. Consequently, red cedars, a native upland tree, are invading this new terrace-like riparian environment. To this end, we apply Bayesian statistical models to investigate patterns of red cedar riparian invasion and assess ecosystem function patterns along this flow-regulated reach. We set up plots within cottonwood stands along a 59-km reach downstream of Gavins Point Dam. Within each plot, we collected soil samples, litter samples, stem densities of trees, and collected cores of the largest cottonwood and largest red cedar in each plot. To assess influences of red cedar on soil indicators of ecosystem function and general patterns of ecosystem function within the study area, we measured organic carbon, nitrogen, pH, electrical conductivity, and hydrophobicity. To determine drivers and patterns of invasion and ecosystem function we conducted Bayesian linear regressions and means comparison tests. Red cedars existed along the floodplain prior to regulation. However, according to our tree age data and stem density data red cedars existed at a lower population than today. We found that 2 out of 565 red cedars established before the dam was completed. Also, we found no significant difference in soil properties between soils with established red cedar and soils with established cottonwood. By studying soil texture data, and interpreting fluvial geomorphic surfaces in the field and via aerial photography, we found soil texture generally reflects the type of fluvial surface

  2. Aromatherapy and Essential Oils (PDQ)

    Science.gov (United States)

    ... Professionals Questions to Ask about Your Treatment Research Aromatherapy and Essential Oils (PDQ®)–Patient Version Overview Go ... FDA) (see Question 6 ). Questions and Answers About Aromatherapy What is aromatherapy? Aromatherapy is the use of ...

  3. MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy.

    Science.gov (United States)

    Zanchi, Cristina; Macconi, Daniela; Trionfini, Piera; Tomasoni, Susanna; Rottoli, Daniela; Locatelli, Monica; Rudnicki, Michael; Vandesompele, Jo; Mestdagh, Pieter; Remuzzi, Giuseppe; Benigni, Ariela; Zoja, Carlamaria

    2017-06-01

    Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis. miRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms. In ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin-induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-κB p65 subunit to miR-184 promoter. These results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial

  4. A dulal-functional medium voltage level DVR to limit downstream fault currents

    DEFF Research Database (Denmark)

    Blaabjerg, Frede; Li, Yun Wei; Vilathgamuwa, D. Mahinda

    2007-01-01

    , the DVR will therefore be tasked to mitigate even more faults involving downstream loads. Large fault currents would flow through the DVR during a downstream fault before the opening of a circuit breaker. This will cause the voltage at point of common coupling (PCC) to drop, which would affect the loads...... on the other parallel feeders connected to PCC. Furthermore, if not controlled properly, the DVR might also contribute to this PCC voltage sag in the process of compensating the missing voltage, thus further worsening the fault situation. To limit the flow of large line currents, and therefore restore the PCC...

  5. Estimating subcatchment runoff coefficients using weather radar and a downstream runoff sensor.

    Science.gov (United States)

    Ahm, Malte; Thorndahl, Søren; Rasmussen, Michael R; Bassø, Lene

    2013-01-01

    This paper presents a method for estimating runoff coefficients of urban drainage subcatchments based on a combination of high resolution weather radar data and flow measurements from a downstream runoff sensor. By utilising the spatial variability of the precipitation it is possible to estimate the runoff coefficients of the separate subcatchments. The method is demonstrated through a case study of an urban drainage catchment (678 ha) located in the city of Aarhus, Denmark. The study has proven that it is possible to use corresponding measurements of the relative rainfall distribution over the catchment and downstream runoff measurements to identify the runoff coefficients at subcatchment level.

  6. Recent hydrocarbon developments in Latin America: Key issues in the downstream oil sector

    International Nuclear Information System (INIS)

    Wu, K.; Pezeshki, S.

    1995-01-01

    This report discusses the following: (1) An overview of major issues in the downstream oil sector, including oil demand and product export availability, the changing product consumption pattern, and refineries being due for major investment; (2) Recent upstream developments in the oil and gas sector in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, Trinidad and Tobago, and Venezuela; (3) Recent downstream developments in the oil and gas sector in Argentina, Chile, Colombia, Ecuador, Mexico, Peru, Cuba, and Venezuela; (4) Pipelines in Argentina, Bolivia, Brazil, Chile, and Mexico; and (5) Regional energy balance. 4 figs., 5 tabs

  7. Recent hydrocarbon developments in Latin America: Key issues in the downstream oil sector

    Energy Technology Data Exchange (ETDEWEB)

    Wu, K.; Pezeshki, S.

    1995-03-01

    This report discusses the following: (1) An overview of major issues in the downstream oil sector, including oil demand and product export availability, the changing product consumption pattern, and refineries being due for major investment; (2) Recent upstream developments in the oil and gas sector in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, Trinidad and Tobago, and Venezuela; (3) Recent downstream developments in the oil and gas sector in Argentina, Chile, Colombia, Ecuador, Mexico, Peru, Cuba, and Venezuela; (4) Pipelines in Argentina, Bolivia, Brazil, Chile, and Mexico; and (5) Regional energy balance. 4 figs., 5 tabs.

  8. The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma.

    Science.gov (United States)

    Canovas Nunes, Sara; Manzoni, Martina; Pizzi, Marco; Mandato, Elisa; Carrino, Marilena; Quotti Tubi, Laura; Zambello, Renato; Adami, Fausto; Visentin, Andrea; Barilà, Gregorio; Trentin, Livio; Manni, Sabrina; Neri, Antonino; Semenzato, Gianpietro; Piazza, Francesco

    2018-02-13

    Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression.

  9. Reservoir stratification affects methylmercury levels in river water, plankton, and fish downstream from Balbina hydroelectric dam, Amazonas, Brazil.

    Science.gov (United States)

    Kasper, Daniele; Forsberg, Bruce R; Amaral, João H F; Leitão, Rafael P; Py-Daniel, Sarah S; Bastos, Wanderley R; Malm, Olaf

    2014-01-21

    The river downstream from a dam can be more contaminated by mercury than the reservoir itself. However, it is not clear how far the contamination occurs downstream. We investigated the seasonal variation of methylmercury levels in the Balbina reservoir and how they correlated with the levels encountered downstream from the dam. Water, plankton, and fishes were collected upstream and at sites between 0.5 and 250 km downstream from the dam during four expeditions in 2011 and 2012. Variations in thermal stratification of the reservoir influenced the methylmercury levels in the reservoir and in the river downstream. Uniform depth distributions of methylmercury and oxygen encountered in the poorly stratified reservoir during the rainy season collections coincided with uniformly low methylmercury levels along the river downstream from the dam. During dry season collections, the reservoir was strongly stratified, and anoxic hypolimnion water with high methylmercury levels was exported downstream. Methylmercury levels declined gradually to 200 km downstream. In general, the methylmercury levels in plankton and fishes downstream from the dam were higher than those upstream. Higher methylmercury levels observed 200-250 km downstream from the dam during flooding season campaigns may reflect the greater inflow from tributaries and flooding of natural wetlands that occurred at this time.

  10. Phosphorylation and dephosphorylation among Dif chemosensory proteins essential for exopolysaccharide regulation in Myxococcus xanthus.

    Science.gov (United States)

    Black, Wesley P; Schubot, Florian D; Li, Zhuo; Yang, Zhaomin

    2010-09-01

    Myxococcus xanthus social gliding motility, which is powered by type IV pili, requires the presence of exopolysaccharides (EPS) on the cell surface. The Dif chemosensory system is essential for the regulation of EPS production. It was demonstrated previously that DifA (methyl-accepting chemotaxis protein [MCP]-like), DifC (CheW-like), and DifE (CheA-like) stimulate whereas DifD (CheY-like) and DifG (CheC-like) inhibit EPS production. DifD was found not to function downstream of DifE in EPS regulation, as a difD difE double mutant phenocopied the difE single mutant. It has been proposed that DifA, DifC, and DifE form a ternary signaling complex that positively regulates EPS production through the kinase activity of DifE. DifD was proposed as a phosphate sink of phosphorylated DifE (DifE approximately P), while DifG would augment the function of DifD as a phosphatase of phosphorylated DifD (DifD approximately P). Here we report in vitro phosphorylation studies with all the Dif chemosensory proteins that were expressed and purified from Escherichia coli. DifE was demonstrated to be an autokinase. Consistent with the formation of a DifA-DifC-DifE complex, DifA and DifC together, but not individually, were found to influence DifE autophosphorylation. DifD, which did not inhibit DifE autophosphorylation directly, was found to accept phosphate from autophosphorylated DifE. While DifD approximately P has an unusually long half-life for dephosphorylation in vitro, DifG efficiently dephosphorylated DifD approximately P as a phosphatase. These results support a model where DifE complexes with DifA and DifC to regulate EPS production through phosphorylation of a downstream target, while DifD and DifG function synergistically to divert phosphates away from DifE approximately P.

  11. Regulation of notochord-specific expression of Ci-Bra downstream genes in Ciona intestinalis embryos.

    Science.gov (United States)

    Takahashi, Hiroki; Hotta, Kohji; Takagi, Chiyo; Ueno, Naoto; Satoh, Nori; Shoguchi, Eiichi

    2010-02-01

    Brachyury, a T-box transcription factor, is expressed in ascidian embryos exclusively in primordial notochord cells and plays a pivotal role in differentiation of notochord cells. Previously, we identified approximately 450 genes downstream of Ciona intestinalis Brachyury (Ci-Bra), and characterized the expression profiles of 45 of these in differentiating notochord cells. In this study, we looked for cisregulatory sequences in minimal enhancers of 20 Ci-Bra downstream genes by electroporating region within approximately 3 kb upstream of each gene fused with lacZ. Eight of the 20 reporters were expressed in notochord cells. The minimal enchancer for each of these eight genes was narrowed to a region approximately 0.5-1.0-kb long. We also explored the genome-wide and coordinate regulation of 43 Ci-Bra-downstream genes. When we determined their chromosomal localization, it became evident that they are not clustered in a given region of the genome, but rather distributed evenly over 13 of the 14 pairs of chromosomes, suggesting that gene clustering does not contribute to coordinate control of the Ci-Bra downstream gene expression. Our results might provide Insights Into the molecular mechanisms underlying notochord formation in chordates.

  12. 5 X 5 rod bundle flow field measurements downstream a PWR spacer grid

    Energy Technology Data Exchange (ETDEWEB)

    Castro, Higor F.P.; Silva, Vitor V A.; Santos, André A.C.; Veloso, Maria A.F., E-mail: higorfabiano@gmail.com, E-mail: mdora@nuclear.ufmg.br, E-mail: vitors@cdtn.br, E-mail: aacs@cdtn.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil); Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

    2017-07-01

    The spacer grids are structures present in nuclear fuel assembly of Pressurized Water Reactors (PWR). They play an important structural role and also assist in heat removal through the assembly by promoting increased turbulence of the flow. Understanding the flow dynamics downstream the spacer grid is paramount for fuel element design and analysis. This paper presents water flow velocity profiles measurements downstream a spacer grid in a 5 x 5 rod bundle test rig with the objective of highlighting important fluid dynamic behavior near the grid and supplying data for CFD simulation validation. These velocity profiles were obtained at two different heights downstream the spacer grid using a LDV (Laser Doppler Velocimetry) through the top of test rig. The turbulence intensities and patterns of the swirl and cross flow were evaluated. The tests were conducted for Reynolds numbers ranging from 1.8 x 10{sup 4} to 5.4 x 10{sup 4}. This experimental research was carried out in thermo-hydraulics laboratory of Nuclear Technology Development Center – CDTN. Results show great repeatability and low uncertainties (< 1.24 %). Details of the flow field show how the mixture and turbulence induced by the spacer grid quickly decays downstream the spacer grid. It is shown that the developed methodology can supply high resolution low uncertainty results that can be used for validation of CFD simulations. (author)

  13. Changes in biodiversity and ecosystem function downstream from mountaintop removal and valley fill coal mining

    Science.gov (United States)

    Mountaintop removal and valley fill coal mining has altered the physicochemical landscape of the Central Appalachian region in the U.S. Increased specific conductance and levels of component ions downstream from valley fill sites are toxic to aquatic life and can negatively impa...

  14. Water stress in global transboundary river basins : Significance of upstream water use on downstream stress

    NARCIS (Netherlands)

    Munia, H.; Guillaume, J. H A; Mirumachi, N.; Porkka, M.; Wada, Y.; Kummu, M.

    2016-01-01

    Growing population and water demand have increased pressure on water resources in various parts of the globe, including many transboundary river basins. While the impacts of upstream water use on downstream water availability have been analysed in many of these international river basins, this has

  15. Investigation of downstream and sideline subsonic jet noise using large Eddy simulation

    Energy Technology Data Exchange (ETDEWEB)

    Bogey, Christophe; Bailly, Christophe [Laboratoire de Mecanique des Fluides et d' Acoustique, UMR CNRS 5509, Ecully (France)

    2006-02-15

    The sound fields radiated by Mach number 0.6 and 0.9, circular jets with Reynolds numbers varying from 1.7 x 10{sup 3} to 4 x 10{sup 5} are investigated using Large Eddy Simulations. As the Reynolds number decreases, the properties of the sound radiation do not change significantly in the downstream direction, whereas they are modified in the sideline direction. At low Reynolds numbers, for large angles downstream from the jet axis, the acoustic levels are indeed remarkably lower and a large high-frequency part of the sound spectra vanishes. For all Reynolds numbers, the downstream and the sideline sound spectra both appear to scale in frequency with the Strouhal number. However their peak amplitudes vary following two different velocity exponents according to the radiation direction. The present observations suggest the presence of two sound sources: a Reynolds number-dependent source, predominant for large radiation angles, connected to the randomly-developing turbulence, and a deterministic source, radiating downstream, related to a mechanism intrinsic to the jet geometry, which is still to be comprehensively described. This view agrees well with the experimental results displaying two distinguishable components in turbulent mixing noise [1, 2]. (orig.)

  16. 40 CFR 80.220 - What are the downstream standards for GPA gasoline?

    Science.gov (United States)

    2010-07-01

    ... GPA gasoline? 80.220 Section 80.220 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Gasoline Sulfur Geographic Phase-in Program § 80.220 What are the downstream standards for GPA gasoline? (a) GPA gasoline. (1) During...

  17. Regulating water extraction in a river basin with upstream-downstream communities

    DEFF Research Database (Denmark)

    Graversen, Mette Kildegaard

    This paper proposes a tax mechanism modelled for water extraction in a river system with upstream and downstream farmers. The tax mechanism is based on the regulator’s own estimation of aggregate extraction and for that reason the tax addresses the problem of asymmetric information...

  18. Physicochemical Characteristics of River Water Downstream of a Large Tropical Hydroelectric Dam

    Directory of Open Access Journals (Sweden)

    Teck-Yee Ling

    2016-01-01

    Full Text Available Water quality in the downstream river of a hydroelectric dam may be affected by the structural design and operation. To date, little is known about the water quality downstream of the largest dam in Malaysia, the Bakun hydroelectric dam. Therefore, the objective of the study was to determine the water quality downstream of the dam when the spillway was closed and when it was opened. Results of the study indicate that the dam plays a significant role in regulating the water quality downstream of it. When the spillway was closed, pH and oxygen were lower in the river where DO was below 5 mg/L. When the spillway was opened, the water quality improved in terms of oxygen content (>8.0 mg/L, total sulphide (TS, and chemical oxygen demand (COD but deteriorated in terms of five-day biochemical oxygen demand (BOD5, total ammonia nitrogen (TAN, and total phosphorus (TP. Additionally, the intensity of the impacts, particularly BOD5, COD, and TAN, shows a declining trend as distance from the dam increases. This study shows that impacts on the water quality extend to a distance of 32 km from the dam particularly turbidity and DO and opening the spillway changes the water quality significantly.

  19. Climate change impact on infection risks during bathing downstream of sewage emissions from CSOs or WWTPs

    NARCIS (Netherlands)

    Sterk, Ankie; de Man, Heleen; Schijven, Jack F; de Nijs, Ton; de Roda Husman, Ana Maria

    2016-01-01

    Climate change is expected to influence infection risks while bathing downstream of sewage emissions from combined sewage overflows (CSOs) or waste water treatment plants (WWTPs) due to changes in pathogen influx, rising temperatures and changing flow rates of the receiving waters. In this study,

  20. Investigation on the intense fringe formation phenomenon downstream hot-image plane.

    Science.gov (United States)

    Hu, Yonghua; Li, Guohui; Zhang, Lifu; Huang, Wenti; Chen, Shuming

    2015-11-30

    The propagation of a high-power flat-topped Gaussian beam, which is modulated by three parallel wirelike scatterers, passing through a downstream Kerr medium slab and free spaces is investigated. A new phenomenon is found that a kind of intense fringe with intensity several times that of the incident beam can be formed in a plane downstream the Kerr medium. This kind of intense fringe is another result in the propagation process of nonlinear imaging and it locates scores of centimeters downstream the predicted hot image plane. Moreover, the intensity of this fringe can achieve the magnitude of that of hot image in corresponding single-scatterer case, and this phenomenon can arise only under certain conditions. As for the corresponding hot images, they are also formed but largely suppressed. The cause of the formation of such an intense fringe is analyzed and found related to interference in the free space downstream the Kerr medium. Moreover, the ways it is influenced by some important factors such as the wavelength of incident beam and the properties of scatterers and Kerr medium are discussed, and some important properties and relations are revealed.

  1. Quantifying sustainability indicators in striped catfish Pangasianodon hypophthalmus downstream and upstream ponds

    NARCIS (Netherlands)

    Nhut, N.; Hao, N.V.; Bosma, R.H.; Verreth, J.A.V.; Verdegem, M.C.J.; Eding, E.H.

    2017-01-01

    To assess the potential for improving sustainability and efficiency in an important Vietnamese finfish culture, we quantified sustainability indicators for 2 downstream and 2 upstream 3 to 4 m deep ponds for striped catfish Pangasianodon hypophthalmus (Sauvage, 1878) production along the Mekong

  2. Estimating Subcatchment Runoff Coefficients using Weather Radar and a Downstream Runoff Sensor

    DEFF Research Database (Denmark)

    Ahm, Malte; Thorndahl, Søren Liedtke; Rasmussen, Michael R.

    2013-01-01

    This paper presents a method for estimating runoff coefficients of urban drainage subcatchments based on a combination of high resolution weather radar data and flow measurements from a downstream runoff sensor. By utilising the spatial variability of the precipitation it is possible to estimate...

  3. Influence of peak flow changes on the macroinvertebrate drift downstream of a Brazilian hydroelectric dam.

    Science.gov (United States)

    Castro, D M P; Hughes, R M; Callisto, M

    2013-11-01

    Successive daily peak flows from hydropower plants can disrupt aquatic ecosystems and alter the composition and structure of macroinvertebrates downstream. We evaluated the influence of peak flow changes on macroinvertebrate drift downstream of a hydroelectric plant as a basis for determining ecological flows that might reduce the disturbance of aquatic biota. The aim of this study was to assess the influence of flow fluctuations on the seasonal and daily drift patterns of macroinvertebrates. We collected macroinvertebrates during fixed flow rates (323 m3.s-1 in the wet season and 111 m3.s-1 in the dry season) and when peak flows fluctuated (378 to 481 m3.s-1 in the wet season, and 109 to 173 m3.s-1 in the dry season) in 2010. We collected 31,924 organisms belonging to 46 taxa in the four sampling periods. Taxonomic composition and densities of drifting invertebrates differed between fixed and fluctuating flows, in both wet and dry seasons, but family richness varied insignificantly. We conclude that macroinvertebrate assemblages downstream of dams are influenced by daily peak flow fluctuations. When making environmental flow decisions for dams, it would be wise to consider drifting macroinvertebrates because they reflect ecological changes in downstream biological assemblages.

  4. Linking Three Gorges Dam and downstream hydrological regimes along the Yangtze River, China

    NARCIS (Netherlands)

    Mei, X.; Dai, Z.; Van Gelder, P.H.A.J.M.; Gao, J.

    2015-01-01

    The magnitude of anthropogenic influence, especially dam regulation, on hydrological system is of scientific and practical value for large river management. As the largest dam in the world by far, Three Gorges Dam (TGD) is expected to be a strong evidence on dam impacts on downstream hydrological

  5. Stress analysis of the modified Pulsed Neutron Activation system downstream shield support structure

    Energy Technology Data Exchange (ETDEWEB)

    Mosby, W.R.

    1980-05-28

    The modified LOFT Pulsed Neutron Activation (PNA) System downstream shielding support structure was stress analyzed for deadweight and worst-case LOCE loads. No deficiencies were found in the structure. This stress analysis was performed for the PNA Shielding Configuration that has been used on Test L3-2 and that is to be used on Test L3-7.

  6. Influence of peak flow changes on the macroinvertebrate drift downstream of a Brazilian hydroelectric dam

    Directory of Open Access Journals (Sweden)

    DMP. Castro

    Full Text Available Successive daily peak flows from hydropower plants can disrupt aquatic ecosystems and alter the composition and structure of macroinvertebrates downstream. We evaluated the influence of peak flow changes on macroinvertebrate drift downstream of a hydroelectric plant as a basis for determining ecological flows that might reduce the disturbance of aquatic biota. The aim of this study was to assess the influence of flow fluctuations on the seasonal and daily drift patterns of macroinvertebrates. We collected macroinvertebrates during fixed flow rates (323 m3.s–1 in the wet season and 111 m3.s–1 in the dry season and when peak flows fluctuated (378 to 481 m3.s–1 in the wet season, and 109 to 173 m3.s–1 in the dry season in 2010. We collected 31,924 organisms belonging to 46 taxa in the four sampling periods. Taxonomic composition and densities of drifting invertebrates differed between fixed and fluctuating flows, in both wet and dry seasons, but family richness varied insignificantly. We conclude that macroinvertebrate assemblages downstream of dams are influenced by daily peak flow fluctuations. When making environmental flow decisions for dams, it would be wise to consider drifting macroinvertebrates because they reflect ecological changes in downstream biological assemblages.

  7. Using forest carbon credits to offset emissions in the downstream business

    NARCIS (Netherlands)

    Hein, Lars

    2017-01-01

    A forthcoming report by Concawe, entitled Using Forest Carbon Credits to Offset Emissions in the Downstream Business, investigated whether, and how, forest carbon credits can be used to offset emissions from the European refining and road transport sectors. Forest carbon plays a major role in the

  8. Concentration of radionuclides in fresh water fish downstream of Rancho Seco Nuclear Generating Plant

    International Nuclear Information System (INIS)

    Noshkin, V.E.; Eagle, R.J.; Dawson, J.M.; Brunk, J.L.; Wong, X.M.

    1984-01-01

    Fish were collected for radionuclide analysis over a 5-month period in 1984 from creeks downstream of the Rancho Seco Nuclear Generating Plant, which has been discharging quantities of some fission and activation products to the waterway since 1981. Among the fish, the bluegill was selected for intensive study because it is very territorial and the radionuclide concentrations detected should be representative of the levels in the local environment at the downstream locations sampled. Among the gamma-emitting radionuclides routinely released, only 134 Cs and 137 Cs were detected in the edible flesh of fish. Concentrations in the flesh of fish decreased with distance from the plant. The relationship between concentration and distance was determined to be exponential. Exponential equations were generated to estimate concentrations in fish at downstream locations where no site-specific information was available. Mean concentrations of 137 Cs in bluegill collected during April, May, July and August from specific downstream stations were not significantly different in spite of the release of 131 mCi to the creeks between April and August. The concentrations in fish are not responding to changes in water concentrations brought about by plant discharges. Diet appears to be a more significant factor than size or weight or water concentration in regulating body burdens of 137 Cs in these fish

  9. 5 X 5 rod bundle flow field measurements downstream a PWR spacer grid

    International Nuclear Information System (INIS)

    Castro, Higor F.P.; Silva, Vitor V A.; Santos, André A.C.; Veloso, Maria A.F.

    2017-01-01

    The spacer grids are structures present in nuclear fuel assembly of Pressurized Water Reactors (PWR). They play an important structural role and also assist in heat removal through the assembly by promoting increased turbulence of the flow. Understanding the flow dynamics downstream the spacer grid is paramount for fuel element design and analysis. This paper presents water flow velocity profiles measurements downstream a spacer grid in a 5 x 5 rod bundle test rig with the objective of highlighting important fluid dynamic behavior near the grid and supplying data for CFD simulation validation. These velocity profiles were obtained at two different heights downstream the spacer grid using a LDV (Laser Doppler Velocimetry) through the top of test rig. The turbulence intensities and patterns of the swirl and cross flow were evaluated. The tests were conducted for Reynolds numbers ranging from 1.8 x 10 4 to 5.4 x 10 4 . This experimental research was carried out in thermo-hydraulics laboratory of Nuclear Technology Development Center – CDTN. Results show great repeatability and low uncertainties (< 1.24 %). Details of the flow field show how the mixture and turbulence induced by the spacer grid quickly decays downstream the spacer grid. It is shown that the developed methodology can supply high resolution low uncertainty results that can be used for validation of CFD simulations. (author)

  10. RNAi-Based Identification of Gene-Specific Nuclear Cofactor Networks Regulating Interleukin-1 Target Genes

    Directory of Open Access Journals (Sweden)

    Johanna Meier-Soelch

    2018-04-01

    Full Text Available The potent proinflammatory cytokine interleukin (IL-1 triggers gene expression through the NF-κB signaling pathway. Here, we investigated the cofactor requirements of strongly regulated IL-1 target genes whose expression is impaired in p65 NF-κB-deficient murine embryonic fibroblasts. By two independent small-hairpin (shRNA screens, we examined 170 genes annotated to encode nuclear cofactors for their role in Cxcl2 mRNA expression and identified 22 factors that modulated basal or IL-1-inducible Cxcl2 levels. The functions of 16 of these factors were validated for Cxcl2 and further analyzed for their role in regulation of 10 additional IL-1 target genes by RT-qPCR. These data reveal that each inducible gene has its own (quantitative requirement of cofactors to maintain basal levels and to respond to IL-1. Twelve factors (Epc1, H2afz, Kdm2b, Kdm6a, Mbd3, Mta2, Phf21a, Ruvbl1, Sin3b, Suv420h1, Taf1, and Ube3a have not been previously implicated in inflammatory cytokine functions. Bioinformatics analysis indicates that they are components of complex nuclear protein networks that regulate chromatin functions and gene transcription. Collectively, these data suggest that downstream from the essential NF-κB signal each cytokine-inducible target gene has further subtle requirements for individual sets of nuclear cofactors that shape its transcriptional activation profile.

  11. Anthropogenic and Geologic Influence on the Downstream Fining Pattern of the Cosumnes River, Central Valley, California

    Science.gov (United States)

    Fehr, C. R.; Mount, J. F.

    2001-05-01

    A geomorphic survey of the Cosumnes River was conducted to identify the effects of anthropogenic change and local geology on downstream changes in grain size. Patterns of downstream fining exhibited by alluvial rivers reflect the processes of abrasion and sediment sorting by selective entrainment, transport and deposition. Longitudinal sorting of gravel is commonly modeled as a downstream exponential decrease in median particle grain size over the length of the profile. This relationship mirrors downstream reduction in gradient and bed shear stress typical of aggrading alluvial channels and is influenced by variations in sediment supply. The impacts of anthropogenic activity on these variables should be reflected by departures in downstream fining patterns from the expected trend. Results from this study show that grain-size change over the longitudinal profile deviates significantly from the predicted model. In addition, grain-size measurements at cross-sections demonstrate poor correlation with average bankfull bed shear stress. At sites where grain size appears unrelated to distance downstream as well as to energy slope, sediment transport may be directly influenced by alterations to the channel such as in-stream mining and the construction of diversion dams. Fluvial response to the cumulative effects of watershed-scale anthropogenic activities has also contributed to the modification of the nature of sediment transport in the channel. Prior to settlement of the Great Valley, the Cosumnes was a shallow, anastomosing alluvial river connected to a broad floodplain. Changes in land-use practices as well as channel regulation have caused rapid river-bed degradation and incision into resistant Quaternary alluvial fan deposits in some locations. Unlike the alluvial reaches studied, those with duripan beds and banks are characterized by a step-pool-like structure and contribute only small volumes of coarse sediment to the river. Data suggest that sediment transport in

  12. Targeted Learning

    CERN Document Server

    van der Laan, Mark J

    2011-01-01

    The statistics profession is at a unique point in history. The need for valid statistical tools is greater than ever; data sets are massive, often measuring hundreds of thousands of measurements for a single subject. The field is ready to move towards clear objective benchmarks under which tools can be evaluated. Targeted learning allows (1) the full generalization and utilization of cross-validation as an estimator selection tool so that the subjective choices made by humans are now made by the machine, and (2) targeting the fitting of the probability distribution of the data toward the targe

  13. Carbon and nutrient export regimes from headwater catchments to downstream reaches

    Directory of Open Access Journals (Sweden)

    R. Dupas

    2017-09-01

    Full Text Available Excessive amounts of nutrients and dissolved organic matter in freshwater bodies affect aquatic ecosystems. In this study, the spatial and temporal variability in nitrate (NO3−, dissolved organic carbon (DOC and soluble reactive phosphorus (SRP was analyzed in the Selke (Germany river continuum from three headwaters draining 1–3 km2 catchments to two downstream reaches representing spatially integrated signals from 184–456 km2 catchments. Three headwater catchments were selected as archetypes of the main landscape units (land use  ×  lithology present in the Selke catchment. Export regimes in headwater catchments were interpreted in terms of NO3−, DOC and SRP land-to-stream transfer processes. Headwater signals were subtracted from downstream signals, with the differences interpreted in terms of in-stream processes and contributions from point sources. The seasonal dynamics for NO3− were opposite those of DOC and SRP in all three headwater catchments, and spatial differences also showed NO3− contrasting with DOC and SRP. These dynamics were interpreted as the result of the interplay of hydrological and biogeochemical processes, for which riparian zones were hypothesized to play a determining role. In the two downstream reaches, NO3− was transported almost conservatively, whereas DOC was consumed and produced in the upper and lower river sections, respectively. The natural export regime of SRP in the three headwater catchments mimicked a point-source signal (high SRP during summer low flow, which may lead to overestimation of domestic contributions in the downstream reaches. Monitoring the river continuum from headwaters to downstream reaches proved effective to jointly investigate land-to-stream and in-stream transport, and transformation processes.

  14. Water stress in global transboundary river basins: significance of upstream water use on downstream stress

    Science.gov (United States)

    Munia, H.; Guillaume, J. H. A.; Mirumachi, N.; Porkka, M.; Wada, Y.; Kummu, M.

    2016-01-01

    Growing population and water demand have increased pressure on water resources in various parts of the globe, including many transboundary river basins. While the impacts of upstream water use on downstream water availability have been analysed in many of these international river basins, this has not been systematically done at the global scale using coherent and comparable datasets. In this study, we aim to assess the change in downstream water stress due to upstream water use in the world’s transboundary river basins. Water stress was first calculated considering only local water use of each sub-basin based on country-basin mesh, then compared with the situation when upstream water use was subtracted from downstream water availability. We found that water stress was generally already high when considering only local water use, affecting 0.95-1.44 billion people or 33%-51% of the population in transboundary river basins. After accounting for upstream water use, stress level increased by at least 1 percentage-point for 30-65 sub-basins, affecting 0.29-1.13 billion people. Altogether 288 out of 298 middle-stream and downstream sub-basin areas experienced some change in stress level. Further, we assessed whether there is a link between increased water stress due to upstream water use and the number of conflictive and cooperative events in the transboundary river basins, as captured by two prominent databases. No direct relationship was found. This supports the argument that conflicts and cooperation events originate from a combination of different drivers, among which upstream-induced water stress may play a role. Our findings contribute to better understanding of upstream-downstream dynamics in water stress to help address water allocation problems.

  15. C, N, P export regimes from headwater catchments to downstream reaches

    Science.gov (United States)

    Dupas, R.; Musolff, A.; Jawitz, J. W.; Rao, P. S.; Jaeger, C. G.; Fleckenstein, J. H.; Rode, M.; Borchardt, D.

    2017-12-01

    Excessive amounts of nutrients and dissolved organic matter in freshwater bodies affect aquatic ecosystems. In this study, the spatial and temporal variability in nitrate (NO3), dissolved organic carbon (DOC) and soluble reactive phosphorus (SRP) was analyzed in the Selke river continuum from headwaters draining 1 - 3 km² catchments to downstream reaches representing spatially integrated signals from 184 - 456 km² catchments (part of TERENO - Terrestrial Environmental Observatories, in Germany). Three headwater catchments were selected as archetypes of the main landscape units (land use x lithology) present in the Selke catchment. Export regimes in headwater catchments were interpreted in terms of NO3, DOC and SRP land-to-stream transfer processes. Headwater signals were subtracted from downstream signals, with the differences interpreted in terms of in-stream processes and contribution of point-source emissions. The seasonal dynamics for NO3 were opposite those of DOC and SRP in all three headwater catchments, and spatial differences also showed NO3 contrasting with DOC and SRP. These dynamics were interpreted as the result of the interplay of hydrological and biogeochemical processes, for which riparian zones were hypothesized to play a determining role. In the two downstream reaches, NO3 was transported almost conservatively, whereas DOC was consumed and produced in the upper and lower river sections, respectively. The natural export regime of SRP in the three headwater catchments mimicked a point-source signal, which may lead to overestimation of domestic contributions in the downstream reaches. Monitoring the river continuum from headwaters to downstream reaches proved effective to investigate jointly land-to-stream and in-stream transport and transformation processes.

  16. Willingness of upstream and downstream resource managers to engage in compensation schemes for environmental services

    Directory of Open Access Journals (Sweden)

    Chapika Sangkapitux

    2009-04-01

    Full Text Available Providing compensation for agricultural conservation practices adopted by upstream farmers is still an alien concept in the Thai political context. The governance of common-pool natural resources, such as forest and water, has traditionally been under the control of powerful government line agencies, while the contribution of local communities to natural resource conservation have been hardly recognized by policy-makers. Drawing on a case study in Mae Sa watershed, Chiang Mai province, northern Thailand, this paper discusses the potential of developing compensation schemes in a socio-political context where upland farmers – mostly belonging to ethnic minority groups – tend to be considered a threat to the natural resource base rather than providers of environmental services. Based on data obtained from 371 households in the upstream communities and 151 households in the downstream communities of the watershed, upstream resource managers’ willingness to accept compensation for the conservation measures and downstream resource managers’ willingness to pay for water resource improvements were estimated through the use of choice experiments. Results from the study suggest that downstream resource managers would be willing to provide on average nearly 1% of their annual income for a substantial improvement of the quantity and quality of water resources, which could be achieved by compensating upstream farmers’ change of their agricultural systems towards more environment-friendly practices. Both willingness to pay of downstream respondents and willingness of upstream resource managers to accept compensation were positively correlated with age, education, participation in environmental conservation activities and previous experiences with droughts and/or erosion. The paper concludes that there is a clear potential for establishing compensation schemes for provision of environmental services in northern Thai watersheds. The important policy

  17. Carbon and nutrient export regimes from headwater catchments to downstream reaches

    Science.gov (United States)

    Dupas, Rémi; Musolff, Andreas; Jawitz, James W.; Rao, P. Suresh C.; Jäger, Christoph G.; Fleckenstein, Jan H.; Rode, Michael; Borchardt, Dietrich

    2017-09-01

    Excessive amounts of nutrients and dissolved organic matter in freshwater bodies affect aquatic ecosystems. In this study, the spatial and temporal variability in nitrate (NO3-), dissolved organic carbon (DOC) and soluble reactive phosphorus (SRP) was analyzed in the Selke (Germany) river continuum from three headwaters draining 1-3 km2 catchments to two downstream reaches representing spatially integrated signals from 184-456 km2 catchments. Three headwater catchments were selected as archetypes of the main landscape units (land use × lithology) present in the Selke catchment. Export regimes in headwater catchments were interpreted in terms of NO3-, DOC and SRP land-to-stream transfer processes. Headwater signals were subtracted from downstream signals, with the differences interpreted in terms of in-stream processes and contributions from point sources. The seasonal dynamics for NO3- were opposite those of DOC and SRP in all three headwater catchments, and spatial differences also showed NO3- contrasting with DOC and SRP. These dynamics were interpreted as the result of the interplay of hydrological and biogeochemical processes, for which riparian zones were hypothesized to play a determining role. In the two downstream reaches, NO3- was transported almost conservatively, whereas DOC was consumed and produced in the upper and lower river sections, respectively. The natural export regime of SRP in the three headwater catchments mimicked a point-source signal (high SRP during summer low flow), which may lead to overestimation of domestic contributions in the downstream reaches. Monitoring the river continuum from headwaters to downstream reaches proved effective to jointly investigate land-to-stream and in-stream transport, and transformation processes.

  18. Water Stress in Global Transboundary River Basins: Significance of Upstream Water Use on Downstream Stress

    Science.gov (United States)

    Munia, H.; Guillaume, J. H. A.; Mirumachi, N.; Porkka,M.; Wada, Yoshihide; Kummu, M.

    2016-01-01

    Growing population and water demand have increased pressure on water resources in various parts of the globe, including many transboundary river basins. While the impacts of upstream water use on downstream water availability have been analyzed in many of these international river basins, this has not been systematically done at the global scale using coherent and comparable datasets. In this study, we aim to assess the change in downstream water stress due to upstream water use in the world's transboundary river basins. Water stress was first calculated considering only local water use of each sub-basin based on country-basin mesh, then compared with the situation when upstream water use was subtracted from downstream water availability. Wefound that water stress was generally already high when considering only local water use, affecting 0.95-1.44 billion people or 33%-51% of the population in transboundary river basins. After accounting for upstream water use, stress level increased by at least 1 percentage-point for 30-65 sub-basins, affecting 0.29-1.13 billion people. Altogether 288 out of 298 middle-stream and downstream sub-basin areas experienced some change in stress level. Further, we assessed whether there is a link between increased water stress due to upstream water use and the number of conflictive and cooperative events in the transboundary river basins, as captured by two prominent databases. No direct relationship was found. This supports the argument that conflicts and cooperation events originate from a combination of different drivers, among which upstream-induced water stress may play a role. Our findings contribute to better understanding of upstream-downstream dynamics in water stress to help address water allocation problems.

  19. CONCENTRATION LEVELS OF ESSENTIAL AND NON-ESSENTIAL ...

    African Journals Online (AJOL)

    Preferred Customer

    non-essential elements (K, Mg, Ca, Na, Fe, Zn, Mn, Cu, Cr, Co, Ni, Cd, and Pb) in the export quality Ethiopian red and white wines (Axumite red wine, Gouder red wine, Awash Crystal white wine, and Kemila white wine), (ii) compare the levels of minerals among the four brands of wines, and (iii) compare the levels of ...

  20. Levels of essential and non-essential elements in commercially ...

    African Journals Online (AJOL)

    The focus of this study was to assess the quality of commercially packaged moringa tea brands available in the retail markets in Nigerian cities on the basis of the essential and nonessential elemental content in their tissues. Four different brands of moringa tea comprising two locally processed teas and two imported teas ...

  1. Theological Compatibilism and Essential Properties

    Directory of Open Access Journals (Sweden)

    Nicola Ciprotti

    2008-03-01

    Full Text Available Alvin Plantinga defends Theological Compatibilism (TC and Essentialism about property possession (E. TC is the claim that human freedom to act otherwise and God's essential omniscience are compatible, while E is the claim that every individual entity whatsoever has a modal profile consisting in having both essential and accidental properties. I purport to show that, if E is assumed in the argument for TC, then the latter leads to a very puzzling upshot. I also intend to show that, even if TC is suitably fixed in order to avoid that upshot, TC is still unconvincing in that it merges into one the de re and the de dicto rendering of 'human freedom to act otherwise'; I end up by briefly sketching why the two renderings should instead be kept well apart.

  2. Emergence and evolutionary analysis of the human DDR network: implications in comparative genomics and downstream analyses.

    Science.gov (United States)

    Arcas, Aida; Fernández-Capetillo, Oscar; Cases, Ildefonso; Rojas, Ana M

    2014-04-01

    The DNA damage response (DDR) is a crucial signaling network that preserves the integrity of the genome. This network is an ensemble of distinct but often overlapping subnetworks, where different components fulfill distinct functions in precise spatial and temporal scenarios. To understand how these elements have been assembled together in humans, we performed comparative genomic analyses in 47 selected species to trace back their emergence using systematic phylogenetic analyses and estimated gene ages. The emergence of the contribution of posttranslational modifications to the complex regulation of DDR was also investigated. This is the first time a systematic analysis has focused on the evolution of DDR subnetworks as a whole. Our results indicate that a DDR core, mostly constructed around metabolic activities, appeared soon after the emergence of eukaryotes, and that additional regulatory capacities appeared later through complex evolutionary process. Potential key posttranslational modifications were also in place then, with interacting pairs preferentially appearing at the same evolutionary time, although modifications often led to the subsequent acquisition of new targets afterwards. We also found extensive gene loss in essential modules of the regulatory network in fungi, plants, and arthropods, important for their validation as model organisms for DDR studies.

  3. Essential Medicines in a High Income Country: Essential to Whom?

    Science.gov (United States)

    Duong, Mai; Moles, Rebekah J; Chaar, Betty; Chen, Timothy F

    2015-01-01

    To explore the perspectives of a diverse group of stakeholders engaged in medicines decision making around what constitutes an "essential" medicine, and how the Essential Medicines List (EML) concept functions in a high income country context. In-depth qualitative semi-structured interviews were conducted with 32 Australian stakeholders, recognised as decision makers, leaders or advisors in the area of medicines reimbursement or supply chain management. Participants were recruited from government, pharmaceutical industry, pharmaceutical wholesale/distribution companies, medicines non-profit organisations, academic health disciplines, hospitals, and consumer groups. Perspectives on the definition and application of the EML concept in a high income country context were thematically analysed using grounded theory approach. Stakeholders found it challenging to describe the EML concept in the Australian context because many perceived it was generally used in resource scarce settings. Stakeholders were unable to distinguish whether nationally reimbursed medicines were essential medicines in Australia. Despite frequent generic drug shortages and high prices paid by consumers, many struggled to describe how the EML concept applied to Australia. Instead, broad inclusion of consumer needs, such as rare and high cost medicines, and consumer involvement in the decision making process, has led to expansive lists of nationally subsidised medicines. Therefore, improved communication and coordination is needed around shared interests between stakeholders regarding how medicines are prioritised and guaranteed in the supply chain. This study showed that decision-making in Australia around reimbursement of medicines has strayed from the fundamental utilitarian concept of essential medicines. Many stakeholders involved in medicine reimbursement decisions and management of the supply chain did not consider the EML concept in their approach. The wide range of views of what stakeholders

  4. Essential Medicines in a High Income Country: Essential to Whom?

    Directory of Open Access Journals (Sweden)

    Mai Duong

    Full Text Available To explore the perspectives of a diverse group of stakeholders engaged in medicines decision making around what constitutes an "essential" medicine, and how the Essential Medicines List (EML concept functions in a high income country context.In-depth qualitative semi-structured interviews were conducted with 32 Australian stakeholders, recognised as decision makers, leaders or advisors in the area of medicines reimbursement or supply chain management. Participants were recruited from government, pharmaceutical industry, pharmaceutical wholesale/distribution companies, medicines non-profit organisations, academic health disciplines, hospitals, and consumer groups. Perspectives on the definition and application of the EML concept in a high income country context were thematically analysed using grounded theory approach.Stakeholders found it challenging to describe the EML concept in the Australian context because many perceived it was generally used in resource scarce settings. Stakeholders were unable to distinguish whether nationally reimbursed medicines were essential medicines in Australia. Despite frequent generic drug shortages and high prices paid by consumers, many struggled to describe how the EML concept applied to Australia. Instead, broad inclusion of consumer needs, such as rare and high cost medicines, and consumer involvement in the decision making process, has led to expansive lists of nationally subsidised medicines. Therefore, improved communication and coordination is needed around shared interests between stakeholders regarding how medicines are prioritised and guaranteed in the supply chain.This study showed that decision-making in Australia around reimbursement of medicines has strayed from the fundamental utilitarian concept of essential medicines. Many stakeholders involved in medicine reimbursement decisions and management of the supply chain did not consider the EML concept in their approach. The wide range of views of

  5. Analgesic Potential of Essential Oils

    Directory of Open Access Journals (Sweden)

    José Ferreira Sarmento-Neto

    2015-12-01

    Full Text Available Pain is an unpleasant sensation associated with a wide range of injuries and diseases, and affects approximately 20% of adults in the world. The discovery of new and more effective drugs that can relieve pain is an important research goal in both the pharmaceutical industry and academia. This review describes studies involving antinociceptive activity of essential oils from 31 plant species. Botanical aspects of aromatic plants, mechanisms of action in pain models and chemical composition profiles of the essential oils are discussed. The data obtained in these studies demonstrate the analgesic potential of this group of natural products for therapeutic purposes.

  6. Tank farms essential drawing plan

    International Nuclear Information System (INIS)

    Domnoske-Rauch, L.A.

    1998-01-01

    The purpose of this document is to define criteria for selecting Essential Drawings, Support Drawings, and Controlled Print File (CPF) drawings and documents for facilities that are part of East and West Tank Farms. Also, the drawings and documents that meet the criteria are compiled separate listings. The Essential Drawing list and the Support Drawing list establish a priority for updating technical baseline drawings. The CPF drawings, denoted by an asterisk (*), defined the drawings and documents that Operations is required to maintain per the TWRS Administration Manual. The Routing Boards in Buildings 272-WA and 272-AW are not part of the CPF

  7. Essential oils in broiler nutrition

    NARCIS (Netherlands)

    Lee, Kyung-woo

    2002-01-01

    Dietary antibiotics at low, subtherapeutic levels have been shown to improve growth performance in farm animals. However, there is a trend to look for alternatives to dietary antibiotics, due to occurrence of antibiotic-resistance bacteria. The present thesis explored the essential oils as the

  8. Essentialism, hybridism and cultural critique

    DEFF Research Database (Denmark)

    Frello, Birgitta

    2007-01-01

    , culture or whatever. The purpose of focusing on concepts of transgression is usually to try to develop conceptual spaces within which it is possible to grasp and to study cultural identity without resorting to cultural essentialism. These attempts open up new possibilities but also new problems - e...

  9. Essential Ideas for Healthy Childhoods

    Science.gov (United States)

    Exchange: The Early Childhood Leaders' Magazine Since 1978, 2012

    2012-01-01

    This article presents essential ideas from various people on how to cultivate healthy childhood. Amelia Gambetti says that in terms of young children, the element of complexity offers to them the possibility to have an opportunity to learn how to think and to generate ideas. Diane Levin shares how a three-year-old kid taught her that children do…

  10. Essential French Vocabulary Teach Yourself

    CERN Document Server

    Saint-Thomas, Noel

    2010-01-01

    Essential French Vocabulary is the course for you if you need help with your study of French. This fully revised edition of our best-selling course now comes with free downloadable audio support containing hints on how to learn vocabulary effectively.

  11. Hyper-V Replica essentials

    CERN Document Server

    Krstevski, Vangel

    2013-01-01

    a in various deployment scenarios.Hyper-V Replica Essentials is for Windows Server administrators who want to improve their system availability and speed up disaster recovery. You will need experience in Hyper-V deployment because Hyper-V Replica is built in the Hyper-V platform.

  12. Intellectual Workers and Essential Freedoms.

    Science.gov (United States)

    Edley, Christopher Jr.

    2000-01-01

    Journalists and college professors deserve certain privileges, including freedom of speech and academic freedom, but they must adapt their work to increasingly diverse populations. They must confront public mistrust, convince people that these freedoms are worthwhile, and protect essential public rights through what they study and teach and to…

  13. Essentials of supply chain management

    CERN Document Server

    Hugos, Michael H

    2011-01-01

    The latest thinking, strategies, developments, and technologies to stay current in supply chain management Presenting the core concepts and techniques of supply chain management in a clear, concise and easily readable style, the Third Edition of Essentials of Supply Chain Management outlines the most crucial tenets and concepts of supply chain management.

  14. Essential Medicines in National Constitutions

    Science.gov (United States)

    Toebes, Brigit; Hogerzeil, Hans

    2016-01-01

    Abstract A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states’ legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions. PMID:27781006

  15. Storage and source of polycyclic aromatic hydrocarbons in sediments downstream of a major coal district in France.

    Science.gov (United States)

    Bertrand, O; Mondamert, L; Grosbois, C; Dhivert, E; Bourrain, X; Labanowski, J; Desmet, M

    2015-12-01

    During the 20th century, the local economy of the Upper Loire Basin (ULB) was essentially based on industrial coal mining extraction. One of the major French coal districts with associated urban/industrial activities and numerous coking/gas plants were developed in the Ondaine-Furan subbasins, two tributaries of the upper Loire main stream. To determine the compositional assemblage, the level and the potential sources of contamination, the historical sedimentary chronicle of the 16 US EPA priority polycyclic aromatic hydrocarbons (PAHs) has been investigated. PAH concentrations were determined using gas chromatography/mass spectrometry (GC/MS) in a dated core, sampled in the Villerest flood-control reservoir located downstream of the Ondaine-Furan corridor (OFC). The most contaminated sediments were deposited prior to 1983 (Σ16PAHs ca. 4429-13,348 ng/g) and during flood events (Σ16PAHs ca. 6380 ng/g - 1996 flood; 5360 ng/g - 2003 flood; 6075 ng/g - 2008 flood), especially in medium and high molecular weight PAHs. Among them, typical pyrogenic PAHs such as FLT, PYR, BbF and BaP were prevalent in most of the core samples. In addition, some PAHs last decade data is available from the Loire Bretagne Water Agency and were analyzed using high-performance liquid chromatography with postcolumn fluorescence derivatization (HPLC/FLD). These results confirm that the most highly contaminated sediments were found downstream of OFC (Σ16PAHs ca. 2264-7460 ng/g). According to the observed molecular distribution, PAHs are originated largely from high-temperature pyrolytic processes. Major sources of pyrogenic PAHs have been emphasized by calculation of specific ratios and by comparison to reported data. Atmospheric deposition of urban and industrial areas, wood combustion and degraded coal tar derived from former factories of coking/gas plants seem to be the major pyrogenic sources. Specifically, particular solid transport conditions that can occur during major flood

  16. Rapid downstream discharge attenuation during recent Icelandic jökulhlaups

    Science.gov (United States)

    Russell, A. J.; Roberts, M. J.; Tweed, F. S.; Knudsen, Ó.; Harris, T. D.; Rushmer, E. L.; Marren, P. M.; Carrivick, J. L.

    2003-04-01

    Little attention has been paid to downstream discharge attenuation during glacier outburst floods (jökulhlaups). In non-glacial environments, floods resulting from dam failure exhibit major downstream reduction of peak discharge. Transmission losses within ephemeral rivers are also well-known for generating large reductions in peak discharge. We report on three recent jökulhlaups associated with major downstream discharge attenuation: (1) Sólheimajökull July 1999; (2) Kverkjökull January 2002; and (3) Tungnaárjökull July 2002. Peak discharges calculated using slope area techniques showed that the 1999 Sólheimahlaup decreased in discharge from 4400 m^3s-1 to 1700 m^3s-1 over a downstream distance of less than 7 km. The Kverkhlaup attenuated from 1700 m^3s-1 to 400 m^3s-1 over a 40 km distance. The July 2002 jökulhlaup peak discharge attenuated from 1300--1700 m^3s-1 at Tungnaárjökull to 600 m^3s-1 over a 23 km distance. The drainage of warm water during these three jökulhlaups is thought to have resulted in a characteristic sudden, short-lived, rise to peak discharge. For the 1999 Sólheimahlaup the hydrograph peak was enhanced by a wave-like burst from a flood-filled ice-dammed lake basin. Transmission losses into permeable outwash plains and flow through high resistance bedrock (lava) and braided channels is effective in damping jökulhlaup peak discharge. Our study of three recent Icelandic jökulhlaups illustrates the operation of major downstream peak of flood discharge attenuation within glaciated volcanic settings. Downstream reductions of peak jökulhlaup discharge have important implications for proglacial geomorphology and sedimentology, and for flood hazard management. In order to provide a true hydrograph record, reconstruction or gauging of jökulhlaup peak discharges needs to be carried out as close to glacier margins as possible. This will permit better understanding of jökulhlaup drainage mechanisms and provide a sound basis for

  17. Flow and mass transfer downstream of an orifice under flow accelerated corrosion conditions

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Wael H., E-mail: ahmedw@kfupm.edu.sa [Department of Mechanical Engineering, King Fahd University of Petroleum and Minerals (KFUPM), P.O. Box 874, Dhahran 31261 (Saudi Arabia); Bello, Mufatiu M.; El Nakla, Meamer; Al Sarkhi, Abdelsalam [Department of Mechanical Engineering, King Fahd University of Petroleum and Minerals (KFUPM), P.O. Box 874, Dhahran 31261 (Saudi Arabia)

    2012-11-15

    Highlights: Black-Right-Pointing-Pointer Mass transfer downstream of orifices was numerically and experimentally investigated. Black-Right-Pointing-Pointer The surface wear pattern is measured and used to validate the present numerical results. Black-Right-Pointing-Pointer The maximum mass transfer coefficient found to occur at approximately 2-3 pipe diameters downstream of the orifice. Black-Right-Pointing-Pointer The FAC wear rates were correlated with the turbulence kinetic energy and wall mass transfer in terms of Sherwood number. Black-Right-Pointing-Pointer The current study offered very useful information for FAC engineers for better preparation of nuclear plant inspection scope. - Abstract: Local flow parameters play an important role in characterizing flow accelerated corrosion (FAC) downstream of sudden area change in power plant piping systems. Accurate prediction of the highest FAC wear rate locations enables the mitigation of sudden and catastrophic failures, and the improvement of the plant capacity factor. The objective of the present study is to evaluate the effect of the local flow and mass transfer parameters on flow accelerated corrosion downstream of an orifice. In the present study, orifice to pipe diameter ratios of 0.25, 0.5 and 0.74 were investigated numerically by solving the continuity and momentum equations at Reynolds number of Re = 20,000. Laboratory experiments, using test sections made of hydrocal (CaSO{sub 4}{center_dot} Vulgar-Fraction-One-Half H{sub 2}O) were carried out in order to determine the surface wear pattern and validate the present numerical results. The numerical results were compared to the plants data as well as to the present experiments. The maximum mass transfer coefficient found to occur at approximately 2-3 pipe diameters downstream of the orifice. This location was also found to correspond to the location of elevated turbulent kinetic energy generated within the flow separation vortices downstream of the orifice

  18. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    International Nuclear Information System (INIS)

    Kim, Kyung-Chang; Kim, Hyeon Guk; Roh, Tae-Young; Park, Jihwan; Jung, Kyung-Min; Lee, Joo-Shil; Choi, Sang-Yun; Kim, Sung Soon; Choi, Byeong-Sun

    2011-01-01

    Research highlights: → CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. → CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. → HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. → H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. → HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56 Lck , ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56 Lck , ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.

  19. Target RNA capture and cleavage by the Cmr type III-B CRISPR-Cas effector complex.

    Science.gov (United States)

    Hale, Caryn R; Cocozaki, Alexis; Li, Hong; Terns, Rebecca M; Terns, Michael P

    2014-11-01

    The effector complex of the Cmr/type III-B CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated) system cleaves RNAs recognized by the CRISPR RNA (crRNA) of the complex and includes six protein subunits of unknown functions. Using reconstituted Pyrococcus furiosus Cmr complexes, we found that each of the six Cmr proteins plays a critical role in either crRNA interaction or target RNA capture. Cmr2, Cmr3, Cmr4, and Cmr5 are all required for formation of a crRNA-containing complex detected by native gel electrophoresis, and the conserved 5' repeat sequence tag and 5'-OH group of the crRNA are essential for the interaction. Interestingly, capture of the complementary target RNA additionally requires both Cmr1 and Cmr6. In detailed functional studies, we determined that P. furiosus Cmr complexes cleave target RNAs at 6-nucleotide (nt) intervals in the region of complementarity, beginning 5 nt downstream from the crRNA tag and continuing to within ∼14 nt of the 3' end of the crRNA. Our findings indicate that Cmr3 recognizes the signature crRNA tag sequence (and depends on protein-protein interactions with Cmr2, Cmr4, and Cmr5), each Cmr4 subunit mediates a target RNA cleavage, and Cmr1 and Cmr6 mediate an essential interaction between the 3' region of the crRNA and the target RNA. © 2014 Hale et al.; Published by Cold Spring Harbor Laboratory Press.

  20. Direct enantiomeric analysis of Mentha essential oils.

    Science.gov (United States)

    Barba, Carmen; Santa-María, Guillermo; Herraiz, Marta; Martínez, Rosa M

    2013-11-01

    A rapid and fully automated screening of chiral compounds in essential oils, aimed to the selection of natural sources of pure enantiomers of limonene and carvone, is performed by using on-line coupled reversed phase liquid chromatography with gas chromatography and mass spectrometry (RPLC-GC-MS). Essential oils obtained from Mentha spicata and Mentha piperita were analysed by direct injection into RPLC. The reported procedure includes fractionation and clean-up in RPLC, selection of the fraction to be transferred from RPLC to GC, trapping and concentration of the target compounds in the interface, thermal desorption and, finally, enantiomeric resolution and identification of chiral compounds by GC-MS. The presence of (S)-limonene and (R)-carvone as the unique enantiomeric forms existing for both compounds could be unambiguously established by transferring different volume fractions from RPLC to GC. Data obtained demonstrate high separation efficiency and well tunable selectivity in the on-line coupled RPLC-GC-MS analysis of chiral compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Relative impact of amyloid-β, lacunes, and downstream imaging markers on cognitive trajectories.

    Science.gov (United States)

    Kim, Hee Jin; Yang, Jin Ju; Kwon, Hunki; Kim, Changsoo; Lee, Jong Min; Chun, Phillip; Kim, Yeo Jin; Jung, Na-Yeon; Chin, Juhee; Kim, Seonwoo; Woo, Sook-Young; Choe, Yearn Seong; Lee, Kyung-Han; Kim, Sung Tae; Kim, Jae Seung; Lee, Jae Hong; Weiner, Michael W; Na, Duk L; Seo, Sang Won

    2016-09-01

    SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness

  2. IMPACT (Imaging and Molecular Markers for Patients with Lung Cancer: Approaches with Molecular Targets and Complementary, Innovative and Therapeutic Modalities)

    National Research Council Canada - National Science Library

    Hong, Waun K; Herbst, Roy

    2008-01-01

    The projects in this proposal specifically target several signal transduction pathways known to be critical for NSCLC pathogenesis including the EGFR pathway and the more downstream ras/raf/Mek/ERK pathway...

  3. IMPACT (Imaging and Molecular Markers for Patients with Lung Cancer: Approaches with Molecular Targets and Complementary, Innovative and Therapeutic Modalities)

    National Research Council Canada - National Science Library

    Hong, Waun Ki; Herbst, Roy

    2006-01-01

    The projects in this proposal specifically target several signal transduction pathways known to be critical for NSCLC pathogenesis including the EGFR pathway and the more downstream ras/raf/Mek/ERK pathway...

  4. IMPACT (Imaging and Molecular Markers for Patients with Lung Cancer: Approaches with Molecular Targets and Complementary, Innovative and Therapeutic Modalities)

    National Research Council Canada - National Science Library

    Hong, Waun K; Herbst, Roy

    2007-01-01

    The projects in this proposal specifically target several signal transduction pathways known to be critical for NSCLC pathogenesis including the EGFR pathway and the more downstream ras/raf/Mek/ERK pathway...

  5. Designing an Autonomous Integrated Downstream Sequence From a Batch Separation Process - An Industrial Case Study.

    Science.gov (United States)

    Löfgren, Anton; Andersson, Niklas; Sellberg, Anton; Nilsson, Bernt; Löfgren, Magnus; Wood, Susanne

    2017-12-16

    This work is a proof of concept of how a sequence of industrial batch separation steps together are used to form an integrated autonomous downstream process. The sequence in this case study consisted of an anion chromatography step, virus inactivation and finally a hydrophobic chromatography step. Moving from batch to integrated separation minimizes hold-up times, storage tanks, and required equipment. The conversion from batch to integrated mode is achieved by extracting operating points and separation data from batch chromatograms. The integrated separation process is realized on an ÄKTA Pure controlled by an open research software called Orbit, making it possible to operate complex process configurations including multiple steps. The results from this case study is the principle and method of the steps taken to automation, achieving a more continuous and efficient downstream process. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Gene expression programming for prediction of scour depth downstream of sills

    Science.gov (United States)

    Azamathulla, H. Md.

    2012-08-01

    SummaryLocal scour is crucial in the degradation of river bed and the stability of grade control structures, stilling basins, aprons, ski-jump bucket spillways, bed sills, weirs, check dams, etc. This short communication presents gene-expression programming (GEP), which is an extension to genetic programming (GP), as an alternative approach to predict scour depth downstream of sills. Published data were compiled from the literature for the scour depth downstream of sills. The proposed GEP approach gives satisfactory results (R2 = 0.967 and RMSE = 0.088) compared to the existing predictors (Chinnarasri and Kositgittiwong, 2008) with R2 = 0.87 and RMSE = 2.452 for relative scour depth.

  7. A novel cell autolysis system for cost-competitive downstream processing.

    Science.gov (United States)

    Hajnal, Ivan; Chen, Xiangbin; Chen, Guo-Qiang

    2016-11-01

    The industrial production of low value-added biological products poses significant challenges due to cost pressures. In recent years, it has been argued that synthetic biology approaches will lead to breakthroughs that eliminate price bottlenecks for the production of a wide range of biological products including bioplastics and biofuels. One significant bottleneck lies in the necessity to break the tough cell walls of microbes in order to release intracellular products. We here report the implementation of the first synthetic biology standard part based on the lambda phage SRRz genes and a synthetic ribosome binding site (RBS) that works in Escherichia coli and Halomonas campaniensis, which enables the producer strains to induce lysis after the addition of small amounts (1-5 %) of solvents or to spontaneously lyse during the stresses of downstream processing, and thus has the potential to eliminate the mechanical cell disruption step as both an efficiency bottleneck and a significant capex barrier when implementing downstream bioprocesses.

  8. Analysis of velocity fluctuations downstream of a bileaflet mechanical heart valve

    Science.gov (United States)

    Forleo, Marcio; Dasi, Lakshmi

    2010-11-01

    Bileaflet mechanical heart valves are widely used to replace diseased aortic heart valves. The stresses induced by the rich and unsteady non-physiological flow structures have been the focus to evaluate red blood cells damage and platelet activation, develop flow control strategies, or improve valve designs. In this study, we analyzed the flow fields obtained downstream of a bileaflet mechanical heart valve using time-resolved particle image velocimetry under pulsatile and steady flow conditions. Our study demonstrates the rich dynamics downstream of the valve and weighs the relevance of unsteady effects vs inertia effects on the different flow structures. Power spectrum analyses of the turbulent fluctuations highlight the highly anisotropic influence and the limited applicability of classical self-similar turbulence theory in describing the small-scale structures in the immediate vicinity of the valve.

  9. Beam Halo on the LHC TCDQ Diluter System and Thermal Load on the Downstream Superconducting Magnets

    CERN Document Server

    Goddard, B; Presland, A; Redaelli, S; Robert-Démolaize, G; Sarchiapone, L; Weiler, T; Weterings, W

    2006-01-01

    The moveable single-jawed graphite TCDQ diluter must be positioned very close to the circulating LHC beam in order to prevent damage to downstream components in the event of an unsynchronised beam abort. A two-jawed graphite TCS.IR6 collimator forms part of the TCDQ system. The requirement to place the jaws close to the beam means that the system can intercept a substantial beam halo load. Initial investigations indicated a worryingly high heat load on the Q4 coils. This paper presents the updated load cases, shielding and simulation geometry, and the results of simulations of the energy deposition in the TCDQ system and in the downstream superconducting Q4 magnet. The implications for the operation of the LHC are discussed.

  10. Method validation for preparing urine samples for downstream proteomic and metabolomic applications.

    OpenAIRE

    Ammerlaan, Wim; Trezzi, Jean-Pierre; Mathay, Conny; Hiller, Karsten; Betsou, Fay

    2014-01-01

    BACKGROUND: Formal validation of methods for biospecimen processing in the context of accreditation in laboratories and biobanks is lacking. A protocol for processing of a biospecimen (urine) was validated for fitness-for-purpose in terms of key downstream endpoints. METHODS: Urine processing was optimized for centrifugation conditions on the basis of microparticle counts at room temperature (RT) and at 4 degrees C. The optimal protocol was validated for performance (microparticle counts), an...

  11. Road Freight Logistics, Competition and Innovation : Downstream Benefits and Policy Implications

    OpenAIRE

    Dutz, Mark

    2005-01-01

    This empirical paper sheds light on a significant element of the debate of whether infrastructure services have a strong impact on economic development by exploring the impact of innovative road freight services on downstream business users. The paper uses a new and purpose-specific survey of 165 logistics service providers and 493 user enterprises in food processing, food distribution, and the automotive industry in the Czech Republic, Hungary, and Poland. The main findings are that there ar...

  12. Suitability of air sampling locations downstream of bends and static mixing elements.

    Science.gov (United States)

    McFarland, A R; Gupta, R; Anand, N K

    1999-12-01

    The revised standard for sampling effluent air from stacks and ducts of the nuclear industry places limits on the non-uniformity of velocity and contaminant profiles at the sampling location; namely, the coefficients of variation must not exceed 20% over an area that encompasses at least the center 2/3 of the cross sectional area. Tests were conducted to characterize the degree of mixing at downstream locations as affected by several types of flow disturbances, including 90 degree elbows and commercial static mixing devices. Flow straighteners were incorporated into the ducting upstream of the mixer to be tested to simulate the dampening of flow turbulence that might occur because of upstream HEPA filters. The coefficients of variation of velocity and tracer gas concentration measured in a straight tube at a distance of 3 diameters downstream from a 90 degree elbow were 17% and 69%, respectively. The mixing is impacted by the upstream flow turbulence. Without a flow straightener, the tracer gas concentration coefficient of variation was reduced to 33% at the 3-diameter location. The use of static mixing elements can greatly enhance the mixing process. A ring placed just downstream of a 90 degree elbow, which blocks the outer 56% of the cross sectional area, results in a coefficient of variation of 19% for tracer gas concentration at the 3-diameter location. Pressure loss across the elbow with the ring is about nine times that of the basic elbow. One of the commercially available static mixers provides coefficients of variation that are less than 10% for both velocity and tracer gas concentration at 4 diameters downstream from the mixer with a pressure loss that is only about 3.5 times as large as that of a 90 degree elbow.

  13. Preliminary Experimental Results on the Technique of Artificial River Replenishment to Mitigate Sediment Loss Downstream Dams

    Science.gov (United States)

    Franca, M. J.; Battisacco, E.; Schleiss, A. J.

    2014-12-01

    The transport of sediments by water throughout the river basins, from the steep slopes of the upstream regions to the sea level, is recognizable important to keep the natural conditions of rivers with a role on their ecology processes. Over the last decades, a reduction on the supply of sand and gravel has been observed downstream dams existing in several alpine rivers. Many studies highlight that the presence of a dam strongly modifies the river behavior in the downstream reach, in terms of morphology and hydrodynamics, with consequences on local ecology. Sediment deficit, bed armoring, river incision and bank instability are the main effects which affect negatively the aquatic habitats and the water quality. One of the proposed techniques to solve the problem of sediment deficit downstream dams, already adopted in few Japanese and German rivers although on an unsatisfactory fashion, is the artificial replenishment of these. Generally, it was verified that the erosion of the replenishments was not satisfactory and the transport rate was not enough to move the sediments to sufficient downstream distances. In order to improve and to provide an engineering answer to make this technique more applicable, a series of laboratory tests are ran as preparatory study to understand the hydrodynamics of the river flow when the replenishment technique is applied. Erodible volumes, with different lengths and submergence conditions, reproducing sediment replenishments volumes, are positioned along a channel bank. Different geometrical combinations of erodible sediment volumes are tested as well on the experimental flume. The first results of the experimental research, concerning erosion time evolution, the influence of discharge and the distance travelled by the eroded sediments, will be presented and discussed.

  14. Wave propagation downstream of a high power helicon in a dipolelike magnetic field

    International Nuclear Information System (INIS)

    Prager, James; Winglee, Robert; Roberson, B. Race; Ziemba, Timothy

    2010-01-01

    The wave propagating downstream of a high power helicon source in a diverging magnetic field was investigated experimentally. The magnetic field of the wave has been measured both axially and radially. The three-dimensional structure of the propagating wave is observed and its wavelength and phase velocity are determined. The measurements are compared to predictions from helicon theory and that of a freely propagating whistler wave. The implications of this work on the helicon as a thruster are also discussed.

  15. Location Specificity and the Transferability of Downstream Assets to Foreign Subsidiaries

    OpenAIRE

    Jaideep Anand; Andrew Delios

    1997-01-01

    We investigate the effect of firm-specific advantages being ‘local’ in scope, and the influence of subsequent location-specific disadvantages, on the choice of foreign entry mode and subsidiary performance. To look into this issue, we examine Japanese FDI data from the wholesale and retail industries – two sectors that have productive activity concentrated in downstream processes and location-bound resources. Our theoretical and empirical analyses demonstrate that, in situations where require...

  16. SWAT Model Prediction of Phosphorus Loading in a South Carolina Karst Watershed with a Downstream Embayment

    Science.gov (United States)

    Devendra M. Amatya; Manoj K. Jha; Thomas M. Williams; Amy E. Edwards; Daniel R.. Hitchcock

    2013-01-01

    The SWAT model was used to predict total phosphorus (TP) loadings for a 1555-ha karst watershed—Chapel Branch Creek (CBC)—which drains to a lake via a reservoir-like embayment (R-E). The model was first tested for monthly streamflow predictions from tributaries draining three potential source areas as well as the downstream R-E, followed by TP loadings using data...

  17. Transcriptomic effects-based monitoring for endocrine active chemicals: Assessing relative contribution of treated wastewater to downstream pollution

    Science.gov (United States)

    Martinovic-Weigelt, Dalma; Mehinto, Alvine C.; Ankley, Gerald T.; Denslow, Nancy D.; Barber, Larry B.; Lee, Kathy E.; King, Ryan J.; Schoenfuss, Heiko L.; Schroeder, Anthony L.; Villeneuve, Daniel L.

    2014-01-01

    The present study investigated whether a combination of targeted analytical chemistry information with unsupervised, data-rich biological methodology (i.e., transcriptomics) could be utilized to evaluate relative contributions of wastewater treatment plant (WWTP) effluents to biological effects. The effects of WWTP effluents on fish exposed to ambient, receiving waters were studied at three locations with distinct WWTP and watershed characteristics. At each location, 4 d exposures of male fathead minnows to the WWTP effluent and upstream and downstream ambient waters were conducted. Transcriptomic analyses were performed on livers using 15 000 feature microarrays, followed by a canonical pathway and gene set enrichment analyses. Enrichment of gene sets indicative of teleost brain–pituitary–gonadal–hepatic (BPGH) axis function indicated that WWTPs serve as an important source of endocrine active chemicals (EACs) that affect the BPGH axis (e.g., cholesterol and steroid metabolism were altered). The results indicated that transcriptomics may even pinpoint pertinent adverse outcomes (i.e., liver vacuolization) and groups of chemicals that preselected chemical analytes may miss. Transcriptomic Effects-Based monitoring was capable of distinguishing sites, and it reflected chemical pollution gradients, thus holding promise for assessment of relative contributions of point sources to pollution and the efficacy of pollution remediation.

  18. Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Mehdi Hayat Shahi

    Full Text Available The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.

  19. β-Arrestin Mediates β1-Adrenergic Receptor-Epidermal Growth Factor Receptor Interaction and Downstream Signaling*

    Science.gov (United States)

    Tilley, Douglas G.; Kim, Il-Man; Patel, Priyesh A.; Violin, Jonathan D.; Rockman, Howard A.

    2009-01-01

    β1-Adrenergic receptor (β1AR) stimulation confers cardioprotection via β-arrestin-de pend ent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the β1AR and EGFR form a complex that differentially directs intracellular signaling pathways. β1AR stimulation and EGF ligand can each induce equivalent EGFR phos pho ryl a tion, internalization, and downstream activation of ERK1/2, but only EGF ligand causes translocation of activated ERK to the nucleus, whereas β1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. β1AR and EGFR are shown to interact as a receptor complex both in cell culture and endogenously in human heart, an interaction that is selective and undergoes dynamic regulation by ligand stimulation. Although catecholamine stimulation mediates the retention of β1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of β1AR with EGFR following activation is dependent upon C-terminal tail GRK phos pho ryl a tion sites of the β1AR and recruitment of β-arrestin. These data reveal a new signaling paradigm in which β-arrestin is required for the maintenance of a β1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation. PMID:19509284

  20. Hydrological Effects of Chashm Dam on the Downstream of Talar River Watershed

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Khaleghi

    2017-02-01

    Full Text Available Introduction: In the last century, dams have constructed with the objective of water supplies for agriculture, drinking water and industry. However, the results from the performance review of dams show adverse effects on the downstream environment and the availability of water resources. The purpose of the Chashm dam construction on the TalarRiver's tributaries is the water supply for Semnan city. Materials and Methods: This study was conducted in TalarRiver watershed. TalarRiveroriginatesfrom AlborzMountains in Mazandaran province, in the southern Caspian Sea basin, in north of Iran and flows parallel with the Firouzkooh-Ghaemshahr road and it arrives to the Caspian beach area in the Malek Kala village. In order to supply the water requirements of Semnan city, the construction of Chashm dam on the TalarRiver's tributaries placed on the agenda of the Ministry of Energy. However, because of the uncontrolled exploitation of agricultural streams and invasion of privacy riverbed, the TalarRiver has acute and critical conditions from the point of hydrologic and environmental. To study the hydrological impacts of Chashm dam, Talar watershed was considered with an area of approximately 1057 square kilometers of the Pole Sefid gauging station using a rainfall-runoff model. Results and Discussion: Simulation of the study area hydrological behavior shows that the Chashm Dam average water discharge is near to 8.6 million m3. This figure will be significant changes during wet and droughtperiods. The minimum and maximum monthly discharge of the Chashm Dam watershed in August and February is equal to 0.31 and 0.55 m3/s respectively. The minimum and maximum monthly water demand in turn in October and August is equal to 0.015 and 0.4 m3/s respectively and this shows that the river discharge in June is lower than the downstream water demand. Based on confirmed studies of the Kamandab Consulting Engineers, drinking water requirement of Semnan province, water

  1. Transport of perfluoroalkyl substances (PFAS) from an arctic glacier to downstream locations: implications for sources.

    Science.gov (United States)

    Kwok, Karen Y; Yamazaki, Eriko; Yamashita, Nobuyoshi; Taniyasu, Sachi; Murphy, Margaret B; Horii, Yuichi; Petrick, Gert; Kallerborn, Roland; Kannan, Kurunthachalam; Murano, Kentaro; Lam, Paul K S

    2013-03-01

    Perfluoroalkyl substances (PFAS) have been globally detected in various environmental matrices, yet their fate and transport to the Arctic is still unclear, especially for the European Arctic. In this study, concentrations of 17 PFAS were quantified in two ice cores (n=26), surface snow (n=9) and surface water samples (n=14) collected along a spatial gradient in Svalbard, Norway. Concentrations of selected ions (Na(+), SO4(2-), etc.) were also determined for tracing the origins and sources of PFAS. Perfluorobutanoate (PFBA), perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) were the dominant compounds found in ice core samples. Taking PFOA, PFNA and perfluorooctane-sulfonate (PFOS) as examples, higher concentrations were detected in the middle layers of the ice cores representing the period of 1997-2000. Lower concentrations of C8-C12 perfluorocarboxylates (PFCAs) were detected in comparison with concentrations measured previously in an ice core from the Canadian Arctic, indicating that contamination levels in the European Arctic are lower. Average PFAS concentrations were found to be lower in surface snow and melted glacier water samples, while increased concentrations were observed in river water downstream near the coastal area. Perfluorohexanesulfonate (PFHxS) was detected in the downstream locations, but not in the glacier, suggesting existence of local sources of this compound. Long-range atmospheric transport of PFAS was the major deposition pathway for the glaciers, while local sources (e.g., skiing activities) were identified in the downstream locations. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Sluiceway Operations for Adult Steelhead Downstream Passage at The Dalles Dam, Columbia River, USA

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Fenton; Royer, Ida M.; Johnson, Gary E.; Tackley, Sean C.

    2013-10-01

    This study evaluated adult steelhead (Oncorhynchus mykiss; fallbacks and kelts) downstream passage at The Dalles Dam in the Columbia River, USA, during the late fall, winter, and early spring months between 2008 and 2011. The purpose of the study was to determine the efficacy of operating the dam’s ice-and-trash sluiceway during non-spill months to provide a relatively safe, non-turbine, surface outlet for overwintering steelhead fallbacks and downstream migrating steelhead kelts. We applied the fixed-location hydroacoustic technique to estimate fish passage rates at the sluiceway and turbines of the dam. The spillway was closed during our sampling periods, which generally occurred in late fall, winter, and early spring. The sluiceway was highly used by adult steelhead (91–99% of total fish sampled passing the dam) during all sampling periods. Turbine passage was low when the sluiceway was not operated. This implies that lack of a sluiceway route did not result in increased turbine passage. However, when the sluiceway was open, adult steelhead used it to pass through the dam. The sluiceway may be operated during late fall, winter, and early spring to provide an optimal, non-turbine route for adult steelhead (fallbacks and kelts) downstream passage at The Dalles Dam.

  3. Approach to downstream planning for nearshore response and sensitive areas protection outside Prince William Sound, Alaska

    International Nuclear Information System (INIS)

    DeCola, E.G.; Robertson, T.L.; Robertson, R.; Banta, J.

    2004-01-01

    This study assessed the need for an oil spill response plan for downstream coastal communities that could be affected by oil spilled from tankers travelling in Prince William Sound, Alaska. For the purpose of oil spill contingency planning, the State of Alaska has been divided into the Kodiak and Cook Inlet sub-areas that are at risk for downstream impacts from a Prince William Sound oil spill. The 1989 Exxon Valdez oil spill provided an example of a worst-case scenario oil spill from a tanker in Prince William Sound, but the oil spill planning system that has evolved in Alaska does not adequately plan for on oil spill that originates in one sub-area of the state, but impacts other sub-areas in the downstream spill path. This study analyzed the gaps that exist in the current response planning system in the Prince William Sound, Cook Inlet and Kodiak sub-areas. A method was proposed to improve the existing response plans so that emergency response teams are better prepared to manage cross-boundary oil spills originating in Prince William Sound. The proposed method focuses on nearshore response and sensitive areas protection for coastlines and communities that are at risk for oil spills from a tanker travelling the Trans-Alaska Pipeline System (TAPS). 11 refs., 3 figs

  4. Downstream passage of fish larvae and eggs through a small-sized reservoir, Mucuri river, Brazil

    Directory of Open Access Journals (Sweden)

    Paulo S. Pompeu

    2011-12-01

    Full Text Available In South America, one important symptom of the failure of fish passages to sustain fish migratory recruitment is the inability of eggs and larvae to reach the nurseries. This is especially so when the breeding areas are located upstream of a reservoir, and the floodplain is downstream of the dam. Therefore, the transport of fish larvae and eggs across reservoir barriers is a key factor in the development of effective conservation strategies. In this paper, we evaluate the potential for migratory fish larvae and egg transportation across a small size reservoir in eastern Brazil. We sampled fish daily between 15th October 2002 and 15th February 2003 (spawning period in the Mucuri River, immediately upstream of the reservoir and downstream of the Santa Clara Power Plant dam. Our study was the first to indicate the possibility of successful larval passage through the reservoir of a hydroelectric reservoir and dam in South America, and showed that the passage of migratory fish larvae was associated significantly with residence time of water in the reservoir. The relatively short water residence time and elevated turbidity of the Santa Clara's reservoir waters during the rainy season certainly contributed to the successful passage, and can be considered as key factors for a priori evaluations of the feasibility of a downstream larval passage.

  5. Correlation between flow accelerated corrosion and wall shear stress downstream from an orifice

    International Nuclear Information System (INIS)

    Utanohara, Yoichi; Nakamura, Akira; Murase, Michio; Kamahori, Koichi; Nagaya, Yukinori

    2013-01-01

    Flow accelerated corrosion (FAC) thinning rate downstream from an orifice was measured under different velocity conditions in a high-temperature water test loop to understand the effects of flow velocity on FAC thinning rate. The FAC tendency differed downstream and upstream from the orifice. The metal loss increased linearly with time downstream from the orifice, though metal loss rate gradually decreased with time upstream. FAC rate increased as flow velocity increased, particularly from 1D to 3D. The maximum FAC thinning rate increased in proportional to the 0.51th power of the mean cross-sectional velocity in this experiment. The root mean square (RMS) of wall shear stress predicted by large eddy simulation (LES) had a clear relationship with FAC thinning rate. This result indicated that FAC thinning rate can be described as a function of the wall shear stress. Additionally, the mass transfer coefficient estimated from the RMS of wall shear stress had an almost linear correlation with FAC thinning rate. (author)

  6. An experimental study on the onset of detonation downstream of a perforated plate with staggered orifices

    Science.gov (United States)

    Lin, Wei; Zhou, Jin; Lin, Zhiyong; Liu, Shijie

    2017-09-01

    The present study investigated the onset of detonation (OD) process which takes place downstream of a 0.9-mm-thick perforated plate. The orifice diameter of the plate is 1.6 mm with a blockage of 59%, and it was placed perpendicular to the axial direction of a smooth detonation tube. `Stable' mixture C2H2 + 2.5O2 + 70%Ar and `unstable' mixture C2H2 + 5N2O were tested, respectively. Ionization probes and smoked foils were used to record detonation velocities and corresponding cellular patterns. Excellent agreement of the velocity trends and smoked foil results shows that a critical pressure range exists to identify `go' and `no go' of OD downstream of the perforated plate. However, the OD mechanisms for these two gaseous mixtures are distinct: for the `stable' mixture, OD occurs in the downstream near field (6 tube diameters in this study), whereas, OD in the `unstable' mixture could also observed in the far field via the transition of deflagration to detonation after a long duration of quasi-steady regime. This distance reaches up to tens of tube diameters when close to the critical pressure.

  7. Optimization of Upstream Detention Reservoir Facilities for Downstream Flood Mitigation in Urban Areas

    Directory of Open Access Journals (Sweden)

    Thi Thuy Ngo

    2016-07-01

    Full Text Available A detention reservoir is one of the most effective engineered solutions for flood damage mitigation in urban areas. Detention facilities are constructed to temporarily store storm water and then slowly drain when the peak period has passed. This delayed drainage may coincide with upstream floods and aggravate the flood risk downstream. Optimal operation and design are needed to improve the performance of detention reservoirs for flood reduction. This study couples hydrologic simulation software (EPA-SWMM with an evolutional optimizer (extraordinary particle swarm optimization, EPSO to minimize flood damage downstream while considering the inundation risk at the detention reservoir. The optimum design and operation are applied to an urban case study in Seoul, Korea, for historical severe flooding events and designed rainfall scenarios. The optimal facilities outperform the present facilities in terms of flood damage reduction both downstream and in the detention reservoir area. Specifically, the peak water level at the detention pond under optimal conditions is significantly smaller than that of the current conditions. The comparison of the total flooded volume in the whole watershed shows a dramatic reduction of 79% in a severe flooding event in 2010 and around 20% in 2011 and in 180 min designed rainfall scenarios.

  8. Optimizing withdrawal from drinking water reservoirs to reduce downstream temperature pollution and reservoir hypoxia.

    Science.gov (United States)

    Weber, M; Rinke, K; Hipsey, M R; Boehrer, B

    2017-07-15

    Sustainable management of drinking water reservoirs requires balancing the demands of water supply whilst minimizing environmental impact. This study numerically simulates the effect of an improved withdrawal scheme designed to alleviate the temperature pollution downstream of a reservoir. The aim was to identify an optimal withdrawal strategy such that water of a desirable discharge temperature can be supplied downstream without leading to unacceptably low oxygen concentrations within the reservoir. First, we calibrated a one-dimensional numerical model for hydrodynamics and oxygen dynamics (GLM-AED2), verifying that the model reproduced water temperatures and hypolimnetic dissolved oxygen concentrations accurately over a 5 year period. Second, the model was extended to include an adaptive withdrawal functionality, allowing for a prescribed withdrawal temperature to be found, with the potential constraint of hypolimnetic oxygen concentration. Scenario simulations on epi-/metalimnetic withdrawal demonstrate that the model is able to autonomously determine the best withdrawal height depending on the thermal structure and the hypolimnetic oxygen concentration thereby optimizing the ability to supply a desirable discharge temperature to the downstream river during summer. This new withdrawal strategy also increased the hypolimnetic raw water volume to be used for drinking water supply, but reduced the dissolved oxygen concentrations in the deep and cold water layers (hypolimnion). Implications of the results for reservoir management are discussed and the numerical model is provided for operators as a simple and efficient tool for optimizing the withdrawal strategy within different reservoir contexts. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Power Plant Bromide Discharges and Downstream Drinking Water Systems in Pennsylvania.

    Science.gov (United States)

    Good, Kelly D; VanBriesen, Jeanne M

    2017-10-17

    Coal-fired power plants equipped with wet flue gas desulfurization (FGD) systems have been implicated in increasing bromide levels and subsequent increases in disinfection byproducts at downstream drinking water plants. Bromide was not included as a regulated constituent in the recent steam electric effluent limitations guidelines and standards (ELGs) since the U.S. EPA analysis suggested few drinking water facilities would be affected by bromide discharges from power plants. The present analysis uses a watershed approach to identify Pennsylvania drinking water intakes downstream of wet FGD discharges and to assess the potential for bromide discharge effects. Twenty-two (22) public drinking water systems serving 2.5 million people were identified as being downstream of at least one wet FGD discharge. During mean August conditions (generally low-flow, minimal dilution) in receiving rivers, the median predicted bromide concentrations contributed by wet FGD at Pennsylvania intake locations ranged from 5.2 to 62 μg/L for the Base scenario (including only natural bromide in coal) and from 16 to 190 μg/L for the Bromide Addition scenario (natural plus added bromide for mercury control); ranges depend on bromide loads and receiving stream dilution capacity.

  10. Environmental hedging: A theory and method for reconciling reservoir operations for downstream ecology and water supply

    Science.gov (United States)

    Adams, L. E.; Lund, J. R.; Moyle, P. B.; Quiñones, R. M.; Herman, J. D.; O'Rear, T. A.

    2017-09-01

    Building reservoir release schedules to manage engineered river systems can involve costly trade-offs between storing and releasing water. As a result, the design of release schedules requires metrics that quantify the benefit and damages created by releases to the downstream ecosystem. Such metrics should support making operational decisions under uncertain hydrologic conditions, including drought and flood seasons. This study addresses this need and develops a reservoir operation rule structure and method to maximize downstream environmental benefit while meeting human water demands. The result is a general approach for hedging downstream environmental objectives. A multistage stochastic mixed-integer nonlinear program with Markov Chains, identifies optimal "environmental hedging," releases to maximize environmental benefits subject to probabilistic seasonal hydrologic conditions, current, past, and future environmental demand, human water supply needs, infrastructure limitations, population dynamics, drought storage protection, and the river's carrying capacity. Environmental hedging "hedges bets" for drought by reducing releases for fish, sometimes intentionally killing some fish early to reduce the likelihood of large fish kills and storage crises later. This approach is applied to Folsom reservoir in California to support survival of fall-run Chinook salmon in the lower American River for a range of carryover and initial storage cases. Benefit is measured in terms of fish survival; maintaining self-sustaining native fish populations is a significant indicator of ecosystem function. Environmental hedging meets human demand and outperforms other operating rules, including the current Folsom operating strategy, based on metrics of fish extirpation and water supply reliability.

  11. Essentials of radiation heat transfer

    CERN Document Server

    Balaji

    2014-01-01

    Essentials of Radiation Heat Transfer is a textbook presenting the essential, fundamental information required to gain an understanding of radiation heat transfer and equips the reader with enough knowledge to be able to tackle more challenging problems. All concepts are reinforced by carefully chosen and fully worked examples, and exercise problems are provided at the end of every chapter. In a significant departure from other books on this subject, this book completely dispenses with the network method to solve problems of radiation heat transfer in surfaces. It instead presents the powerful radiosity-irradiation method and shows how this technique can be used to solve problems of radiation in enclosures made of one to any number of surfaces. The network method is not easily scalable. Secondly, the book introduces atmospheric radiation, which is now being considered as a potentially important area, in which engineers can contribute to the technology of remote sensing and atmospheric sciences in general, b...

  12. Communication: essential strategies for success.

    Science.gov (United States)

    O'Connor, Mary

    2013-06-01

    This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advance organizational change, content includes evidence-based projects, tool, and resources that mobilize and sustain organizational change initiatives. In this article, the author discusses strategies for communication for change processes, whether large or small. Intentional planning and development of a communication strategy alongside, not as an afterthought, to change initiatives are essential.

  13. Essential themes in Personnel economics

    OpenAIRE

    Josheski, Dushko

    2014-01-01

    In this paper are presented essential themes in the subject of personnel economics. In the first part analysis has been conducted on the impact of peer pressure on workplace behaviour. Then again models for compensation structures within firms, and their influence on the utility of work by employees. In the final section of the paper the productivity spillover effect has been analyzed, and the causes of existence of spillovers and their impact on workers’ productivity

  14. Repelling mosquitoes with essential oils

    Science.gov (United States)

    Riley, L.

    2017-12-01

    Mosquitoes carry diseases than can lead to serious illness and death. According to the World Health Organization, mosquitoes infect over 300 million people a year with Malaria and Dengue Fever, two life threatening diseases vectored by mosquitoes. Although insecticides are the most effective way to control mosquitoes, they are not always environmentally friendly. Therefore, alternative tactics should be considered. In this study, we looked at the repellency of various essential oils on female Aedes aegypti through a series of laboratory assays.

  15. Essentials of natural gas microturbines

    CERN Document Server

    Boicea, Valentin A

    2013-01-01

    Addressing a field which, until now, has not been sufficiently investigated, Essentials of Natural Gas Microturbines thoroughly examines several natural gas microturbine technologies suitable not only for distributed generation but also for the automotive industry. An invaluable resource for power systems, electrical, and computer science engineers as well as operations researchers, microturbine operators, policy makers, and other industry professionals, the book: Explains the importance of natural gas microturbines and their use in distributed energy resource (DER) systemsDiscusses the histor

  16. Essentials of nuclear medicine imaging

    CERN Document Server

    Mettler, Fred A. Jr

    2012-01-01

    Essentials of Nuclear Medicine Imaging, by Drs. Fred A Mettler and Milton J Guiberteau, provides the practical and comprehensive guidance you need to master key nuclear imaging techniques. From physics, instrumentation, quality control, and legal requirements to hot topics such as sodium fluoride, radiopharmaceuticals, and recommended pediatric administered doses and guidelines, this sixth edition covers the fundamentals and recent developments in the practice of nuclear medicine.

  17. Low methane (CH4) emissions downstream of a monomictic subtropical hydroelectric reservoir (Nam Theun 2, Lao PDR)

    Science.gov (United States)

    Deshmukh, Chandrashekhar; Guérin, Frédéric; Labat, David; Pighini, Sylvie; Vongkhamsao, Axay; Guédant, Pierre; Rode, Wanidaporn; Godon, Arnaud; Chanudet, Vincent; Descloux, Stéphane; Serça, Dominique

    2016-03-01

    Methane (CH4) emissions from hydroelectric reservoirs could represent a significant fraction of global CH4 emissions from inland waters and wetlands. Although CH4 emissions downstream of hydroelectric reservoirs are known to be potentially significant, these emissions are poorly documented in recent studies. We report the first quantification of emissions downstream of a subtropical monomictic reservoir. The Nam Theun 2 Reservoir (NT2R), located in the Lao People's Democratic Republic, was flooded in 2008 and commissioned in April 2010. This reservoir is a trans-basin diversion reservoir which releases water into two downstream streams: the Nam Theun River below the dam and an artificial channel downstream of the powerhouse and a regulating pond that diverts the water from the Nam Theun watershed to the Xe Bangfai watershed. We quantified downstream emissions during the first 4 years after impoundment (2009-2012) on the basis of a high temporal (weekly to fortnightly) and spatial (23 stations) resolution of the monitoring of CH4 concentration. Before the commissioning of NT2R, downstream emissions were dominated by a very significant degassing at the dam site resulting from the occasional spillway discharge for controlling the water level in the reservoir. After the commissioning, downstream emissions were dominated by degassing which occurred mostly below the powerhouse. Overall, downstream emissions decreased from 10 GgCH4 yr-1 after the commissioning to 2 GgCH4 yr-1 4 years after impoundment. The downstream emissions contributed only 10 to 30 % of total CH4 emissions from the reservoir during the study. Most of the downstream emissions (80 %) occurred within 2-4 months during the transition between the warm dry season (WD) and the warm wet season (WW) when the CH4 concentration in hypolimnic water is maximum (up to 1000 µmol L-1) and downstream emissions are negligible for the rest of the year. Emissions downstream of NT2R are also lower than expected because

  18. Accelerator target

    Science.gov (United States)

    Schlyer, David J.; Ferrieri, Richard A.; Koehler, Conrad

    1999-01-01

    A target includes a body having a depression in a front side for holding a sample for irradiation by a particle beam to produce a radioisotope. Cooling fins are disposed on a backside of the body opposite the depression. A foil is joined to the body front side to cover the depression and sample therein. A perforate grid is joined to the body atop the foil for supporting the foil and for transmitting the particle beam therethrough. A coolant is circulated over the fins to cool the body during the particle beam irradiation of the sample in the depression.

  19. Targeting ILK and β4 integrin abrogates the invasive potential of ovarian cancer

    International Nuclear Information System (INIS)

    Choi, Yoon Pyo; Kim, Baek Gil; Gao, Ming-Qing; Kang, Suki; Cho, Nam Hoon

    2012-01-01

    Highlights: ► The potential of targeting ILK and integrins for highly aggressive ovarian cancer. ► Unanticipated synergistic effect for the combination of ILK/β4 integrin. ► Combination of ILK/β4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. ► Targeting of β4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of β1 and β4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of β1 and β4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of β4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of β4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting β4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  20. Targeting ILK and {beta}4 integrin abrogates the invasive potential of ovarian cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yoon Pyo; Kim, Baek Gil [BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Gao, Ming-Qing; Kang, Suki [Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cho, Nam Hoon, E-mail: cho1988@yuhs.ac [BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul (Korea, Republic of); Department of Pathology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The potential of targeting ILK and integrins for highly aggressive ovarian cancer. Black-Right-Pointing-Pointer Unanticipated synergistic effect for the combination of ILK/{beta}4 integrin. Black-Right-Pointing-Pointer Combination of ILK/{beta}4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. Black-Right-Pointing-Pointer Targeting of {beta}4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of {beta}1 and {beta}4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of {beta}1 and {beta}4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of {beta}4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of {beta}4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting {beta}4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  1. Coarse and fine sediment transportation patterns and causes downstream of the Three Gorges Dam

    Science.gov (United States)

    Li, Songzhe; Yang, Yunping; Zhang, Mingjin; Sun, Zhaohua; Zhu, Lingling; You, Xingying; Li, Kanyu

    2017-11-01

    Reservoir construction within a basin affects the process of water and sediment transport downstream of the dam. The Three Gorges Reservoir (TGR) affects the sediment transport downstream of the dam. The impoundment of the TGR reduced total downstream sediment. The sediment group d≤0.125 mm (fine particle) increased along the path, but the average was still below what existed before the reservoir impoundment. The sediments group d>0.125 mm (coarse particle) was recharged in the Yichang to Jianli reach, but showed a deposition trend downstream of Jianli. The coarse sediment in the Yichang to Jianli section in 2003 to 2007 was above the value before the TGR impoundment. However, the increase of both coarse and fine sediments in 2008 to 2014 was less than that in 2003 to 2007. The sediment retained in the dam is the major reason for the sediment reduction downstream. However, the retention in different river reaches is affected by riverbed coarsening, discharge, flow process, and conditions of lake functioning and recharging from the tributaries. The main conclusions derived from our study are as follows: 1) The riverbed in the Yichang to Shashi section was relatively coarse, thereby limiting the supply of fine and coarse sediments. The fine sediment supply was mainly controlled by TGR discharge, whereas the coarse sediment supply was controlled by the duration of high flow and its magnitude. 2) The supply of both coarse and fine sediments in the Shashi to Jianli section was controlled by the amount of total discharge. The sediment supply from the riverbed was higher in flood years than that in the dry years. The coarse sediment tended to deposit, and the deposition in the dry years was larger than that in the flood years. 3) The feeding of the fine sediment in the Luoshan to Hankou section was mainly from the riverbed. The supply in 2008 to 2014 was more than that in 2003 to 2007. Around 2010, the coarse sediments transited from depositing to scouring that was

  2. Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth-suppressor gene

    Science.gov (United States)

    Ifere, Godwin O.; Equan, Anita; Gordon, Kereen; Nagappan, Peri; Igietseme, Joseph U.; Ananaba, Godwin A.

    2010-01-01

    Background The purpose of our study was to show the distinction between the apoptotic and anti-proliferative signaling of phytosterols and cholesterol enrichment in prostate cancer cell lines, mediated by the differential transcription of caveolin-1, and N-myc downstream regulated gene1 (NDRG1), a pro-apoptotic androgen-regulated tumor suppressor. Methods PC-3 and DU145 cells were treated with sterols (cholesterol and phytosterols) for 72 h, followed by trypan blue dye exclusion measurement of necrosis and cell growth measured with a Coulter counter. Sterol induction of cell growth-suppressor gene expression was evaluated by mRNA transcription using RT-PCR, while cell cycle analysis was performed by FACS analysis. Altered expression of Ndrg1 protein was confirmed by Western blot analysis. Apoptosis was evaluated by real time RT-PCR amplification of P53, Bcl-2 gene and its related pro- and anti-apoptotic family members. Results Physiological doses (16 µM) of cholesterol and phytosterols were not cytotoxic in these cells. Cholesterol enrichment promoted cell growth (Pphytosterols significantly induced growth-suppression (Pphytosterols decreased mitotic subpopulations. We demonstrated for the first time that cholesterols concertedly attenuated the expression of caveolin-1(cav-1) and NDRG1 genes in both prostate cancer cell lines. Phytosterols had the opposite effect by inducing overexpression of cav-1, a known mediator of androgen-dependent signals that presumably control cell growth or apoptosis. Conclusions Cholesterol and phytosterol treatment differentially regulated the growth of prostate cancer cells and the expression of p53 and cav-1, a gene that regulates androgen-regulated signals. These sterols also differentially regulated cell cycle arrest, downstream pro-apoptotic androgen-regulated tumor-suppressor, NDRG1 suggesting that cav-1 may mediate pro-apoptotic NDRG1 signals. Elucidation of the mechanism for sterol modulation of growth and apoptosis signaling

  3. Retention of ferrofluid aggregates at the target site during magnetic drug targeting

    Energy Technology Data Exchange (ETDEWEB)

    Asfer, Mohammed, E-mail: asfer786@gmail.com [School of Engineering and Technology, BML Munjal University, Haryana (India); Saroj, Sunil Kumar [Department of Mechanical Engineering, IIT Kanpur, Kanpur (India); Panigrahi, Pradipta Kumar, E-mail: panig@iitk.ac.in [Department of Mechanical Engineering, IIT Kanpur, Kanpur (India)

    2017-08-15

    Highlights: • The present in vitro work reports the retention dynamics of ferrofluid aggregates at the target site against a bulk flow of DI water inside a micro capillary during magnetic drug targeting. • The recirculation zone at the downstream of the aggregate is found to be a function of aggregate height, Reynolds number and the degree of surface roughness of the outer boundary of the aggregate. • The reported results of the present work can be used as a guideline for the better design of MDT technique for in vivo applications. - Abstract: The present study reports the retention dynamics of a ferrofluid aggregate localized at the target site inside a glass capillary (500 × 500 µm{sup 2} square cross section) against a bulk flow of DI water (Re = 0.16 and 0.016) during the process of magnetic drug targeting (MDT). The dispersion dynamics of iron oxide nanoparticles (IONPs) into bulk flow for different initial size of aggregate at the target site is reported using the brightfield visualization technique. The flow field around the aggregate during the retention is evaluated using the µPIV technique. IONPs at the outer boundary experience a higher shear force as compared to the magnetic force, resulting in dispersion of IONPs into the bulk flow downstream to the aggregate. The blockage effect and the roughness of the outer boundary of the aggregate resulting from chain like clustering of IONPs contribute to the flow recirculation at the downstream region of the aggregate. The entrapment of seeding particles inside the chain like clusters of IONPs at the outer boundary of the aggregate reduces the degree of roughness resulting in a streamlined aggregate at the target site at later time. The effect of blockage, structure of the aggregate, and disturbed flow such as recirculation around the aggregate are the primary factors, which must be investigated for the effectiveness of the MDT process for in vivo applications.

  4. Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor.

    Science.gov (United States)

    Delgado-Calle, Jesus; Tu, Xiaolin; Pacheco-Costa, Rafael; McAndrews, Kevin; Edwards, Rachel; Pellegrini, Gretel G; Kuhlenschmidt, Kali; Olivos, Naomie; Robling, Alexander; Peacock, Munro; Plotkin, Lilian I; Bellido, Teresita

    2017-03-01

    Osteocytes integrate the responses of bone to mechanical and hormonal stimuli by poorly understood mechanisms. We report here that mice with conditional deletion of the parathyroid hormone (PTH) receptor 1 (Pth1r) in dentin matrix protein 1 (DMP1)-8kb-expressing cells (cKO) exhibit a modest decrease in bone resorption leading to a mild increase in cancellous bone without changes in cortical bone. However, bone resorption in response to endogenous chronic elevation of PTH in growing or adult cKO mice induced by a low calcium diet remained intact, because the increased bone remodeling and bone loss was indistinguishable from that exhibited by control littermates. In contrast, the bone gain and increased bone formation in cancellous and cortical bone induced by daily injections of PTH and the periosteal bone apposition induced by axial ulna loading were markedly reduced in cKO mice compared to controls. Remarkably, however, wild-type (WT) control littermates and transgenic mice overexpressing SOST injected daily with PTH exhibit similar activation of Wnt/β-catenin signaling, increased bone formation, and cancellous and cortical bone gain. Taken together, these findings demonstrate that Pth1r in DMP1-8kb-expressing cells is required to maintain basal levels of bone resorption but is dispensable for the catabolic action of chronic PTH elevation; and it is essential for the anabolic actions of daily PTH injections and mechanical loading. However, downregulation of Sost/sclerostin, previously shown to be required for bone anabolism induced by mechanical loading, is not required for PTH-induced bone gain, showing that other mechanisms downstream of the Pth1r in DMP1-8kb-expressing cells are responsible for the hormonal effect. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

  5. Linear feedback controls the essentials

    CERN Document Server

    Haidekker, Mark A

    2013-01-01

    The design of control systems is at the very core of engineering. Feedback controls are ubiquitous, ranging from simple room thermostats to airplane engine control. Helping to make sense of this wide-ranging field, this book provides a new approach by keeping a tight focus on the essentials with a limited, yet consistent set of examples. Analysis and design methods are explained in terms of theory and practice. The book covers classical, linear feedback controls, and linear approximations are used when needed. In parallel, the book covers time-discrete (digital) control systems and juxtapos

  6. Axure RP 6 Prototyping Essentials

    CERN Document Server

    Schwartz, Ezra

    2012-01-01

    Axure RP 6 Prototyping Essentials is a detailed, practical primer on the leading rapid prototyping tool. Short on jargon and high on concepts, real-life scenarios and step-by-step guidance through hands-on examples, this book will show you how to integrate Axure into your UX workflow. This book is written for UX practitioners, business analysts, product managers, and anyone else who is involved in UX projects. The book assumes that you have no or very little familiarity with Axure. It will help you if you are evaluating the tool for an upcoming project or are required to quickly get up to spee

  7. Microsoft Windows Operating System Essentials

    CERN Document Server

    Carpenter, Tom

    2012-01-01

    A full-color guide to key Windows 7 administration concepts and topics Windows 7 is the leading desktop software, yet it can be a difficult concept to grasp, especially for those new to the field of IT. Microsoft Windows Operating System Essentials is an ideal resource for anyone new to computer administration and looking for a career in computers. Delving into areas such as fundamental Windows 7 administration concepts and various desktop OS topics, this full-color book addresses the skills necessary for individuals looking to break into a career in IT. Each chapter begins with a list of topi

  8. Cyber essentials a pocket guide

    CERN Document Server

    Calder, Alan

    2014-01-01

    Every year, thousands of computer systems in the UK are compromised. The majority fall victim to easily preventable cyber attacks, carried out with tools which are freely available on the Internet.   Cyber Essentials is the UK Government's reaction to the proliferation of these attacks. It requires that organisations put basic security measures in place, enabling them to reliably counter the most common tactics employed by cyber criminals. From 1 October 2014, all suppliers bidding for a range of government ICT contracts - in particu

  9. Essentials of Electromagnetics for Engineering

    Science.gov (United States)

    de Wolf, David A.

    2000-11-01

    Essentials of Electromagnetics for Engineering introduces the key physical and engineering principles of electromagnetics. Throughout the book, David de Wolf describes the intermediate steps in mathematical derivations that many other textbooks leave out. He covers in depth the concepts of fields and potentials and then progresses to magnetostatics, Maxwell's equations, electrodynamics and wave propagation, waveguides, transmission lines, and antennas. At each stage, de Wolf stresses the physical principles underlying the mathematical results. He also includes homework exercises, a separate chapter on numerical methods in electromagnetics, and a broad range of worked examples to illustrate important concepts. Solutions manual available.

  10. La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1).

    Science.gov (United States)

    Fonseca, Bruno D; Zakaria, Chadi; Jia, Jian-Jun; Graber, Tyson E; Svitkin, Yuri; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, Jacob M; Diao, Ilo T; Lussier, Alexandre; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta-Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, Jose L; Hernández, Greco; Alain, Tommy; Damgaard, Christian K

    2015-06-26

    The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5'TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Essential amino acid enriched high-protein enteral nutrition modulates insulin-like growth factor-1 system function in a rat model of trauma-hemorrhagic shock.

    Directory of Open Access Journals (Sweden)

    Xianfeng Xia

    Full Text Available Nutrition support for critically ill patients supplemented with additional modular protein may promote skeletal muscle protein anabolism in addition to counteracting acute nitrogen loss. The present study was designed to investigate whether the essential amino acid (EAA enriched high-protein enteral nutrition (EN modulates the insulin-like growth factor-1 (IGF-1 system and activates the mammalian target of rapamycin (mTOR anabolic signaling pathway in a trauma-hemorrhagic shock (T-HS rat model.Male Sprague-Dawley rats (n = 90, 278.18 ± 0.94 g were randomly assigned to 5 groups: (1 normal control, (2 pair-fed, (3 T-HS, (4 T-HS and standard EN, and (5 T-HS and EAA enriched high-protein EN. Six animals from each group were harvested on days 2, 4, and 6 for serum, gastrocnemius, soleus, and extensor digitorum longus sample collection. T-HS significantly reduced muscle mass. Nutrition support maintained muscle mass, especially the EAA enriched high-protein EN. Meanwhile, a pronounced derangement in IGF-1-IGFBPs axis as well as impaired mTOR transduction was observed in the T-HS group. Compared with animals receiving standard EN, those receiving EAA enriched high-protein EN presented 18% higher serum free IGF-1 levels following 3 days of nutrition support and 22% higher after 5 days. These changes were consistent with the concomitant elevation in serum insulin and reduction in corticosterone levels. In addition, phosphorylations of downstream anabolic signaling effectors - including protein kinase B, mTOR, and ribosomal protein S6 kinase1 - increased significantly in rats receiving EAA enriched high-protein EN.Our findings firstly demonstrate the beneficial effect of EAA enriched high-protein EN on the metabolic modulation of skeletal muscle protein anabolism by regulating the IGF-1 system and downstream anabolic signaling transduction.

  12. Emerging treatments for essential thrombocythemia

    Directory of Open Access Journals (Sweden)

    Okoli S

    2011-12-01

    Full Text Available Steven Okoli, Claire HarrisonDepartment of Haematology, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, UKAbstract: In 1934, Epstein and Goedel used the term hemorrhagic thrombocythemia to describe a disorder characterized by permanent elevation of a platelet count to more than three times normal, hyperplasia of megakaryocytes, and the tendency for venous thrombosis and spontaneous hemorrhage. Over the last 75 years, and particularly in the past 6 years, major progress has been made in our understanding of essential thrombocythemia (ET and its pathogenesis with the identification of the highly prevalent JAK-2 V617F and other mutations. Current management of this condition is based upon historical data and with treatments that have not changed significantly for nearly two decades. This study discusses this and recent progress, highlighting exciting new data with old and new drugs, as well as which patients in particular should be evaluated for these new therapies.Keywords: essential thrombocythemia, interferon, JAK inhibitor

  13. Essential Tremor: A Neurodegenerative Disease?

    Directory of Open Access Journals (Sweden)

    Julian Benito-Leon

    2014-07-01

    Full Text Available Background: Essential tremor (ET is one of the most common neurological disorders among adults, and is the most common of the many tremor disorders. It has classically been viewed as a benign monosymptomatic condition, yet over the past decade, a growing body of evidence indicates that ET is a progressive condition that is clinically heterogeneous, as it may be associated with a spectrum of clinical features, with both motor and non‐motor elements. In this review, I will describe the most significant emerging milestones in research which, when taken together, suggest that ET is a neurodegenerative condition.Methods: A PubMed search conducted in June 2014 crossing the terms “essential tremor” (ET and “neurodegenerative” yielded 122 entries, 20 of which included the term “neurodegenerative” in the article title. This was supplemented by articles in the author's files that pertained to this topic.Results/Discussion: There is an open and active dialogue in the medical community as to whether ET is a neurodegenerative disease, with considerable evidence in favor of this. Specifically, ET is a progressive disorder of aging associated with neuronal loss (reduction in Purkinje cells as well as other post‐mortem changes that occur in traditional neurodegenerative disorders. Along with this, advanced neuroimaging techniques are now demonstrating distinct structural changes, several of which are consistent with neuronal loss, in patients with ET. However, further longitudinal clinical and neuroimaging longitudinal studies to assess progression are required.

  14. Dams and Rivers: A Primer on the Downstream Effects of Dams

    Science.gov (United States)

    Collier, Michael; Webb, Robert H.; Schmidt, John C.

    1996-01-01

    The U.S. Geological Survey is charged with monitoring the water and mineral resources of the United States. Beginning in 1889, the Survey established a network of water gaging stations across most of the country's rivers; some also measured sediment content of the water. Consequently, we now have valuable long-term data with which to track water supply, sediment transport, and the occurrence of floods. Many variables affect the flow of water from mountain brook to river delta. Some are short-term perturbations like summer thunderstorms. Others occur over a longer period of time, like the El Ninos that might be separated by a decade or more. We think of these variables as natural occurrences, but humans have exerted some of the most important changes -- water withdrawals for agriculture, inter-basin transfers, and especially the construction of an extensive system of dams. Dams have altered the flow of many of the Nation's rivers to meet societal needs. We expect floods to be contained. Irrigation is possible where deserts once existed. And water is released downstream not according to natural cycles but as dictated by a region's hour-by-hour needs for water or electricity. As a result, river channels below dams have changed dramatically. Depending on annual flow, flood peaks, and a river's sediment load, we might see changes such as sand building up in one channel, vegetation crowding into another, and extensive bank erosion in another. This Circular explores the emerging scientific arena of change in rivers below dams. This science tries first to understand and then anticipate changes to river beds and banks, and to riparian habitats and animal communities. To some degree, these downstream changes can be influenced by specific strategies of dam management. Scientists and resource managers have a duty to assemble this information and present it without bias to the rest of society. Society can then more intelligently choose a balance between the benefits and adverse

  15. Downstream Fining of Polydispersed Gravity Currents Along a V-Shaped Valley.

    Science.gov (United States)

    Besson, C. K.; Meriaux, C. A. M. D.

    2014-12-01

    Turbidity currents belong to the class of currents transporting sediments, whose deposits exhibit downstream grain size fining. In this study, the objective was to better understand the relationship between downstream fining and grain sizes at the source. To this end, we performed four lock-exchange experiments of polydispersed and turbulent gravity currents flowing along a 5-m long V-shaped valley. The particle volumetric concentrations were typically 3%. The four currents were made of 1) Silicon Carbide (SiC), 2) Glass Beads (GBs), 3) a combined poorly sorted SiC/GBs, and 4) a moderately sorted combined SiC/GBs. We used the Morphologi G3 tool developed by Malvern Instruments Corporate (Malvern Instruments Ltd, UK) for the grain size analyses. We first established a criterion for identifying the appropriate number of grain size classes nbclassfor characterizing the grain size distributions. We considered the four statistical indicators that are the arithmetic mean size dmean, the standard deviation σd, the skewness Skd, and the kurtosis Kd, and show that the four indicators for the initial grain size distributions reach plateaux when nb_class≥ 20. Hence we chose nbclass=20 as being our appropriate bin width. These four indicators were then calculated for samples taken along the deposits to establish the grain size distributions along the deposits. The subsequent profiles of dmean, σd, Skd, and Kd with distance from the lock show highly variable behaviours between the different initial distributions. In particular, the distance over which the loss of the largest grains of the initial distribution occurs [dmean> dmean(initial)], can cover up to half the runout length. Curiously, the different rates of fining estimated from the curves (dmean/ dmean(initial)) as a function of downstream distance (x/x_runout) do not appear to be well correlated with the sedimentation velocities based on dmean(initial). This is currently being investigated.

  16. On the electron temperature downstream of the solar wind termination shock

    Directory of Open Access Journals (Sweden)

    I. V. Chashei

    2013-07-01

    Full Text Available In this paper we study the temperatures of electrons convected with the solar wind to large solar distances and finally transported over the solar wind termination shock. Nearly nothing, unless at high energies in the cosmic ray regime, is known about the thermodynamical behaviour of these distant electrons from in~situ plasma observations. Hence it is tacitly assumed these electrons, due to their adiabatic behaviour and vanishing heat conduction or energization processes, have rapidly cooled off to very low temperatures once they eventually arrive at the solar wind termination shock (at about 100 AU. In this paper we show that such electrons, however, at their passage over the termination shock due to the shock–electric field action undergo an over-adiabatic heating and therefore appear on the downstream side as a substantially heated plasma species. Looking quantitatively into this heating process we find that solar wind electrons achieve temperatures of the order of 2–4 × 106 K downstream of the termination shock, depending on the upstream solar wind bulk velocity and the shock compression ratio. Hence these electrons therewith play an important dynamical role in structuring this shock and determining the downstream plasma flow properties. Furthermore, they present an additional ionization source for incoming neutral interstellar hydrogen and excite X-ray emission. They also behave similar to cosmic ray electrons and extend to some limited region upstream of the shock of the order of 0.1 AU by spatial diffusion and thereby also modify the upstream solar wind properties.

  17. To what extent can green infrastructure mitigate downstream flooding in a peri-urban catchment?

    Science.gov (United States)

    Schubert, J. E.; Burns, M.; Sanders, B. F.; Flethcher, T.

    2016-12-01

    In this research, we couple an urban hydrologic model (MUSIC, eWater, AUS) with a fine resolution 2D hydrodynamic model (BreZo, UC Irvine, USA) to test to what extent retrofitting an urban watershed with stormwater control measures (SCMs) can propagate flood management benefits downstream. Our study site is the peri-urban Little Stringybark Creek (LSC) catchment in eastern Melbourne, AUS, with an area of 4.5 km2 and connected impervious area of 9%. Urban development is mainly limited to the upper 2 km2of the catchment. Since 2009 the LSC catchment has been the subject of a large-scale experiment aiming to restore morenatural flow by implementing over 300 SCMs, such as rain tanks and infiltration trenches, resulting in runoff from 50% of connected impervious areas now being intercepted by some form of SCM. For our study we calibrated the hydrologic and hydraulic models based on current catchment conditions, then we developed models representing alternative SCM scenarios including a complete lack of SCMs versus a full implementation of SCMs. Flow in the hydrologic/hydraulic models is forced using a range of synthetic rainfall events with annual exceedance probabilities (AEPs) between 63-1% and durations between 10 min to 24 hr. Metrics of SCM efficacy in changing flood regime include flood depths and extents, flow intensity (m2/s), flood duration, and critical storm duration leading to maximum flood conditions. Results indicate that across the range of AEPs tested and for storm durations equal or less than 3 hours, current SCM conditions reduce downstream flooded area on average by 29%, while a full implementation of SCMs would reduce downstream flooded area on average by 91%. A full implementation of SCMs could also lower maximum flow intensities by 83% on average, reducing damage potential to structures in the flow path and increasing the ability for vehicles to evacuate flooded streets. We also found that for storm durations longer than 3 hours, the SCMs capacity

  18. Aerodynamic Mixing Downstream from Line Source of Heat in High-intensity Sound Field

    Science.gov (United States)

    Mickelson, William R; Baldwin, Lionel V

    1956-01-01

    Theory and measurement showed that the heat wake downstream from a line source is displaced by a transverse standing sound wave in a manner similar to a flag waving in a harmonic mode. With a 147 db, 104 cps standing wave, time-mean temperatures were reduced by an order of magnitude except near the displacement-pattern nodal points. The theory showed that a 161 db, 520 cps standing wave considerably increased the mixing in both the time-mean and instantaneous senses.

  19. Downstream natural gas in Europe-High hopes dashed for upstream oil and gas companies

    International Nuclear Information System (INIS)

    Eikeland, Per Ove

    2007-01-01

    Access for independents to retail gas markets was a central concern in European policy reform efforts in the 1990s. Upstream oil and gas companies reacted with strategic intentions of forward integration. By late 2004, forward integration was still weak, however. An important explanation of the gap between announced strategic re-orientation and actual strategy implementation lies in the political failure of EU member states to dismantle market barriers to entry for independents. Variations between companies in downstream strategy implementation are explained by variations in business opportunities and internal company factors

  20. Downstream natural gas in Europe - high hopes dashed for upstream oil and gas companies

    International Nuclear Information System (INIS)

    Eikeland, P.O.

    2007-01-01

    Access for independents to retail gas markets was a central concern in European policy reform efforts in the 1990s. Upstream oil and gas companies reacted with strategic intentions of forward integration. By late 2004, forward integration was still weak, however. An important explanation of the gap between announced strategic re-orientation and actual strategy implementation lies in the political failure of EU member states to dismantle market barriers to entry for independents. Variations between companies in downstream strategy implementation are explained by variations in business opportunities and internal company factors. [Author

  1. European downstream oil industry safety performance. Statistical summary of reported incidents 2009

    International Nuclear Information System (INIS)

    Burton, A.; Den Haan, K.H.

    2010-10-01

    The sixteenth such report by CONCAWE, this issue includes statistics on workrelated personal injuries for the European downstream oil industry's own employees as well as contractors for the year 2009. Data were received from 33 companies representing more than 97% of the European refining capacity. Trends over the last sixteen years are highlighted and the data are also compared to similar statistics from related industries. In addition, this report presents the results of the first Process Safety Performance Indicator data gathering exercise amongst the CONCAWE membership.

  2. Has dyke development in the Vietnamese Mekong Delta shifted flood hazard downstream?

    Science.gov (United States)

    Van Khanh Triet, Nguyen; Viet Dung, Nguyen; Fujii, Hideto; Kummu, Matti; Merz, Bruno; Apel, Heiko

    2017-08-01

    In the Vietnamese part of the Mekong Delta (VMD) the areas with three rice crops per year have been expanded rapidly during the last 15 years. Paddy-rice cultivation during the flood season has been made possible by implementing high-dyke flood defenses and flood control structures. However, there are widespread claims that the high-dyke system has increased water levels in downstream areas. Our study aims at resolving this issue by attributing observed changes in flood characteristics to high-dyke construction and other possible causes. Maximum water levels and duration above the flood alarm level are analysed for gradual trends and step changes at different discharge gauges. Strong and robust increasing trends of peak water levels and duration downstream of the high-dyke areas are found with a step change in 2000/2001, i.e. immediately after the disastrous flood which initiated the high-dyke development. These changes are in contrast to the negative trends detected at stations upstream of the high-dyke areas. This spatially different behaviour of changes in flood characteristics seems to support the public claims. To separate the impact of the high-dyke development from the impact of the other drivers - i.e. changes in the flood hydrograph entering the Mekong Delta, and changes in the tidal dynamics - hydraulic model simulations of the two recent large flood events in 2000 and 2011 are performed. The hydraulic model is run for a set of scenarios whereas the different drivers are interchanged. The simulations reveal that for the central VMD an increase of 9-13 cm in flood peak and 15 days in duration can be attributed to high-dyke development. However, for this area the tidal dynamics have an even larger effect in the range of 19-32 cm. However, the relative contributions of the three drivers of change vary in space across the delta. In summary, our study confirms the claims that the high-dyke development has raised the flood hazard downstream. However, it is not

  3. Induction of postmitotic neuroretina cell proliferation by distinct Ras downstream signaling pathways.

    Science.gov (United States)

    Peyssonnaux, C; Provot, S; Felder-Schmittbuhl, M P; Calothy, G; Eychène, A

    2000-10-01

    Ras-induced cell transformation is mediated through distinct downstream signaling pathways, including Raf, Ral-GEFs-, and phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathways. In some cell types, strong activation of the Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) cascade leads to cell cycle arrest rather than cell division. We previously reported that constitutive activation of this pathway induces sustained proliferation of primary cultures of postmitotic chicken neuroretina (NR) cells. We used this model system to investigate the respective contributions of Ras downstream signaling pathways in Ras-induced cell proliferation. Three RasV12 mutants (S35, G37, and C40) which differ by their ability to bind to Ras effectors (Raf, Ral-GEFs, and the p110 subunit of PI 3-kinase, respectively) were able to induce sustained NR cell proliferation, although none of these mutants was reported to transform NIH 3T3 cells. Furthermore, they all repressed the promoter of QR1, a neuroretina growth arrest-specific gene. Overexpression of B-Raf or activated versions of Ras effectors Rlf-CAAX and p110-CAAX also induced NR cell division. The mitogenic effect of the RasC40-PI 3-kinase pathway appears to involve Rac and RhoA GTPases but not the antiapoptotic Akt (protein kinase B) signaling. Division induced by RasG37-Rlf appears to be independent of Ral GTPase activation and presumably requires an unidentified mechanism. Activation of either Ras downstream pathway resulted in ERK activation, and coexpression of a dominant negative MEK mutant or mKsr-1 kinase domain strongly inhibited proliferation induced by the three Ras mutants or by their effectors. Similar effects were observed with dominant negative mutants of Rac and Rho. Thus, both the Raf-MEK-ERK and Rac-Rho pathways are absolutely required for Ras-induced NR cell division. Activation of these two pathways by the three distinct Ras downstream effectors possibly relies on an autocrine or paracrine loop

  4. Corrosion mechanisms downstream the nuclear cycle: from processing-recycling to transmutation

    International Nuclear Information System (INIS)

    Balbaud-Celerier, F.

    2010-01-01

    The author gives a detailed overview of his scientific and research activities in the field of material behaviour in environments met during the downstream part of the nuclear cycle. In the first part, he presents his works on material corrosion in concentrated and high temperature nitric acid, and more particularly on the phenomenon which governs this corrosion: the nitric acid reduction mechanism. In the second part, he reports researches performed within the frame of hybrid reactor development for the processing of future fuels. In both parts, he also discusses the perspectives for new researches and developments

  5. Sediment conditions in the San Antonio River Basin downstream from San Antonio, Texas, 2000-13

    Science.gov (United States)

    Ockerman, Darwin J.; Banta, J. Ryan; Crow, Cassi L.; Opsahl, Stephen P.

    2015-01-01

    Sediment plays an important role in the ecological health of rivers and estuaries and consequently is an important issue for water-resource managers. To better understand sediment characteristics in the San Antonio River Basin, the U.S. Geological Survey, in cooperation with the San Antonio River Authority, completed a two-part study in the San Antonio River Basin downstream from San Antonio, Texas, to (1) collect and analyze sediment data to characterize sediment conditions and (2) develop and calibrate a watershed model to simulate hydrologic conditions and suspended-sediment loads during 2000–12.

  6. Price rigidity in the downstream petroleum industry in New Zealand. Where does it happen?

    International Nuclear Information System (INIS)

    Delpachitra, Sarath B.

    2002-01-01

    This paper examines the pricing behaviour of the downstream petroleum product market in New Zealand using multivariate error correction models. The unique feature of these models is the use of actual weekly wholesale and retail prices of diesel and unleaded petrol to measure the relative rigidity of domestic prices. The results suggest that price adjustments in domestic markets in response to price changes in world crude oil markets and refined product markets are very weak. Domestic wholesale prices appear to be the key variable in determining retail prices. Lack of competition in the wholesale sector is found to be the main reason for weak price adjustments

  7. Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides.

    Science.gov (United States)

    Zhou, Zheng; Hu, Taishan; Xu, Zhiheng; Lin, Zhaohu; Zhang, Zhisen; Feng, Teng; Zhu, Liangcheng; Rong, Yiping; Shen, Hong; Luk, John M; Zhang, Xiongwen; Qin, Ning

    2015-02-01

    Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes-associated protein (YAP)-transcriptional enhancer activation domain family member (TEAD) association is essential for YAP-driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP-like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP-TEAD interaction in vitro. To confirm that blocking YAP-TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant-negative mutation (Y406H) of TEAD1 to abolish YAP-TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP-induced oncogenesis. © FASEB.

  8. Combined toxicity of three essential oils against Aedes aegypti (Diptera: Culicidae) larvae

    Science.gov (United States)

    Essential oils are potential alternatives to synthetic insecticides because they have low mammalian toxicity, degrade rapidly in the environment, and possess complex mixtures of bioactive constituents with multi-modal activity against the target insect populations. Twenty one essential oils were ini...

  9. Current essentials in inflammatory myopathies

    Directory of Open Access Journals (Sweden)

    Maren Breithaupt

    2013-08-01

    Full Text Available Inflammatory myopathies are a heterogeneous group of acquired systemic diseases, which include dermatomyositis (DM, polymyositis (PM, necrotising myopathy (NM and inclusion body myositis (IBM. All four disease entities share certain clinical characteristics, such as progressive muscle weakness and elevated muscle enzymes. Other characteristic-associated features such as skin involvement in DM or the detection of myositis-specific antibodies, may be indicative of a particular subtype. However, muscle biopsy is still essential for the diagnosis and shows distinct histopathological characteristics for each subtype of myositis. Treatment of inflammatory myopathies is still based on clinical experience, since placebo-controlled trials are scarce. While DM, PM and NM respond well to immunosuppressive treatment, IBM is usually resistant to immunotherapy. This review aims to give a concise overview and provide guidance for general management of myositis.

  10. Essential AOP: The A Calculus

    DEFF Research Database (Denmark)

    De Fraine, Bruno; Ernst, Erik; Südholt, Mario

    2012-01-01

    Aspect-oriented programming (AOP) has produced interesting language designs, but also ad hoc semantics that needs clarification. We contribute to this clarification with a calculus that models essential AOP, both simpler and more general than existing formalizations. In AOP, advice may intercept......-oriented code. Two well-known pointcut categories, call and execution, are commonly considered similar.We formally expose their differences, and resolve the associated soundness problem. Our calculus includes type ranges, an intuitive and concise alternative to explicit type variables that allows advice...... to be polymorphic over intercepted methods. We use calculus parameters to cover type safety for a wide design space of other features. Type soundness is verified in Coq....

  11. Pathology Informatics Essentials for Residents

    Science.gov (United States)

    Karcher, Donald S.; Harrison, James H.; Sinard, John H.; Riben, Michael W.; Boyer, Philip J.; Plath, Sue; Thompson, Arlene; Pantanowitz, Liron

    2016-01-01

    Context: Recognition of the importance of informatics to the practice of pathology has surged. Training residents in pathology informatics has been a daunting task for most residency programs in the United States because faculty often lacks experience and training resources. Nevertheless, developing resident competence in informatics is essential for the future of pathology as a specialty. Objective: To develop and deliver a pathology informatics curriculum and instructional framework that guides pathology residency programs in training residents in critical pathology informatics knowledge and skills, and meets Accreditation Council for Graduate Medical Education Informatics Milestones. Design: The College of American Pathologists, Association of Pathology Chairs, and Association for Pathology Informatics formed a partnership and expert work group to identify critical pathology informatics training outcomes and to create a highly adaptable curriculum and instructional approach, supported by a multiyear change management strategy. Results: Pathology Informatics Essentials for Residents (PIER) is a rigorous approach for educating all pathology residents in important pathology informatics knowledge and skills. PIER includes an instructional resource guide and toolkit for incorporating informatics training into residency programs that vary in needs, size, settings, and resources. PIER is available at http://www.apcprods.org/PIER (accessed April 6, 2016). Conclusions: PIER is an important contribution to informatics training in pathology residency programs. PIER introduces pathology trainees to broadly useful informatics concepts and tools that are relevant to practice. PIER provides residency program directors with a means to implement a standardized informatics training curriculum, to adapt the approach to local program needs, and to evaluate resident performance and progress over time. PMID:28725772

  12. Pathology Informatics Essentials for Residents

    Directory of Open Access Journals (Sweden)

    Walter H. Henricks MD

    2016-07-01

    Full Text Available Context: Recognition of the importance of informatics to the practice of pathology has surged. Training residents in pathology informatics has been a daunting task for most residency programs in the United States because faculty often lacks experience and training resources. Nevertheless, developing resident competence in informatics is essential for the future of pathology as a specialty. Objective: To develop and deliver a pathology informatics curriculum and instructional framework that guides pathology residency programs in training residents in critical pathology informatics knowledge and skills, and meets Accreditation Council for Graduate Medical Education Informatics Milestones. Design: The College of American Pathologists, Association of Pathology Chairs, and Association for Pathology Informatics formed a partnership and expert work group to identify critical pathology informatics training outcomes and to create a highly adaptable curriculum and instructional approach, supported by a multiyear change management strategy. Results: Pathology Informatics Essentials for Residents (PIER is a rigorous approach for educating all pathology residents in important pathology informatics knowledge and skills. PIER includes an instructional resource guide and toolkit for incorporating informatics training into residency programs that vary in needs, size, settings, and resources. PIER is available at http://www.apcprods.org/PIER (accessed April 6, 2016. Conclusions: PIER is an important contribution to informatics training in pathology residency programs. PIER introduces pathology trainees to broadly useful informatics concepts and tools that are relevant to practice. PIER provides residency program directors with a means to implement a standardized informatics training curriculum, to adapt the approach to local program needs, and to evaluate resident performance and progress over time.

  13. Biomass Demand-Resources Value Targeting

    International Nuclear Information System (INIS)

    Lim, Chun Hsion; Lam, Hon Loong

    2014-01-01

    Highlights: • Introduce DRVT supply chain modelling approach to consider underutilised biomass. • Advantages of the novel DRVT biomass supply chain approach. • A case study is presented to demonstrate the improvement of the system. - Abstract: With the global awareness towards sustainability, biomass industry becomes one of the main focuses in the search of alternative renewable resources for energy and downstream product. However, the efficiency of the biomass management, especially in supply chain is still questionable. Even though many researches and integrations of supply chain network have been conducted, less has considered underutilised biomass. This leads to the ignorance of potential value in particular biomass species. A new Demand-Resources Value Targeting (DRVT) approach is introduced in this study to investigate the value of each biomass available in order to fully utilise the biomass in respective applications. With systematic biomass value classification, integration of supply chain based on biomass value from biomass resources-to-downstream product can be developed. DRVT model allows better understanding of biomass and their potential downstream application. A simple demonstration of DRVT approach is conducted based on biomass resources in Malaysia

  14. Quality assessment of biobanked nucleic acid extracts for downstream molecular analysis.

    Science.gov (United States)

    Wahlberg, Karin; Huggett, Jim; Sanders, Rebecca; Whale, Alexandra S; Bushell, Claire; Elaswarapu, Ramnath; Scott, Daniel J; Foy, Carole A

    2012-06-01

    Sample quality is of major importance when conducting molecular analysis of nucleic acids, and factors such as degradation, presence of impurities, and enzymatic inhibitors may have a significant impact on the quality of data. Issues of quality assessment become more important as the increased use of biobanking means that whole blood samples are being stored for longer periods. A range of commercially available kits/methods have been specifically developed for extraction of high quality nucleic acids from a variety of clinical samples, including blood, but there is limited information on how best to quality assess the extracts to determine their fitness for purpose in specific downstream applications. In this study, we have performed nucleic acid extractions from stored blood using a number of different methods. The resulting extracts were analyzed by a panel of quantity and quality metrics including UV spectrophotometry, PicoGreen fluorescence, electrophoresis, and a PCR approach. To evaluate the relevance of different metrics, DNA samples were subsequently assessed for their performance in real time PCR and microarray experiments. Our findings demonstrate that the most suitable extraction technique and quality assessment approach depends on the required downstream analytical method.

  15. A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib.

    Science.gov (United States)

    Sun, Tianliang; Yang, Lida; Kaur, Harmandeep; Pestel, Jenny; Looso, Mario; Nolte, Hendrik; Krasel, Cornelius; Heil, Daniel; Krishnan, Ramesh K; Santoni, Marie-Josée; Borg, Jean-Paul; Bünemann, Moritz; Offermanns, Stefan; Swiercz, Jakub M; Worzfeld, Thomas

    2017-01-02

    Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration. © 2017 Sun et al.

  16. Resolution of thermal striping issue downstream of a horizontal pipe elbow in stratified pipe flow

    International Nuclear Information System (INIS)

    Kuzay, T.M.; Kasza, K.E.

    1985-01-01

    A thermally stratified pipe flow produced by a thermal transient when passing through a horizontal elbow as a result of secondary flow gives rise to large thermal fluctuations on the inner curvature wall of the downstream piping. These fluctuations were measured in a specially instrumented horizontal pipe and elbow system on a test set-up using water in the Mixing Components Technology Facility (MCTF) at Argonne National Laboratory (ANL). This study is part of a larger program which is studying the influence of thermal buoyancy on general reactor component performance. This paper discusses the influence of pipe flow generated thermal oscillations on the thermal stresses induced in the pipe walls. The instrumentation was concentrated around the exit plane of the 90 0 sweep elbow, since prior tests had indicated that the largest thermal fluctuations would occur within about one hydraulic diameter downstream of the elbow exit. The thermocouples were located along the inner curvature of the piping and measured the near surface fluid temperature. The test matrix involved thermal downramps under turbulent flow conditions

  17. Delineation of downstream signalling components during acrosome reaction mediated by heat solubilized human zona pellucida

    Directory of Open Access Journals (Sweden)

    Talwar Pankaj

    2010-01-01

    Full Text Available Abstract Background Human egg is enveloped by a glycoproteinaceous matrix, zona pellucida (ZP, responsible for binding of the human spermatozoa to the egg and induction of acrosomal exocytosis in the spermatozoon bound to ZP. In the present manuscript, attempts have been made to delineate the downstream signalling components employed by human ZP to induce acrosome reaction. Methods Heat-solubilized human ZP (SIZP was used to study the induction of acrosome reaction in capacitated human spermatozoa using tetramethylrhodamine isothiocyanate conjugated Pisum sativum agglutinin (TRITC-PSA in absence or presence of various pharmacological inhibitors. In addition, intracellular calcium ([Ca2+]i levels in sperm using Fluo-3 acetoxymethyl ester as fluorescent probe were also estimated in response to SIZP. Results SIZP induces acrosomal exocytosis in capacitated human sperm in a dose dependent manner accompanied by an increase in [Ca2+]i. Human SIZP mediated induction of acrosome reaction depends on extracellular Ca2+ and involves activation of Gi protein-coupled receptor, tyrosine kinase, protein kinases A & C and phosphoinositide 3 (PI3- kinase. In addition, T-type voltage operated calcium channels and GABA-A receptor associated chloride (Cl- channels play an important role in SIZP mediated induction of acrosome reaction. Conclusions Results described in the present study provide a comprehensive account of the various downstream signalling components associated with human ZP mediated acrosome reaction.

  18. Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors.

    Science.gov (United States)

    Ma, Gary S; Aznar, Nicolas; Kalogriopoulos, Nicholas; Midde, Krishna K; Lopez-Sanchez, Inmaculada; Sato, Emi; Dunkel, Ying; Gallo, Richard L; Ghosh, Pradipta

    2015-05-19

    In eukaryotes, receptor tyrosine kinases (RTKs) and trimeric G proteins are two major signaling hubs. Signal transduction via trimeric G proteins has long been believed to be triggered exclusively by G protein-coupled receptors (GPCRs). This paradigm has recently been challenged by several studies on a multimodular signal transducer, Gα-Interacting Vesicle associated protein (GIV/Girdin). We recently demonstrated that GIV's C terminus (CT) serves as a platform for dynamic association of ligand-activated RTKs with Gαi, and for noncanonical transactivation of G proteins. However, exogenous manipulation of this platform has remained beyond reach. Here we developed cell-permeable GIV-CT peptides by fusing a TAT-peptide transduction domain (TAT-PTD) to the minimal modular elements of GIV that are necessary and sufficient for activation of Gi downstream of RTKs, and used them to engineer signaling networks and alter cell behavior. In the presence of an intact GEF motif, TAT-GIV-CT peptides enhanced diverse processes in which GIV's GEF function has previously been implicated, e.g., 2D cell migration after scratch-wounding, invasion of cancer cells, and finally, myofibroblast activation and collagen production. Furthermore, topical application of TAT-GIV-CT peptides enhanced the complex, multireceptor-driven process of wound repair in mice in a GEF-dependent manner. Thus, TAT-GIV peptides provide a novel and versatile tool to manipulate Gαi activation downstream of growth factors in a diverse array of pathophysiologic conditions.

  19. Estimating the wake deflection downstream of a wind turbine in different atmospheric stabilities: an LES study

    Directory of Open Access Journals (Sweden)

    L. Vollmer

    2016-09-01

    Full Text Available An intentional yaw misalignment of wind turbines is currently discussed as one possibility to increase the overall energy yield of wind farms. The idea behind this control is to decrease wake losses of downstream turbines by altering the wake trajectory of the controlled upwind turbines. For an application of such an operational control, precise knowledge about the inflow wind conditions, the magnitude of wake deflection by a yawed turbine and the propagation of the wake is crucial. The dependency of the wake deflection on the ambient wind conditions as well as the uncertainty of its trajectory are not sufficiently covered in current wind farm control models. In this study we analyze multiple sources that contribute to the uncertainty of the estimation of the wake deflection downstream of yawed wind turbines in different ambient wind conditions. We find that the wake shapes and the magnitude of deflection differ in the three evaluated atmospheric boundary layers of neutral, stable and unstable thermal stability. Uncertainty in the wake deflection estimation increases for smaller temporal averaging intervals. We also consider the choice of the method to define the wake center as a source of uncertainty as it modifies the result. The variance of the wake deflection estimation increases with decreasing atmospheric stability. Control of the wake position in a highly convective environment is therefore not recommended.

  20. Featured collection introduction: Connectivity of streams and wetlands to downstream waters

    Science.gov (United States)

    Alexander, Laurie C.; Fritz, Ken M.; Schofield, Kate; Autrey, Bradley; DeMeester, Julie; Golden, Heather E.; Goodrich, David C.; Kepner, William G.; Kiperwas, Hadas R.; Lane, Charles R.; LeDuc, Stephen D.; Leibowitz, Scott; McManus, Michael G.; Pollard, Amina I.; Ridley, Caroline E.; Vanderhoof, Melanie; Wigington, Parker J.

    2018-01-01

    Connectivity is a fundamental but highly dynamic property of watersheds. Variability in the types and degrees of aquatic ecosystem connectivity presents challenges for researchers and managers seeking to accurately quantify its effects on critical hydrologic, biogeochemical, and biological processes. However, protecting natural gradients of connectivity is key to protecting the range of ecosystem services that aquatic ecosystems provide. In this featured collection, we review the available evidence on connections and functions by which streams and wetlands affect the integrity of downstream waters such as large rivers, lakes, reservoirs, and estuaries. The reviews in this collection focus on the types of waters whose protections under the U.S. Clean Water Act have been called into question by U.S. Supreme Court cases. We synthesize 40+ years of research on longitudinal, lateral, and vertical fluxes of energy, material, and biota between aquatic ecosystems included within the Act's frame of reference. Many questions about the roles of streams and wetlands in sustaining downstream water integrity can be answered from currently available literature, and emerging research is rapidly closing data gaps with exciting new insights into aquatic connectivity and function at local, watershed, and regional scales. Synthesis of foundational and emerging research is needed to support science‐based efforts to provide safe, reliable sources of fresh water for present and future generations.