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Sample records for downstream targets suggest

  1. Targeting pathways downstream of KRAS in lung adenocarcinoma.

    PubMed

    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. PMID:25303301

  2. Targeting pathways downstream of KRAS in lung adenocarcinoma

    PubMed Central

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

    2014-01-01

    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. PMID:25303301

  3. Commissioning The Darht-II Accelerator Downstream Transport And Target

    SciTech Connect

    Ekdahl, Carl; Schulze, Martin E

    2008-01-01

    The DARHT-II accelerator produces a 2-kA, 17-MeV beam in a 1600-ns pulse. After exiting the accelerator, the pulse is sliced into four short pulses by a kicker and quadrupole septum and then transported for several meters to a tantalum target for conversion to x-rays for radiography. They describe the commissioning of the kicker, septum, transport, and multi-pulse converter target. The results of beam measurements made during the commissioning of the downstream transport are described.

  4. Analysis of plausible downstream target genes of Hoxc8 in F9 teratocarcinoma cells. Putative downstream target genes of Hoxc8.

    PubMed

    Kwon, Yunjeong; Ko, Jeong Heon; Byung-Gyu, Kim; Kim, Myoung Hee; Kim, Byungkyu

    2003-09-01

    Although Hox genes are known to mediate developmental decisions involved in pattern formation during embryogenesis, it is still not well understood what Hox regulates. In order to analyze Hoxc8 downstream target genes, a stable cell line overexpressing Hoxc8 was established using F9 murine teratocarcinoma cells, proteom samples were analyzed by 2-DE, and compared with controls. The protein spots having differences more than 4 fold in intensity were selected, analyzed by MALDI-TOF, and grouped in terms of putative function; cytoskeleton and motility (vimentin, gamma-actin, tropomyosin, and tubulin beta-5 chain); folding, modification and degradation of protein (GRP78, proteasome subunit alpha type 5, 26S proteasome regulatory subunit p27 protein, and PDIR); metabolism (ATP synthase beta subunit, Pgam1, and CAII); transcription/translation factors and general nucleic acid binding proteins (RbAp46, PCNA, eEF-1-beta, and nucleophosmin). Although it may not be significant, 50% of the genes were located on chromosomes 2 and 3, suggesting the possibility of a non-random distribution of Hox downstream genes. Almost 50% of the genes analyzed showed some relation with Hox protein directly or indirectly; i.e., tubulin beta 5, EF-1 beta and PCNA have been reported to contain putative Hox binding regulatory sites and genes like vimentin, pgam1 and nucleophosmin to be regulated by RA, a potent modulator of Hox expression. These results altogether imply that proteom analysis could be a possible tool for the analysis of the potent Hox realizator genes, which provides a new insight into the function of Hox on pattern formation during embryogenesis. PMID:12974468

  5. Slug is a novel downstream target of MyoD. Temporal profiling in muscle regeneration.

    PubMed

    Zhao, Po; Iezzi, Simona; Carver, Ethan; Dressman, Devin; Gridley, Thomas; Sartorelli, Vittorio; Hoffman, Eric P

    2002-08-16

    Temporal expression profiling was utilized to define transcriptional regulatory pathways in vivo in a mouse muscle regeneration model. Potential downstream targets of MyoD were identified by temporal expression, promoter data base mining, and gel shift assays; Slug and calpain 6 were identified as novel MyoD targets. Slug, a member of the snail/slug family of zinc finger transcriptional repressors critical for mesoderm/ectoderm development, was further shown to be a downstream target by using promoter/reporter constructs and demonstration of defective muscle regeneration in Slug null mice. PMID:12023284

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

    SciTech Connect

    Min, Hyehyun; Lee, Ji-Yeon; Bok, Jinwoong; Chung, Hyun Joo; Kim, Myoung Hee

    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.

  7. Targeting the cis-dimerization of LINGO-1 with low MW compounds affects its downstream signalling

    PubMed Central

    Cobret, L; De Tauzia, M L; Ferent, J; Traiffort, E; Hénaoui, I; Godin, F; Kellenberger, E; Rognan, D; Pantel, J; Bénédetti, H; Morisset-Lopez, S

    2015-01-01

    Background and Purpose The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation and myelination. However, the molecular mechanisms regulating its functions are poorly understood. In the present study, we investigated the formation and the role of LINGO-1 cis-dimers in the regulation of its biological activity. Experimental Approach LINGO-1 homodimers were identified in both HEK293 and SH-SY5Y cells using co-immunoprecipitation experiments and BRET saturation analysis. We performed a hypothesis-driven screen for identification of small-molecule protein–protein interaction modulators of LINGO-1 using a BRET-based assay, adapted for screening. The compound identified was further assessed for effects on LINGO-1 downstream signalling pathways using Western blotting analysis and AlphaScreen technology. Key Results LINGO-1 was present as homodimers in primary neuronal cultures. LINGO-1 interacted homotypically in cis-orientation and LINGO-1 cis-dimers were formed early during LINGO-1 biosynthesis. A BRET-based assay allowed us to identify phenoxybenzamine as the first conformational modulator of LINGO-1 dimers. In HEK-293 cells, phenoxybenzamine was a positive modulator of LINGO-1 function, increasing the LINGO-1-mediated inhibition of EGF receptor signalling and Erk phosphorylation. Conclusions and Implications Our data suggest that LINGO-1 forms constitutive cis-dimers at the plasma membrane and that low MW compounds affecting the conformational state of these dimers can regulate LINGO-1 downstream signalling pathways. We propose that targeting the LINGO-1 dimerization interface opens a new pharmacological approach to the modulation of its function and provides a new strategy for drug discovery. PMID:25257685

  8. Human muscle fibre type-specific regulation of AMPK and downstream targets by exercise

    PubMed Central

    Kristensen, Dorte E; Albers, Peter H; Prats, Clara; Baba, Otto; Birk, Jesper B; Wojtaszewski, Jørgen F P

    2015-01-01

    AMP-activated protein kinase (AMPK) is a regulator of energy homeostasis during exercise. Studies suggest muscle fibre type-specific AMPK expression. However, fibre type-specific regulation of AMPK and downstream targets during exercise has not been demonstrated. We hypothesized that AMPK subunits are expressed in a fibre type-dependent manner and that fibre type-specific activation of AMPK and downstream targets is dependent on exercise intensity. Pools of type I and II fibres were prepared from biopsies of vastus lateralis muscle from healthy men before and after two exercise trials: (1) continuous cycling (CON) for 30 min at 69 ± 1% peak rate of O2 consumption () or (2) interval cycling (INT) for 30 min with 6 × 1.5 min high-intensity bouts peaking at 95 ± 2% . In type I vs. II fibres a higher β1 AMPK (+215%) and lower γ3 AMPK expression (−71%) was found. α1, α2, β2 and γ1 AMPK expression was similar between fibre types. In type I vs. II fibres phosphoregulation after CON was similar (AMPKThr172, ACCSer221, TBC1D1Ser231 and GS2+2a) or lower (TBC1D4Ser704). Following INT, phosphoregulation in type I vs. II fibres was lower (AMPKThr172, TBC1D1Ser231, TBC1D4Ser704 and ACCSer221) or higher (GS2+2a). Exercise-induced glycogen degradation in type I vs. II fibres was similar (CON) or lower (INT). In conclusion, a differentiated response to exercise of metabolic signalling/effector proteins in human type I and II fibres was evident during interval exercise. This could be important for exercise type-specific adaptations, i.e. insulin sensitivity and mitochondrial density, and highlights the potential for new discoveries when investigating fibre type-specific signalling. PMID:25640469

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

    SciTech Connect

    Wang, Yelin; Hu, Chen; Cheng, Jun; Chen, Binquan; Ke, Qinghong; Lv, Zhen; Wu, Jian; Zhou, Yanfeng

    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.

  10. Investment prioritization based on broadscale spatial budgeting to meet downstream targets for suspended sediment loads

    NASA Astrophysics Data System (ADS)

    Lu, Hua; Moran, C. J.; Prosser, Ian P.; Derose, Ronald

    2004-09-01

    On the basis of a spatially distributed sediment budget across a large basin, costs of achieving certain sediment reduction targets in rivers were estimated. A range of investment prioritization scenarios were tested to identify the most cost-effective strategy to control suspended sediment loads. The scenarios were based on successively introducing more information from the sediment budget. The relationship between spatial heterogeneity of contributing sediment sources on cost effectiveness of prioritization was investigated. Cost effectiveness was shown to increase with sequential introduction of sediment budget terms. The solution which most decreased cost was achieved by including spatial information linking sediment sources to the downstream target location. This solution produced cost curves similar to those derived using a genetic algorithm formulation. Appropriate investment prioritization can offer large cost savings because the magnitude of the costs can vary by several times depending on what type of erosion source or sediment delivery mechanism is targeted. Target settings which only consider the erosion source rates can potentially result in spending more money than random management intervention for achieving downstream targets. Coherent spatial patterns of contributing sediment emerge from the budget model and its many inputs. The heterogeneity in these patterns can be summarized in a succinct form. This summary was shown to be consistent with the cost difference between local and regional prioritization for three of four test catchments. To explain the effect for the fourth catchment, the detail of the individual sediment sources needed to be taken into account.

  11. Using mechanistic Bayesian networks to identify downstream targets of the Sonic Hedgehog pathway

    PubMed Central

    2009-01-01

    Background The topology of a biological pathway provides clues as to how a pathway operates, but rationally using this topology information with observed gene expression data remains a challenge. Results We introduce a new general-purpose analytic method called Mechanistic Bayesian Networks (MBNs) that allows for the integration of gene expression data and known constraints within a signal or regulatory pathway to predict new downstream pathway targets. The MBN framework is implemented in an open-source Bayesian network learning package, the Python Environment for Bayesian Learning (PEBL). We demonstrate how MBNs can be used by modeling the early steps of the sonic hedgehog pathway using gene expression data from different developmental stages and genetic backgrounds in mouse. Using the MBN approach we are able to automatically identify many of the known downstream targets of the hedgehog pathway such as Gas1 and Gli1, along with a short list of likely targets such as Mig12. Conclusions The MBN approach shown here can easily be extended to other pathways and data types to yield a more mechanistic framework for learning genetic regulatory models. PMID:20021670

  12. Pharmacologically targeting the primary defect and downstream pathology in Duchenne muscular dystrophy.

    PubMed

    Fairclough, Rebecca J; Perkins, Kelly J; Davies, Kay E

    2012-06-01

    DMD is a devastatingly progressive muscle wasting disorder of childhood that significantly shortens life expectancy. Despite efforts to develop an effective therapy that dates back over a century, clinical interventions are still restricted to management of symptoms rather than a cure. The rationale to develop effective therapies changed in 1986 with the discovery of the dystrophin gene. Since then extensive research into both the molecular basis and pathophysiology of DMD has paved the way not only for development of strategies which aim to correct the primary defect, but also towards the identification of countless therapeutic targets with the potential to alleviate the downstream pathology. In addition to gene and cell-based therapies, which aim to deliver the missing gene and/or protein, an exciting spectrum of pharmacological approaches aimed at modulating therapeutic targets within DMD muscle cells through the use of small drugs are also being developed. This review presents promising pharmacological approaches aimed at targeting the primary defect, including suppression of nonsense mutations and functional compensation by upregulation of the dystrophin homologue, utrophin. Downstream of the primary membrane fragility, inflammation and fibrosis are reduced by blocking NF-κB, TGF-α and TGF-β, and free radical damage has been targeted using antioxidants and dietary/nutritional supplements. There are new hopes that ACE and PDE5 inhibitors can protect against skeletal as well as cardiac pathology, and modulating Ca2+ influx, NO, BMP, protein degradation and the mitochondrial permeability pore hold further promise in tackling the complex pathogenesis of this multifaceted disorder. PMID:22571500

  13. Ethnobiology of snappers (Lutjanidae): target species and suggestions for management.

    PubMed

    Begossi, Alpina; Salivonchyk, Svetlana V; Araujo, Luciana G; Andreoli, Tainá B; Clauzet, Mariana; Martinelli, Claudia M; Ferreira, Allan G I; Oliveira, Luiz E C; Silvano, Renato A M

    2011-01-01

    In this study, we sought to investigate the biology (diet and reproduction) and ethnobiology (fishers knowledge and fishing spots used to catch snappers) of five species of snappers (Lutjanidae), including Lutjanus analis, Lutjanus synagris, Lutjanus vivanus, Ocyurus chrysurus, and Romboplites saliens at five sites along the northeast (Riacho Doce, Maceió in Alagoas State, and Porto do Sauípe, Entre Rios at Bahia State) and the southeast (SE) Brazilian coast (Paraty and Rio de Janeiro cities at Rio de Janeiro State, and Bertioga, at São Paulo State.).We collected 288 snappers and interviewed 86 fishermen. The stomach contents of each fish were examined and macroscopic gonad analysis was performed. Snappers are very important for the fisheries of NE Brazil, and our results indicated that some populations, such as mutton snapper (L. analis) and lane snapper (L. synagris), are being caught when they are too young, at early juvenile stages.Local knowledge has been shown to be a powerful tool for determining appropriate policies regarding management of target species, and artisanal fishermen can be included in management processes. Other suggestions for managing the fisheries are discussed, including proposals that could provide motivation for artisanal fishermen to participate in programs to conserve resources, such as co-management approaches that utilize local knowledge, the establishment of fishing seasons, and compensation of fishermen, through 'payment for environmental services'. These suggestions may enhance the participation of local artisanal fishermen in moving to a more realistic and less top-down management approach of the fish population. PMID:21410969

  14. Ethnobiology of snappers (Lutjanidae): target species and suggestions for management

    PubMed Central

    2011-01-01

    In this study, we sought to investigate the biology (diet and reproduction) and ethnobiology (fishers knowledge and fishing spots used to catch snappers) of five species of snappers (Lutjanidae), including Lutjanus analis, Lutjanus synagris, Lutjanus vivanus, Ocyurus chrysurus, and Romboplites saliens at five sites along the northeast (Riacho Doce, Maceió in Alagoas State, and Porto do Sauípe, Entre Rios at Bahia State) and the southeast (SE) Brazilian coast (Paraty and Rio de Janeiro cities at Rio de Janeiro State, and Bertioga, at São Paulo State.). We collected 288 snappers and interviewed 86 fishermen. The stomach contents of each fish were examined and macroscopic gonad analysis was performed. Snappers are very important for the fisheries of NE Brazil, and our results indicated that some populations, such as mutton snapper (L. analis) and lane snapper (L. synagris), are being caught when they are too young, at early juvenile stages. Local knowledge has been shown to be a powerful tool for determining appropriate policies regarding management of target species, and artisanal fishermen can be included in management processes. Other suggestions for managing the fisheries are discussed, including proposals that could provide motivation for artisanal fishermen to participate in programs to conserve resources, such as co-management approaches that utilize local knowledge, the establishment of fishing seasons, and compensation of fishermen, through 'payment for environmental services'. These suggestions may enhance the participation of local artisanal fishermen in moving to a more realistic and less top-down management approach of the fish population. PMID:21410969

  15. Upstream Regulators and Downstream Effectors of NADPH Oxidases as Novel Therapeutic Targets for Diabetic Kidney Disease

    PubMed Central

    Gorin, Yves; Wauquier, Fabien

    2015-01-01

    Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, the complication of diabetes in the kidney. NADPH oxidases of the Nox family, and in particular the homologue Nox4, are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current knowledge related to the understanding of the role of Nox enzymes in the processes that control mesangial cell, podocyte and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-β. The nature of the upstream modulators of Nox enzymes as well as the downstream targets of the Nox NADPH oxidases implicated in the propagation of the redox processes that alter renal biology in diabetes will be highlighted. PMID:25824546

  16. A long downstream probe-based platform for multiplex target capture.

    PubMed

    Wang, Ping; Huang, Jianqin; Xu, Yingwu

    2015-12-15

    A simple and rapid detection platform was established for multiplex target capture through generating single-strand long downstream probe (ssLDP), which was integrated with the ligase detection reaction (LDR) method for the purpose of multiplicity and high specificity. To increase sensitivity, the ladder-like polymerase chain reaction (PCR) amplicons were generated by using universal primers that complement ligated products. Each of the amplicons contained a stuffer sequence with a defined yet variable length. Thus, the length of the amplicon is an index of the specific suppressor, allowing its identification via electrophoresis. The multiplexed diagnostic platform was optimized using standard plasmids and validated by using potato virus suppressors as a detection model. This technique can detect down to 1.2 × 10(3) copies for single or two mixed target plasmids. When compared with microarray results, the electrophoresis showed 98.73-100% concordance rates for the seven suppressors in the 79 field samples. This strategy could be applied to detect a large number of targets in field and clinical surveillance. PMID:26344895

  17. Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development

    PubMed Central

    Makki, Nadja; Capecchi, Mario R.

    2011-01-01

    Hoxgenes play a crucial role during embryonic patterning and organogenesis. Of the 39 Hox genes, Hoxa1 is the first to be expressed during embryogenesis and the only anterior Hox gene linked to a human syndrome. Hoxa1 is necessary for proper development of the brainstem, inner ear and heart in humans and mice; however, almost nothing is known about the molecular downstream targets through which it exerts its function. To gain insight into the transcriptional network regulated by this protein, we performed microarray analysis on tissue microdissected from the prospective rhombomere 3–5 region of Hoxa1 null and wild type embryos. Due to the very early and transient expression of this gene, dissections were performed on early somite stage embryos during an eight-hour time window of development. Our array yielded a list of around 300 genes differentially expressed between the two samples. Many of the identified genes play a role in a specific developmental or cellular process. Some of the validated targets regulate early neural crest induction and specification. Interestingly, three of these genes, Zic1, Hnf1b and Foxd3, were down-regulated in the posterior hindbrain, where cardiac neural crest cells arise, which pattern the outflow tract of the heart. Other targets are necessary for early inner ear development, e.g. Pax8 and Fgfr3 or are expressed in specific hindbrain neurons regulating respiration, e.g. Lhx5. These findings allow us to propose a model where Hoxa1 acts in a genetic cascade upstream of genes controlling specific aspects of embryonic development, thereby providing insight into possible mechanisms underlying the human HoxA1-syndrome. PMID:21784065

  18. RNA Interference Mediated Interleukin-1β Silencing in Inflamed Chondrocytes Decreases Target and Downstream Catabolic Responses

    PubMed Central

    Ortved, Kyla F.; Austin, Bethany S.; Scimeca, Michael S.; Nixon, Alan J.

    2016-01-01

    Posttraumatic activation of the catabolic cascade plays a major role in degradation of cartilage. Interleukin-1β (IL-1β), a primary instigator in the catabolic axis, is upregulated in chondrocytes following injury. IL-1β activates key degradative enzymes, including MMPs and aggrecanases, and other proinflammatory mediators such as PGE2 which contribute to ECM breakdown. Posttranscriptional silencing of IL-1β by RNA interference (RNAi) may drive a reduction in IL-1β. We hypothesized that transduction of chondrocytes using rAAV2 expressing a short hairpin RNAi motif targeting IL-1β (shIL-1β) would significantly decrease IL-1β expression and, in turn, decrease expression of other catabolic enzymes. Chondrocyte cultures were transduced with rAAV2-tdT-shIL-1β in serum-free media. The fluorescent protein, tdTomato, was used to determine transduction efficiency via flow cytometry and fluorescent microscopy. Cells were stimulated with lipopolysaccharide (LPS) 48 hours following transduction. After 24-hour stimulation, supernatants were collected for cytokine analysis, and cells lysed for gene expression analysis. IL-1β knockdown led to significantly decreased expression of IL-1β, TNF-α, and ADAMTS5. PGE2 synthesis was also significantly downregulated. Overall, effective silencing of IL-1β using rAAV2 vector expressing a short hairpin IL-1β knockdown sequence was shown. Additionally, significant downstream effects were evident, including decreased expression of TNF-α and ADAMTS5. Targeted silencing of catabolic cytokines may provide a promising treatment avenue for osteoarthritic (OA) joints. PMID:27073697

  19. RNA Interference Mediated Interleukin-1β Silencing in Inflamed Chondrocytes Decreases Target and Downstream Catabolic Responses.

    PubMed

    Ortved, Kyla F; Austin, Bethany S; Scimeca, Michael S; Nixon, Alan J

    2016-01-01

    Posttraumatic activation of the catabolic cascade plays a major role in degradation of cartilage. Interleukin-1β (IL-1β), a primary instigator in the catabolic axis, is upregulated in chondrocytes following injury. IL-1β activates key degradative enzymes, including MMPs and aggrecanases, and other proinflammatory mediators such as PGE2 which contribute to ECM breakdown. Posttranscriptional silencing of IL-1β by RNA interference (RNAi) may drive a reduction in IL-1β. We hypothesized that transduction of chondrocytes using rAAV2 expressing a short hairpin RNAi motif targeting IL-1β (shIL-1β) would significantly decrease IL-1β expression and, in turn, decrease expression of other catabolic enzymes. Chondrocyte cultures were transduced with rAAV2-tdT-shIL-1β in serum-free media. The fluorescent protein, tdTomato, was used to determine transduction efficiency via flow cytometry and fluorescent microscopy. Cells were stimulated with lipopolysaccharide (LPS) 48 hours following transduction. After 24-hour stimulation, supernatants were collected for cytokine analysis, and cells lysed for gene expression analysis. IL-1β knockdown led to significantly decreased expression of IL-1β, TNF-α, and ADAMTS5. PGE2 synthesis was also significantly downregulated. Overall, effective silencing of IL-1β using rAAV2 vector expressing a short hairpin IL-1β knockdown sequence was shown. Additionally, significant downstream effects were evident, including decreased expression of TNF-α and ADAMTS5. Targeted silencing of catabolic cytokines may provide a promising treatment avenue for osteoarthritic (OA) joints. PMID:27073697

  20. Rbfox proteins regulate microRNA biogenesis by sequence-specific binding to their precursors and target downstream Dicer

    PubMed Central

    Chen, Yu; Zubovic, Lorena; Yang, Fan; Godin, Katherine; Pavelitz, Tom; Castellanos, Javier; Macchi, Paolo; Varani, Gabriele

    2016-01-01

    Rbfox proteins regulate tissue-specific splicing by targeting a conserved GCAUG sequence within pre-mRNAs. We report here that sequence-specific binding of the conserved Rbfox RRM to miRNA precursors containing the same sequence motif in their terminal loops, including miR-20b and miR-107, suppresses their nuclear processing. The structure of the complex between precursor miR-20b and Rbfox RRM shows the molecular basis for recognition, and reveals changes in the stem-loop upon protein binding. In mammalian cells, Rbfox2 downregulates mature miR-20b and miR-107 levels and increases the expression of their downstream targets PTEN and Dicer, respectively, suggesting that Rbfox2 indirectly regulates many more cellular miRNAs. Thus, some of the widespread cellular functions of Rbfox2 protein are attributable to regulation of miRNA biogenesis, and might include the mis-regulation of miR-20b and miR-107 in cancer and neurodegeneration. PMID:27001519

  1. Rbfox proteins regulate microRNA biogenesis by sequence-specific binding to their precursors and target downstream Dicer.

    PubMed

    Chen, Yu; Zubovic, Lorena; Yang, Fan; Godin, Katherine; Pavelitz, Tom; Castellanos, Javier; Macchi, Paolo; Varani, Gabriele

    2016-05-19

    Rbfox proteins regulate tissue-specific splicing by targeting a conserved GCAUG sequence within pre-mRNAs. We report here that sequence-specific binding of the conserved Rbfox RRM to miRNA precursors containing the same sequence motif in their terminal loops, including miR-20b and miR-107, suppresses their nuclear processing. The structure of the complex between precursor miR-20b and Rbfox RRM shows the molecular basis for recognition, and reveals changes in the stem-loop upon protein binding. In mammalian cells, Rbfox2 downregulates mature miR-20b and miR-107 levels and increases the expression of their downstream targets PTEN and Dicer, respectively, suggesting that Rbfox2 indirectly regulates many more cellular miRNAs. Thus, some of the widespread cellular functions of Rbfox2 protein are attributable to regulation of miRNA biogenesis, and might include the mis-regulation of miR-20b and miR-107 in cancer and neurodegeneration. PMID:27001519

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

    PubMed

    Wada, Takeyoshi; Asahi, Toru; Sawamura, Naoya

    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. PMID:27329811

  3. Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer

    PubMed Central

    Heinonen, Henna; Nieminen, Anni; Saarela, Matti; Kallioniemi, Anne; Klefström, Juha; Hautaniemi, Sampsa; Monni, Outi

    2008-01-01

    Background The 70 kDa ribosomal protein S6 kinase (RPS6KB1), located at 17q23, is amplified and overexpressed in 10–30% of primary breast cancers and breast cancer cell lines. p70S6K is a serine/threonine kinase regulated by PI3K/mTOR pathway, which plays a crucial role in control of cell cycle, growth and survival. Our aim was to determine p70S6K and PI3K/mTOR/p70S6K pathway dependent gene expression profiles by microarrays using five breast cancer cell lines with predefined gene copy number and gene expression alterations. The p70S6K dependent profiles were determined by siRNA silencing of RPS6KB1 in two breast cancer cell lines overexpressing p70S6K. These profiles were further correlated with gene expression alterations caused by inhibition of PI3K/mTOR pathway with PI3K inhibitor Ly294002 or mTOR inhibitor rapamycin. Results Altogether, the silencing of p70S6K altered the expression of 109 and 173 genes in two breast cancer cell lines and 67 genes were altered in both cell lines in addition to RPS6KB1. Furthermore, 17 genes including VTCN1 and CDKN2B showed overlap with genes differentially expressed after PI3K or mTOR inhibition. The gene expression signatures responsive to both PI3K/mTOR pathway and p70S6K inhibitions revealed previously unidentified genes suggesting novel downstream targets for PI3K/mTOR/p70S6K pathway. Conclusion Since p70S6K overexpression is associated with aggressive disease and poor prognosis of breast cancer patients, the potential downstream targets of p70S6K and the whole PI3K/mTOR/p70S6K pathway identified in our study may have diagnostic value. PMID:18652687

  4. Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin

    PubMed Central

    Law, Ivy Ka Man; Jensen, Dane; Bunnett, Nigel W.; Pothoulakis, Charalabos

    2016-01-01

    Neurotensin (NT) triggers signaling in human colonic epithelial cells by activating the G protein-coupled receptor, the neurotensin receptor 1 (NTR1). Activated NTR1 traffics from the plasma membrane to early endosomes, and then recycles. Although sustained NT/NTR1 signaling requires efficient NTR1 recycling, little is known about the regulation of NTR1 recycling. We recently showed that NT/NTR1 signaling increases expression of miR-133α. Herein, we studied the mechanism of NT-regulated miR-133α expression and examined the role of miR-133α in intracellular NTR1 trafficking in human NCM460 colonocytes. We found that NT-induced miR-133α upregulation involves the negative transcription regulator, zinc finger E-box binding homeobox 1. Silencing of miR-133α or overexpression of aftiphilin (AFTPH), a binding target of miR-133α, attenuated NTR1 trafficking to plasma membrane in human colonocytes, without affecting NTR1 internalization. We localized AFTPH to early endosomes and the trans-Golgi network (TGN) in unstimulated human colonic epithelial cells. AFTPH overexpression reduced NTR1 localization in early endosomes and increased expression of proteins related to endosomes and the TGN trafficking pathway. AFTPH overexpression and de-acidification of intracellular vesicles increased NTR1 expression. Our results suggest a novel mechanism of GPCR trafficking in human colonic epithelial cells by which a microRNA, miR-133α regulates NTR1 trafficking through its downstream target AFTPH. PMID:26902265

  5. Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin.

    PubMed

    Law, Ivy Ka Man; Jensen, Dane; Bunnett, Nigel W; Pothoulakis, Charalabos

    2016-01-01

    Neurotensin (NT) triggers signaling in human colonic epithelial cells by activating the G protein-coupled receptor, the neurotensin receptor 1 (NTR1). Activated NTR1 traffics from the plasma membrane to early endosomes, and then recycles. Although sustained NT/NTR1 signaling requires efficient NTR1 recycling, little is known about the regulation of NTR1 recycling. We recently showed that NT/NTR1 signaling increases expression of miR-133α. Herein, we studied the mechanism of NT-regulated miR-133α expression and examined the role of miR-133α in intracellular NTR1 trafficking in human NCM460 colonocytes. We found that NT-induced miR-133α upregulation involves the negative transcription regulator, zinc finger E-box binding homeobox 1. Silencing of miR-133α or overexpression of aftiphilin (AFTPH), a binding target of miR-133α, attenuated NTR1 trafficking to plasma membrane in human colonocytes, without affecting NTR1 internalization. We localized AFTPH to early endosomes and the trans-Golgi network (TGN) in unstimulated human colonic epithelial cells. AFTPH overexpression reduced NTR1 localization in early endosomes and increased expression of proteins related to endosomes and the TGN trafficking pathway. AFTPH overexpression and de-acidification of intracellular vesicles increased NTR1 expression. Our results suggest a novel mechanism of GPCR trafficking in human colonic epithelial cells by which a microRNA, miR-133α regulates NTR1 trafficking through its downstream target AFTPH. PMID:26902265

  6. Salicylate-mediated suppression of jasmonate-responsive gene expression in Arabidopsis is targeted downstream of the jasmonate biosynthesis pathway

    PubMed Central

    Leon-Reyes, Antonio; Van der Does, Dieuwertje; De Lange, Elvira S.; Delker, Carolin; Wasternack, Claus; Van Wees, Saskia C. M.; Ritsema, Tita

    2010-01-01

    Jasmonates (JAs) and salicylic acid (SA) are plant hormones that play pivotal roles in the regulation of induced defenses against microbial pathogens and insect herbivores. Their signaling pathways cross-communicate providing the plant with a regulatory potential to finely tune its defense response to the attacker(s) encountered. In Arabidopsis thaliana, SA strongly antagonizes the jasmonic acid (JA) signaling pathway, resulting in the downregulation of a large set of JA-responsive genes, including the marker genes PDF1.2 and VSP2. Induction of JA-responsive marker gene expression by different JA derivatives was equally sensitive to SA-mediated suppression. Activation of genes encoding key enzymes in the JA biosynthesis pathway, such as LOX2, AOS, AOC2, and OPR3 was also repressed by SA, suggesting that the JA biosynthesis pathway may be a target for SA-mediated antagonism. To test this, we made use of the mutant aos/dde2, which is completely blocked in its ability to produce JAs because of a mutation in the ALLENE OXIDE SYNTHASE gene. Mutant aos/dde2 plants did not express the JA-responsive marker genes PDF1.2 or VSP2 in response to infection with the necrotrophic fungus Alternaria brassicicola or the herbivorous insect Pieris rapae. Bypassing JA biosynthesis by exogenous application of methyl jasmonate (MeJA) rescued this JA-responsive phenotype in aos/dde2. Application of SA suppressed MeJA-induced PDF1.2 expression to the same level in the aos/dde2 mutant as in wild-type Col-0 plants, indicating that SA-mediated suppression of JA-responsive gene expression is targeted at a position downstream of the JA biosynthesis pathway. PMID:20839007

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

    NASA Astrophysics Data System (ADS)

    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

  8. RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo.

    PubMed

    Takeda, Yukimasa; Jothi, Raja; Birault, Veronique; Jetten, Anton M

    2012-09-01

    In this study, we demonstrate that the lack of retinoic acid-related orphan receptor (ROR) γ or α expression in mice significantly reduced the peak expression level of Cry1, Bmal1, E4bp4, Rev-Erbα and Per2 in an ROR isotype- and tissue-selective manner without affecting the phase of their rhythmic expression. Analysis of RORγ/RORα double knockout mice indicated that in certain tissues RORγ and RORα exhibited a certain degree of redundancy in regulating clock gene expression. Reporter gene analysis showed that RORγ was able to induce reporter gene activity through the RORE-containing regulatory regions of Cry1, Bmal1, Rev-Erbα and E4bp4. Co-expression of Rev-Erbα or addition of a novel ROR antagonist repressed this activation. ChIP-Seq and ChIP-Quantitative real-time polymerase chain reaction (QPCR) analysis demonstrated that in vivo RORγ regulate these genes directly and in a Zeitgeber time (ZT)-dependent manner through these ROREs. This transcriptional activation by RORs was associated with changes in histone acetylation and chromatin accessibility. The rhythmic expression of RORγ1 by clock proteins may lead to the rhythmic expression of RORγ1 target genes. The presence of RORγ binding sites and its down-regulation in RORγ-/- liver suggest that the rhythmic expression of Avpr1a depends on RORγ consistent with the concept that RORγ1 provides a link between the clock machinery and its regulation of metabolic genes. PMID:22753030

  9. Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1.

    PubMed

    Lai, Yu-Chiang; Kondapalli, Chandana; Lehneck, Ronny; Procter, James B; Dill, Brian D; Woodroof, Helen I; Gourlay, Robert; Peggie, Mark; Macartney, Thomas J; Corti, Olga; Corvol, Jean-Christophe; Campbell, David G; Itzen, Aymelt; Trost, Matthias; Muqit, Miratul Mk

    2015-11-12

    Mutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser(65)) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub-family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser(111)) in response to PINK1 activation. Using phospho-specific antibodies raised against Ser(111) of each of the Rabs, we demonstrate that Rab Ser(111) phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient-derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser(111) phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser(111) phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser(65). We further show mechanistically that phosphorylation at Ser(111) significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser(111) may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase-mediated signalling may represent a major mechanism

  10. Uncovering potential downstream targets of oncogenic GRPR overexpression in prostate carcinomas harboring ETS rearrangements.

    PubMed

    Santos, Joana; Mesquita, Diana; Barros-Silva, João D; Jerónimo, Carmen; Henrique, Rui; Morais, António; Paulo, Paula; Teixeira, Manuel R

    2015-01-01

    Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in several human malignancies, including prostate cancer, and has been implicated in multiple important neoplastic signaling pathways. We recently have shown that GRPR is an ERG and ETV1 target gene in prostate cancer, using a genome-wide scale and exon-level expression microarray platform. Due to its cellular localization, the relevance of its function and the availability of blocking agents, GRPR seems to be a promising candidate as therapeutic target. Our present work shows that effective knockdown of GRPR in LNCaP and VCaP cells attenuates their malignant phenotype by decreasing proliferation, invasion and anchorage-independent growth, while increasing apoptosis. Using an antibody microarray we were able to validate known and identify new targets of GRPR pathway, namely AKT1, PKCε, TYK2 and MST1. Finally, we show that overexpression of these GRPR targets is restricted to prostate carcinomas harboring ERG and/or ETV1 rearrangements, establishing their potential as therapeutic targets for these particular molecular subsets of the disease. PMID:26097883

  11. Uncovering potential downstream targets of oncogenic GRPR overexpression in prostate carcinomas harboring ETS rearrangements

    PubMed Central

    Santos, Joana; Mesquita, Diana; Barros-Silva, João D.; Jerónimo, Carmen; Henrique, Rui; Morais, António; Paulo, Paula; Teixeira, Manuel R.

    2015-01-01

    Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in several human malignancies, including prostate cancer, and has been implicated in multiple important neoplastic signaling pathways. We recently have shown that GRPR is an ERG and ETV1 target gene in prostate cancer, using a genome-wide scale and exon-level expression microarray platform. Due to its cellular localization, the relevance of its function and the availability of blocking agents, GRPR seems to be a promising candidate as therapeutic target. Our present work shows that effective knockdown of GRPR in LNCaP and VCaP cells attenuates their malignant phenotype by decreasing proliferation, invasion and anchorage-independent growth, while increasing apoptosis. Using an antibody microarray we were able to validate known and identify new targets of GRPR pathway, namely AKT1, PKCε, TYK2 and MST1. Finally, we show that overexpression of these GRPR targets is restricted to prostate carcinomas harboring ERG and/or ETV1 rearrangements, establishing their potential as therapeutic targets for these particular molecular subsets of the disease. PMID:26097883

  12. Identification of cyclins A1, E1 and vimentin as downstream targets of heme oxygenase-1 in vascular endothelial growth factor-mediated angiogenesis

    PubMed Central

    Bauer, Andrea; Mylroie, Hayley; Thornton, C. Clare; Calay, Damien; Birdsey, Graeme M.; Kiprianos, Allan P.; Wilson, Garrick K.; Soares, Miguel P.; Yin, Xiaoke; Mayr, Manuel; Randi, Anna M.; Mason, Justin C.

    2016-01-01

    Angiogenesis is an essential physiological process and an important factor in disease pathogenesis. However, its exploitation as a clinical target has achieved limited success and novel molecular targets are required. Although heme oxygenase-1 (HO-1) acts downstream of vascular endothelial growth factor (VEGF) to modulate angiogenesis, knowledge of the mechanisms involved remains limited. We set out identify novel HO-1 targets involved in angiogenesis. HO-1 depletion attenuated VEGF-induced human endothelial cell (EC) proliferation and tube formation. The latter response suggested a role for HO-1 in EC migration, and indeed HO-1 siRNA negatively affected directional migration of EC towards VEGF; a phenotype reversed by HO-1 over-expression. EC from Hmox1−/− mice behaved similarly. Microarray analysis of HO-1-depleted and control EC exposed to VEGF identified cyclins A1 and E1 as HO-1 targets. Migrating HO-1-deficient EC showed increased p27, reduced cyclin A1 and attenuated cyclin-dependent kinase 2 activity. In vivo, cyclin A1 siRNA inhibited VEGF-driven angiogenesis, a response reversed by Ad-HO-1. Proteomics identified structural protein vimentin as an additional VEGF-HO-1 target. HO-1 depletion inhibited VEGF-induced calpain activity and vimentin cleavage, while vimentin silencing attenuated HO-1-driven proliferation. Thus, vimentin and cyclins A1 and E1 represent VEGF-activated HO-1-dependent targets important for VEGF-driven angiogenesis. PMID:27388959

  13. Requirement of Mammalian Target of Rapamycin Complex 1 Downstream Effectors in Cued Fear Memory Reconsolidation and Its Persistence

    PubMed Central

    Huynh, Thu N.; Santini, Emanuela

    2014-01-01

    Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)–eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2-nitrophenyl)]propionic acid), an inhibitor of eFI4E–eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E–eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted in memory destabilization 10 d after reactivation, whereas inhibition of eIF4E–eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence of memory at longer intervals after memory reactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence. PMID:24990923

  14. GSK3β, But Not GSK3α, Inhibits the Neuronal Differentiation of Neural Progenitor Cells As a Downstream Target of Mammalian Target of Rapamycin Complex1

    PubMed Central

    Ahn, Jyhyun; Jang, Jiwon; Choi, Jinyong; Lee, Junsub; Oh, Seo-Ho; Lee, Junghun; Yoon, Keejung

    2014-01-01

    Glycogen synthase kinase 3 (GSK3) acts as an important regulator during the proliferation and differentiation of neural progenitor cells (NPCs), but the roles of the isoforms of this molecule (GSK3α and GSK3β) have not been clearly defined. In this study, we investigated the functions of GSK3α and GSK3β in the context of neuronal differentiation of murine NPCs. Treatment of primary NPCs with a GSK3 inhibitor (SB216763) resulted in an increase in the percentage of TuJ1-positive immature neurons, suggesting an inhibitory role of GSK3 in embryonic neurogenesis. Downregulation of GSK3β expression increased the percentage of TuJ1-positive cells, while knock-down of GSK3α seemed to have no effect. When primary NPCs were engineered to stably express either isoform of GSK3 using retroviral vectors, GSK3β, but not GSK3α, inhibited neuronal differentiation and helped the cells to maintain the characteristics of NPCs. Mutant GSK3β (Y216F) failed to suppress neuronal differentiation, indicating that the kinase activity of GSK3β is important for this regulatory function. Similar results were obtained in vivo when a retroviral vector expressing GSK3β was delivered to E9.5 mouse brains using the ultrasound image-guided gene delivery technique. In addition, SB216763 was found to block the rapamycin-mediated inhibition of neuronal differentiation of NPCs. Taken together, our results demonstrate that GSK3β, but not GSK3α, negatively controls the neuronal differentiation of progenitor cells and that GSK3β may act downstream of the mammalian target of rapamycin complex1 signaling pathway. PMID:24397546

  15. C. elegans sym-1 is a downstream target of the hunchback-like-1 developmental timing transcription factor

    PubMed Central

    Niwa, Ryusuke; Hada, Kazumasa; Moliyama, Kouichi; Ohniwa, Ryosuke L.; Tan, Yi-Meng; Olsson-Carter, Katherine; Chi, Woo; Reinke, Valerie; Slack, Frank J.

    2010-01-01

    In the nematode Caenorhabditis elegans, the let-7 microRNA (miRNA) and its family members control the timing of key developmental events in part by directly regulating expression of hunchback-like-1 (hbl-1). C. elegans hbl-1 mutants display multiple developmental timing deficiencies, including cell cycle defects during larval development. While hbl-1 is predicted to encode a transcriptional regulator, downstream targets of HBL-1 have not been fully elucidated. Here we report using microarray analysis to uncover genes downstream of HBL-1. We established a transgenic strain that overexpresses hbl-1 under the control of a heat shock promoter. Heat shock-induced hbl-1 overexpression led to retarded hypodermal structures at the adult stage, opposite to the effect seen in loss of function (lf) hbl-1 mutants. The microarray screen identified numerous potential genes that are upregulated or downregulated by HBL-1, including sym-1, which encodes a leucine-rich repeat protein with a signal sequence. We found an increase in sym-1 transcription in the heat shock-induced hbl-1 overexpression strain, while loss of hbl-1 function caused a decrease in sym-1 expression levels. Furthermore, we found that sym-1(lf) modified the hypodermal abnormalities in hbl-1 mutants. Given that SYM-1 is a protein secreted from hypodermal cells to the surrounding cuticle, we propose that the adult-specific cuticular structures may be under the temporal control of HBL-1 through regulation of sym-1 transcription. PMID:19923914

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

    SciTech Connect

    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.

  17. Chick Lrrn2, a novel downstream effector of Hoxb1 and Shh, functions in the selective targeting of rhombomere 4 motor neurons

    PubMed Central

    Andreae, Laura C; Lumsden, Andrew; Gilthorpe, Jonathan D

    2009-01-01

    Background Capricious is a Drosophila adhesion molecule that regulates specific targeting of a subset of motor neurons to their muscle target. We set out to identify whether one of its vertebrate homologues, Lrrn2, might play an analogous role in the chick. Results We have shown that Lrrn2 is expressed from early development in the prospective rhombomere 4 (r4) of the chick hindbrain. Subsequently, its expression in the hindbrain becomes restricted to a specific group of motor neurons, the branchiomotor neurons of r4, and their pre-muscle target, the second branchial arch (BA2), along with other sites outside the hindbrain. Misexpression of the signalling molecule Sonic hedgehog (Shh) via in ovo electroporation results in upregulation of Lrrn2 exclusively in r4, while the combined expression of Hoxb1 and Shh is sufficient to induce ectopic Lrrn2 in r1/2. Misexpression of Lrrn2 in r2/3 results in axonal rerouting from the r2 exit point to the r4 exit point and BA2, suggesting a direct role in motor axon guidance. Conclusion Lrrn2 acts downstream of Hoxb1 and plays a role in the selective targeting of r4 motor neurons to BA2. PMID:19602272

  18. Arsenic-induced mitochondrial oxidative damage is mediated by decreased PGC-1α expression and its downstream targets in rat brain.

    PubMed

    Prakash, Chandra; Kumar, Vijay

    2016-08-25

    The present study was carried out to investigate the molecular mechanism of arsenic-induced mitochondrial oxidative damage and its relation to biogenesis in rat brain. Chronic sodium arsenite (25 ppm, orally) administration for 12 weeks decreased mitochondrial complexes activities and mRNA expression of selective complexes subunits. The expression of mitochondrial biogenesis regulator PGC-1α, and its downstream targets NRF-1, NRF-2 and Tfam were decreased significantly both at mRNA and protein levels suggesting impaired biogenesis following chronic arsenic-exposure. In addition to this, protein expression analysis also revealed activation of Bax and caspase-3, leading to translocation of cytochrome c from mitochondria to cytosol suggesting induction of apoptotic pathway under oxidative stress. This was further confirmed by electron microscopy study which depicted morphological changes in mitochondria in terms of altered nuclear and mitochondrial shape and chromatin condensation in arsenic-treated rats. The immunohistochemical studies showed both nuclear and cytosolic localization of NRF-1 and NRF-2 in arsenic-exposed rat brain further suggesting regulatory role of these transcription factors under arsenic neurotoxicity. The results of present study indicate that arsenic-induced mitochondrial oxidative damage is associated with decreased mitochondrial biogenesis in rat brain that may present as important target to reveal the mechanism for arsenic-induced neurotoxicity. PMID:27425645

  19. Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model

    PubMed Central

    Lineweaver, Charles H.; Davies, Paul C.W.; Vincent, Mark D.

    2014-01-01

    In the atavistic model of cancer progression, tumor cell dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities. The more recently evolved capabilities are compromised first during cancer progression. This suggests a therapeutic strategy for targeting cancer: design challenges to cancer that can only be met by the recently evolved capabilities no longer functional in cancer cells. We describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. This leaves tumor cells more vulnerable than healthy tissue to pathogenic attack. Such a target-the-weakness therapeutic strategy has broad applications, and contrasts with current therapies that target the main strength of cancer: cell proliferation. PMID:25043755

  20. T3-induced liver AMP-activated protein kinase signaling: Redox dependency and upregulation of downstream targets

    PubMed Central

    Videla, Luis A; Fernández, Virginia; Cornejo, Pamela; Vargas, Romina; Morales, Paula; Ceballo, Juan; Fischer, Alvaro; Escudero, Nicolás; Escobar, Oscar

    2014-01-01

    AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver. METHODS: Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T3. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA). RESULTS: T3 upregulates AMPK signaling, including the upstream kinases Ca2+-calmodulin-dependent protein kinase kinase-β and transforming growth factor-β-activated kinase-1, with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1α (CPT-1α) activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO. CONCLUSION: T3 administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T3 preconditioning against ischemia-reperfusion injury. PMID:25516653

  1. Epigenetic regulation of miRNA-124 and multiple downstream targets is associated with treatment response in myeloid malignancies

    PubMed Central

    Liu, Hongbin; Pattie, Phillip; Chandrasekara, Sahan; Spencer, Andrew; Dear, Anthony E.

    2016-01-01

    Epigenetic regulation of microRNA (miRNA) expression has recently been implicated in the pathogenesis of myelodysplastic syndrome (MDS). Particular interest has focused on miRNA-124 expression, which is inhibited in MDS and has recently been demonstrated to be upregulated in response to epigenetic treatment (EGT). Previous studies have determined the in vitro and in vivo expression of miRNA-124 and several molecular targets, including cyclin-dependent kinase (CDK) 4, CDK6 and enhancer of zeste homolog 2 (EZH2), in order to elucidate the molecular mechanisms associated with the miRNA-124-mediated therapeutic response to EGT in MDS and identify additional potential biomarkers of early EGT treatment response in myeloid malignancies. In vitro studies in the HL60 leukemic cell line identified upregulation of miRNA-124 expression in response to single-agent EGT with either azacytidine (AZA) or the histone deacetylase inhibitor panobinostat (LBH589). Combination EGT with AZA and LBH589 resulted in significant additive induction of miRNA-124 expression. Expression of downstream targets of miRNA-124, including CDK4, CDK6 and EZH2, in response to single agent and combined EGT was determined in HL60 cells. Single and combination EGT treatment resulted in inhibition of CDK4, CDK6 and EZH2 expression with combination EGT resulting in a significant and additive inhibitory effect. In vivo studies using peripheral blood mononuclear cells from patients receiving combination EGT for high risk MDS or acute myeloid leukemia demonstrated significant induction of miRNA-124 and inhibition CDK4 and CDK6 messenger (m)RNA expression in patients that responded to combination EGT. A trend to inhibited EZH2 mRNA expression was also identified in response to combination EGT. Overall, the present observations identify a potential molecular mechanism for miRNA-124-mediated response to EGT involving regulation of CDK4, CDK6 and EZH2 expression. In addition, the present findings further qualify mi

  2. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.

    PubMed

    Tee, Andrew R; Fingar, Diane C; Manning, Brendan D; Kwiatkowski, David J; Cantley, Lewis C; Blenis, John

    2002-10-15

    Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased association of 4E-BP1 with eIF4E; importantly, a mutant of TSC2 derived from TSC patients was defective in repressing phosphorylation of 4E-BP1. Second, the activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the activity of rapamycin-resistant mutants of S6K1 were not affected, implicating mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR. These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets. PMID:12271141

  3. Identification of several potential chromatin binding sites of HOXB7 and its downstream target genes in breast cancer

    PubMed Central

    Heinonen, Henna; Lepikhova, Tatiana; Sahu, Biswajyoti; Pehkonen, Henna; Pihlajamaa, Päivi; Louhimo, Riku; Gao, Ping; Wei, Gong‐Hong; Hautaniemi, Sampsa; Jänne, Olli A.

    2015-01-01

    HOXB7 encodes a transcription factor that is overexpressed in a number of cancers and encompasses many oncogenic functions. Previous results have shown it to promote cell proliferation, angiogenesis, epithelial–mesenchymal transition, DNA repair and cell survival. Because of its role in many cancers and tumorigenic processes, HOXB7 has been suggested to be a potential drug target. However, HOXB7 binding sites on chromatin and its targets are poorly known. The aim of our study was to identify HOXB7 binding sites on breast cancer cell chromatin and to delineate direct target genes located nearby these binding sites. We found 1,504 HOXB7 chromatin binding sites in BT‐474 breast cancer cell line that overexpresses HOXB7. Seventeen selected binding sites were validated by ChIP‐qPCR in several breast cancer cell lines. Furthermore, we analyzed expression of a large number of genes located nearby HOXB7 binding sites and found several new direct targets, such as CTNND2 and SCGB1D2. Identification of HOXB7 chromatin binding sites and target genes is essential to understand better the role of HOXB7 in breast cancer and mechanisms by which it regulates tumorigenic processes. PMID:26014856

  4. Identification of Aurora Kinase B and Wee1-Like Protein Kinase as Downstream Targets of V600EB-RAF in Melanoma

    PubMed Central

    Sharma, Arati; Madhunapantula, SubbaRao V.; Gowda, Raghavendra; Berg, Arthur; Neves, Rogerio I.; Robertson, Gavin P.

    2014-01-01

    BRAF is the most mutated gene in melanoma, with approximately 50% of patients containing V600E mutant protein. V600EB-RAF can be targeted using pharmacological agents, but resistance develops in patients by activating other proteins in the signaling pathway. Identifying downstream members in this signaling cascade is important to design strategies to avoid the development of resistance. Unfortunately, downstream proteins remain to be identified and therapeutic potential requires validation. A kinase screen was undertaken to identify downstream targets in the V600EB-RAF signaling cascade. Involvement of aurora kinase B (AURKB) and Wee1-like protein kinase (WEE1) as downstream proteins in the V600EB-RAF pathway was validated in xenografted tumors, and mechanisms of action were characterized in size- and time-matched tumors. Levels of only AURKB and WEE1 decreased in melanoma cells, when V600EB-RAF, mitogen-activated protein kinase 1/2, or extracellular signal–regulated kinase 1/2 protein levels were reduced using siRNA compared with other identified kinases. AURKB and WEE1 were expressed in tumors of patients with melanoma at higher levels than observed in normal human melanocytes. Targeting these proteins reduced tumor development by approximately 70%, similar to that observed when inhibiting V600EB-RAF. Furthermore, protein or activity levels of AURKB and WEE1 decreased in melanoma cells when pharmacological agents targeting upstream V600EB-RAF or mitogen-activated protein kinase were used to inhibit the V600EB-RAF pathway. Thus, AURKB and WEE1 are targets and biomarkers of therapeutic efficacy, lying downstream of V600EB-RAF in melanomas. PMID:23416158

  5. Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci

    PubMed Central

    Miller, Clint; Pjanic, Milos; Castano, Victor G.; Kim, Juyong B.; Salfati, Elias L.; Kundaje, Anshul B.; Bejerano, Gill; Assimes, Themistocles; Yang, Xia; Quertermous, Thomas

    2015-01-01

    To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including “growth factor binding,” “matrix interaction,” and “smooth muscle contraction.” We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology. PMID:26020271

  6. ZBTB16 as a Downstream Target Gene of Osterix Regulates Osteoblastogenesis of Human Multipotent Mesenchymal Stromal Cells.

    PubMed

    Onizuka, Satoru; Iwata, Takanori; Park, Sung-Joon; Nakai, Kenta; Yamato, Masayuki; Okano, Teruo; Izumi, Yuichi

    2016-10-01

    Human multipotent mesenchymal stromal cells (hMSCs) possess the ability to differentiate into osteoblasts, and they can be utilized as a source for bone regenerative therapy. Osteoinductive pretreatment, which induces the osteoblastic differentiation of hMSCs in vitro, has been widely used for bone tissue engineering prior to cell transplantation. However, the molecular basis of osteoblastic differentiation induced by osteoinductive medium (OIM) is still unknown. Therefore, we used a next-generation sequencer to investigate the changes in gene expression during the osteoblastic differentiation of hMSCs. The hMSCs used in this study possessed both multipotency and self-renewal ability. Whole-transcriptome analysis revealed that the expression of zinc finger and BTB domain containing 16 (ZBTB16) was significantly increased during the osteoblastogenesis of hMSCs. ZBTB16 mRNA and protein expression was enhanced by culturing the hMSCs with OIM. Small interfering RNA (siRNA)-mediated gene silencing of ZBTB16 decreased the activity of alkaline phosphatase (ALP); the expression of osteogenic genes, such as osteocalcin (OCN) and bone sialoprotein (BSP), and the mineralized nodule formation induced by OIM. siRNA-mediated gene silencing of Osterix (Osx), which is known as an essential regulator of osteoblastic differentiation, markedly downregulated the expression of ZBTB16. In addition, chromatin immunoprecipitation (ChIP) assays showed that Osx associated with the ZBTB16 promoter region containing the GC-rich canonical Sp1 sequence, which is the specific Osx binding site. These findings suggest that ZBTB16 acts as a downstream transcriptional regulator of Osx and can be useful as a late marker of osteoblastic differentiation. J. Cell. Biochem. 117: 2423-2434, 2016. © 2016 Wiley Periodicals, Inc. PMID:27335174

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

    PubMed

    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

    2014-08-15

    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

  8. New surveys of the Chesapeake Bay impact structure suggest melt pockets and target-structure effect

    USGS Publications Warehouse

    Shah, A.K.; Brozena, J.; Vogt, P.; Daniels, D.; Plescia, J.

    2005-01-01

    We present high-resolution gravity and magnetic field survey results over the 85-km-diameter Chesapeake Bay impact structure. Whereas a continuous melt sheet is anticipated at a crater this size, shallow-source magnetic field anomalies of ???100 nT instead suggest that impact melt pooled in kilometer-scaled pockets surrounding the base of a central peak. A central anomaly of ???300 nT may represent additional melt or rock that underwent shock-induced remagnetization. Models predict that the total volume of the melt ranges from ???0.4 to 10 km3, a quantity that is several orders of magnitude smaller than expected for an impact structure this size. However, this volume is within predictions given a transient crater of diameter of 20-40 km for a target covered with water and sedimentary deposits such that melt fragments were widely dispersed at the time of impact. Gravity data delineate a gently sloping inner basin and a central peak via a contrast between crystalline and sedimentary rock. Both features are ovoid, oriented parallel to larger preimpact basement structures. Conceptual models suggest how lateral differences in rock strength due to these preimpact structures helped to shape the crater's morphology during transient-crater modification. ?? 2005 Geological Society of America.

  9. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

    PubMed

    Lindner, Robert; Sullivan, Catherine; Offor, Onyinye; Lezon-Geyda, Kimberly; Halligan, Kyle; Fischbach, Neal; Shah, Mansi; Bossuyt, Veerle; Schulz, Vincent; Tuck, David P; Harris, Lyndsay N

    2013-01-01

    suggest that targeted therapy choices should be considered in the context of race. PMID:24260093

  10. Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells

    PubMed Central

    Sattu, Kamaraj; Hochgräfe, Falko; Wu, Jianmin; Umapathy, Ganesh; Schönherr, Christina; Ruuth, Kristina; Chand, Damini; Witek, Barbara; Fuchs, James; Li, Pui-Kai; Hugosson, Fredrik; Daly, Roger J; Palmer, Ruth H; Hallberg, Bengt

    2013-01-01

    Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is a key oncogenic mechanism in a growing number of tumor types. In the majority of cases, ALK is activated by fusion with a dimerizing partner protein as a result of chromosomal translocation events, most studied in the case of the nucleophosmin–ALK and echinoderm microtubule-associated protein-like 4–ALK oncoproteins. It is now also appreciated that the full-length ALK receptor can be activated by point mutations and by deletions within the extracellular domain, such as those observed in neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates of ALK fusion proteins. In this study, we used MS-based phosphotyrosine profiling to characterize phosphotyrosine signaling events associated with the full-length ALK receptor. A number of previously identified and novel targets were identified. One of these, signal transducer and activator of transcription 3 (STAT3), has previously been observed to be activated in response to oncogenic ALK signaling, but the significance of this in signaling from the full-length ALK receptor has not been explored further. We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines. Furthermore, knockdown of STAT3 by RNA interference resulted in a reduction in myelocytomatosis neuroblastom (MYCN) protein levels downstream of ALK signaling. These observations, together with a decreased level of MYCN and inhibition of neuroblastoma cell growth in the presence of STAT3 inhibitors, suggest that activation of STAT3 is important for ALK signaling activity in neuroblastoma. PMID:23889739

  11. Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission.

    PubMed

    Tabata, Takako; Petitt, Matthew; Puerta-Guardo, Henry; Michlmayr, Daniela; Wang, Chunling; Fang-Hoover, June; Harris, Eva; Pereira, Lenore

    2016-08-10

    Zika virus (ZIKV) infection during pregnancy is linked to severe birth defects, but mother-to-fetus transmission routes are unknown. We infected different primary cell types from mid- and late-gestation placentas and explants from first-trimester chorionic villi with the prototype Ugandan and a recently isolated Nicaraguan ZIKV strain. ZIKV infects primary human placental cells and explants-cytotrophoblasts, endothelial cells, fibroblasts, and Hofbauer cells in chorionic villi and amniotic epithelial cells and trophoblast progenitors in amniochorionic membranes-that express Axl, Tyro3, and/or TIM1 viral entry cofactors. ZIKV produced NS3 and E proteins and generated higher viral titers in amniotic epithelial cells from mid-gestation compared to late-gestation placentas. Duramycin, a peptide that binds phosphatidylethanolamine in enveloped virions and precludes TIM1 binding, reduced ZIKV infection in placental cells and explants. Our results suggest that ZIKV spreads from basal and parietal decidua to chorionic villi and amniochorionic membranes and that targeting TIM1 could suppress infection at the uterine-placental interface. PMID:27443522

  12. Stromal progesterone receptors mediate induction of Indian Hedgehog (IHH) in uterine epithelium and its downstream targets in uterine stroma.

    PubMed

    Simon, Liz; Spiewak, Kerry A; Ekman, Gail C; Kim, Jaeyeon; Lydon, John P; Bagchi, Milan K; Bagchi, Indrani C; DeMayo, Francesco J; Cooke, Paul S

    2009-08-01

    Uterine receptivity to embryo implantation depends on appropriate progesterone (P4) and estrogen stimulation. P4 rapidly stimulates production of the morphogen Indian hedgehog (IHH) in murine uterine epithelium as well as downstream molecules in the hedgehog pathway such as Patched homolog 1 (PTCH1) and nuclear receptor subfamily 2, group F, member 2 (NR2F2) in uterine stroma. Studies using IHH-null mice indicate that IHH is obligatory for the normal P4 response in the uterus. To determine whether IHH induction in uterine epithelium is mediated through P4 receptor (PR) in epithelium (E) and/or stroma (S), we produced tissue recombinants using uteri from neonatal PR knockout (ko) mice and wild-type (wt) mice containing PR in S and/or E or lacking PR altogether using a tissue recombinant methodology and assessed their response to P4. In tissue recombinants containing wt-S (wt-S + wt-E and wt-S + ko-E), P4 induced Ihh mRNA expression at 6 h that was 6-fold greater than in oil-treated controls (P < 0.05; n = 6) in both types of tissue recombinants despite the absence of epithelial PR in wt-S + ko-E grafts. Conversely, Ihh mRNA expression was unaffected by P4 in ko-S + ko-E and ko-S + wt-E grafts despite epithelial PR expression in the latter. Nr2f2 and Ptch1 mRNA expression was similar in that it was stimulated by P4 only in recombinants containing stromal PR. These results indicate that stromal PR is both necessary and sufficient for P4 stimulation of epithelial IHH as well as downstream events such as PTCH1 and NR2F2 increases in stroma. PMID:19372202

  13. Bringing in the target audience in bystander social marketing materials for communities: suggestions for practitioners.

    PubMed

    Potter, Sharyn J; Stapleton, Jane G

    2011-06-01

    The Know Your Power™ social marketing campaign images model active bystander behaviors that target audience members can use in situations where sexual and relationship violence and stalking are occurring, have occurred, or have the potential to occur. In this practitioner note, we describe strategies that we have used to engage target audience members in the development of the social marketing campaign that we hope can be used by practitioners. We give examples from the development and evaluation of the Know Your Power(TM) social marketing campaign that used focus group and other types of feedback from the target audience to inform the direction of the campaign. PMID:21727157

  14. Neutrino Factory Downstream Systems

    SciTech Connect

    Zisman, Michael S.

    2009-12-23

    We describe the Neutrino Factory accelerator systems downstream from the target and capture area. These include the bunching and phase rotation, cooling, acceleration, and decay ring systems. We also briefly discuss the R&D program under way to develop these systems, and indicate areas where help from CERN would be invaluable.

  15. Evolutionary triage governs fitness in driver and passenger mutations and suggests targeting never mutations

    PubMed Central

    Gatenby, R A.; Cunningham, J. J.; Brown, J. S.

    2014-01-01

    Genetic and epigenetic changes in cancer cells are typically divided into “drivers” and “passengers”. Drug development strategies target driver mutations, but inter- and intra-tumoral heterogeneity usually results in emergence of resistance. Here we model intratumoral evolution in the context of a fecundity/survivorship trade-off. Simulations demonstrate the fitness value, of any genetic change is not fixed but dependent on evolutionary triage governed by initial cell properties, current selection forces, and prior genotypic/phenotypic trajectories. We demonstrate spatial variations in molecular properties of tumor cells are the result of changes in environmental selection forces such as blood flow. Simulated therapies targeting fitness-increasing (driver) mutations usually decrease the tumor burden but almost inevitably fail due to population heterogeneity. An alternative strategy targets gene mutations that are never observed. Because up or down regulation of these genes unconditionally reduces cellular fitness, they are eliminated by evolutionary triage but can be exploited for targeted therapy. PMID:25407411

  16. FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer.

    PubMed

    Fan, Qipeng; Cai, Qingchun; Xu, Yan

    2015-09-29

    Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human epithelial ovarian cancers (EOC). We conducted in vitro mechanistic studies using pharmacological inhibitors, genetic forms of the signaling molecules, and RNAi-mediated gene knock-down to uncover the molecular mechanisms of how these two molecules interact in EOC cells. Additionally, in vivo mouse studies were performed to confirm the functional involvement of FOXM1 in EOC tumor formation and progression. We show for the first time that LPA up-regulates expression of active FOXM1 splice variants in a time- and dose-dependent manner in the human EOC cell lines OVCA433, CAOV3, and OVCAR5. Gi-PI3K-AKT and G12/13-Rho-YAP signaling pathways were both involved in the LPA receptor (LPA1-3) mediated up-regulation of FOXM1 at the transcriptional level. In addition, down-regulation of FOXM1 in CAOV3 xenografts significantly reduced tumor and ascites formation, metastasis, and expression of FOXM1 target genes involved in cell proliferation, migration, or invasion. Collectively, our data link the oncolipid LPA, the oncogene YAP, and the central regulator of cell proliferation/mutagenesis FOXM1 in EOC cells. Moreover, these results provide further support for the importance of these pathways as potential therapeutic targets in EOC. PMID:26299613

  17. LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.

    PubMed

    Maeda, Takahiro; Ito, Keisuke; Merghoub, Taha; Poliseno, Laura; Hobbs, Robin M; Wang, Guocan; Dong, Lin; Maeda, Manami; Dore, Louis C; Zelent, Arthur; Luzzatto, Lucio; Teruya-Feldstein, Julie; Weiss, Mitchell J; Pandolfi, Pier Paolo

    2009-10-01

    GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF. PMID:19853566

  18. LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis

    PubMed Central

    Maeda, Takahiro; Ito, Keisuke; Merghoub, Taha; Poliseno, Laura; Hobbs, Robin M.; Wang, Guocan; Dong, Lin; Maeda, Manami; Dore, Louis C.; Zelent, Arthur; Luzzatto, Lucio; Teruya-Feldstein, Julie; Weiss, Mitchell J.; Pandolfi, Pier Paolo

    2011-01-01

    SUMMARY GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential anti-apoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late stage erythroblasts. This programmed cell death is Arf- and p53-independent and is instead mediated by up-regulation of the pro-apoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim-loss delays the lethality of Lrf-deficient embryos and rescues their anemia-phenotype. Thus, our data defines a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF. PMID:19853566

  19. Salicylic Acid Suppresses Jasmonic Acid Signaling Downstream of SCFCOI1-JAZ by Targeting GCC Promoter Motifs via Transcription Factor ORA59[C][W][OA

    PubMed Central

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C.; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P.; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C.M.; Pieterse, Corné M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCFCOI1, which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCFCOI1-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID:23435661

  20. Proteome analysis for downstream targets of oncogenic KRAS--the potential participation of CLIC4 in carcinogenesis in the lung.

    PubMed

    Okudela, Koji; Katayama, Akira; Woo, Tetsukan; Mitsui, Hideaki; Suzuki, Takehisa; Tateishi, Yoko; Umeda, Shigeaki; Tajiri, Michihiko; Masuda, Munetaka; Nagahara, Noriyuki; Kitamura, Hitoshi; Ohashi, Kenichi

    2014-01-01

    This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated. PMID:24503901

  1. Proteome Analysis for Downstream Targets of Oncogenic KRAS - the Potential Participation of CLIC4 in Carcinogenesis in the Lung

    PubMed Central

    Okudela, Koji; Katayama, Akira; Woo, Tetsukan; Mitsui, Hideaki; Suzuki, Takehisa; Tateishi, Yoko; Umeda, Shigeaki; Tajiri, Michihiko; Masuda, Munetaka; Nagahara, Noriyuki; Kitamura, Hitoshi; Ohashi, Kenichi

    2014-01-01

    This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated. PMID:24503901

  2. Local estrogen metabolism in epithelial ovarian cancer suggests novel targets for therapy

    PubMed Central

    Ren, Xia; Wu, Xuan; Hillier, Stephen G.; Fegan, K. Scott; Critchley, Hilary O.D.; Mason, J. Ian; Sarvi, Sana; Harlow, Christopher R.

    2015-01-01

    Epithelial ovarian cancer (EOC) accounts for about 90% of malignant ovarian tumors, and estrogen is often implicated in disease progression. We therefore compared the potential for gating of estrogen action via pre-receptor metabolism in normal human ovarian surface epithelium (OSE), EOC and selected EOC cell lines (SKOV3 and PEO1). Steroid sulphatase (STS), estrogen sulfotransferase (EST), 17β-hydroxysteroid dehydrogenases 2 (17BHSD2) and 5 (17BHSD5) mRNAs, proteins and enzymatic activities were all detectable in primary cell cultures of OSE and EOC, whereas aromatase and 17BHSD1 expression was negligible. qRT-PCR assay on total mRNA revealed significantly higher EST mRNA expression in OSE compared to EOC (P < 0.05). Radioenzymatic measurements confirmed reduced sulfoconjugation (neutralization) of free estrogen in EOC relative to OSE. OSE cells were more effective at converting free [3H]-E1 to [3H]-E1S or [3H]-E2S, while EOC cell lines mainly converted [3H]-E1 to [3H]-E2 with minimal formation of [3H]-E1S or [3H]-E2S. IL1α treatment suppressed EST (P < 0.01) and 17BHSD2 (P < 0.001) mRNA levels in OSE and stimulated STS mRNA levels (P < 0.001) in cancer (SKOV3) cells. These results show that estrogen is differentially metabolized in OSE and EOC cells, with E2 ‘activation’ from conjugated estrogen predominating in EOC. Inflammatory cytokines may further augment the local production of E2 by stimulating STS and suppressing EST. We conclude that local estrogen metabolism may be a target for EOC treatment. PMID:25817828

  3. Local estrogen metabolism in epithelial ovarian cancer suggests novel targets for therapy.

    PubMed

    Ren, Xia; Wu, Xuan; Hillier, Stephen G; Fegan, K Scott; Critchley, Hilary O D; Mason, J Ian; Sarvi, Sana; Harlow, Christopher R

    2015-06-01

    Epithelial ovarian cancer (EOC) accounts for about 90% of malignant ovarian tumors, and estrogen is often implicated in disease progression. We therefore compared the potential for gating of estrogen action via pre-receptor metabolism in normal human ovarian surface epithelium (OSE), EOC and selected EOC cell lines (SKOV3 and PEO1). Steroid sulphatase (STS), estrogen sulfotransferase (EST), 17β-hydroxysteroid dehydrogenases 2 (17BHSD2) and 5 (17BHSD5) mRNAs, proteins and enzymatic activities were all detectable in primary cell cultures of OSE and EOC, whereas aromatase and 17BHSD1 expression was negligible. qRT-PCR assay on total mRNA revealed significantly higher EST mRNA expression in OSE compared to EOC (P<0.05). Radioenzymatic measurements confirmed reduced sulfoconjugation (neutralization) of free estrogen in EOC relative to OSE. OSE cells were more effective at converting free [(3)H]-E1 to [(3)H]-E1S or [(3)H]-E2S, while EOC cell lines mainly converted [(3)H]-E1 to [(3)H]-E2 with minimal formation of [(3)H]-E1S or [(3)H]-E2S. IL1α treatment suppressed EST (P<0.01) and 17BHSD2 (P<0.001) mRNA levels in OSE and stimulated STS mRNA levels (P<0.001) in cancer (SKOV3) cells. These results show that estrogen is differentially metabolized in OSE and EOC cells, with E2 'activation' from conjugated estrogen predominating in EOC. Inflammatory cytokines may further augment the local production of E2 by stimulating STS and suppressing EST. We conclude that local estrogen metabolism may be a target for EOC treatment. PMID:25817828

  4. Methamphetamine Administration Targets Multiple Immune Subsets and Induces Phenotypic Alterations Suggestive of Immunosuppression

    PubMed Central

    Harms, Robert; Morsey, Brenda; Boyer, Craig W.; Fox, Howard S.; Sarvetnick, Nora

    2012-01-01

    Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1high monocytes/macrophages were also decreased in abundance while Gr-1low monocytes/macrophages appear to show signs of perturbation. CD4 and CD8 T cell subsets were affected by methamphetamine, both showing a reduction in antigen-experienced subsets. CD4 T cells also exhibited signs of activation, with increased expression of CD150 on CD226-expressing cells and an expansion of KLRG1+, FoxP3− cells. These results exhibit that meth has the ability to disrupt immune homeostasis and impact key subsets of leukocytes which may leave users more vulnerable to pathogens. PMID:23227154

  5. Early Events following Experimental Infection with Peste-Des-Petits Ruminants Virus Suggest Immune Cell Targeting

    PubMed Central

    Pope, Robert A.; Parida, Satya; Bailey, Dalan; Brownlie, Joe; Barrett, Thomas; Banyard, Ashley C.

    2013-01-01

    Peste-des-petits ruminants virus (PPRV) is a viral pathogen that causes a devastating plague of small ruminants. PPRV is an economically significant disease that continues to be a major obstacle to the development of sustainable agriculture across the developing world. The current understanding of PPRV pathogenesis has been heavily assumed from the closely related rinderpest virus (RPV) and other morbillivirus infections alongside data derived from field outbreaks. There have been few studies reported that have focused on the pathogenesis of PPRV and very little is known about the processes underlying the early stages of infection. In the present study, 15 goats were challenged by the intranasal route with a virulent PPRV isolate, Côte d’Ivoire ’89 (CI/89) and sacrificed at strategically defined time-points post infection to enable pre- and post-mortem sampling. This approach enabled precise monitoring of the progress and distribution of virus throughout the infection from the time of challenge, through peak viraemia and into a period of convalescence. Observations were then related to findings of previous field studies and experimental models of PPRV to develop a clinical scoring system for PPRV. Importantly, histopathological investigations demonstrated that the initial site for virus replication is not within the epithelial cells of the respiratory mucosa, as has been previously reported, but is within the tonsillar tissue and lymph nodes draining the site of inoculation. We propose that virus is taken up by immune cells within the respiratory mucosa which then transport virus to lymphoid tissues where primary virus replication occurs, and from where virus enters circulation. Based on these findings we propose a novel clinical scoring methodology for PPRV pathogenesis and suggest a fundamental shift away from the conventional model of PPRV pathogenesis. PMID:23418464

  6. Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: A novel strategy for human BRAF-driven colorectal carcinoma

    PubMed Central

    Sisinni, Lorenza; Lettini, Giacomo; Matassa, Danilo Swann; Piscazzi, Annamaria; Palladino, Giuseppe; Amoroso, Maria Rosaria; Esposito, Franca; Landriscina, Matteo

    2015-01-01

    The HSP90 chaperone TRAP1 is translational regulator of BRAF synthesis/ubiquitination, since BRAF down-regulation, ERK signaling inhibition and delay of cell cycle progression occur upon TRAP1 silencing/inhibition. Since TRAP1 is upregulated in human colorectal carcinomas (CRCs) and involved in protection from apoptosis and as human BRAF-driven CRCs are poorly responsive to anticancer therapies, the relationship between TRAP1 regulation of mitochondrial apoptotic pathway and BRAF antiapoptotic signaling has been further evaluated. This study reports that BRAF cytoprotective signaling involves TRAP1-dependent inhibition of the mitochondrial apoptotic pathway. It is worth noting that BRAF and TRAP1 interact and that the activation of BRAF signaling results in enhanced TRAP1 serine-phosphorylation, a condition associated with resistance to apoptosis. Consistently, a BRAF dominant-negative mutant prevents TRAP1 serine phosphorylation and restores drug sensitivity in BRAFV600E CRC drug-resistant cells with high TRAP1 levels. In addition, TRAP1 targeting by the mitochondria-directed HSP90 chaperones inhibitor gamitrinib induces apoptosis and inhibits colony formation in BRAF-driven CRC cells. Thus, TRAP1 is a downstream effector of BRAF cytoprotective pathway in mitochondria and TRAP1 targeting may represent a novel strategy to improve the activity of proapoptotic agents in BRAF-driven CRC cells. PMID:26084290

  7. Egr1 protein acts downstream of estrogen-leukemia inhibitory factor (LIF)-STAT3 pathway and plays a role during implantation through targeting Wnt4.

    PubMed

    Liang, Xiao-Huan; Deng, Wen-Bo; Li, Ming; Zhao, Zhen-Ao; Wang, Tong-Song; Feng, Xu-Hui; Cao, Yu-Jing; Duan, En-Kui; Yang, Zeng-Ming

    2014-08-22

    Embryo implantation is a highly synchronized process between an activated blastocyst and a receptive uterus. Successful implantation relies on the dynamic interplay of estrogen and progesterone, but the key mediators underlying embryo implantation are not fully understood. Here we show that transcription factor early growth response 1 (Egr1) is regulated by estrogen as a downstream target through leukemia inhibitory factor (LIF) signal transducer and activator of transcription 3 (STAT3) pathway in mouse uterus. Egr1 is localized in the subluminal stromal cells surrounding the implanting embryo on day 5 of pregnancy. Estrogen rapidly, markedly, and transiently enhances Egr1 expression in uterine stromal cells, which fails in estrogen receptor α knock-out mouse uteri. STAT3 is phosphorylated by LIF and subsequently recruited on Egr1 promoter to induce its expression. Our results of Egr1 expression under induced decidualization in vivo and in vitro show that Egr1 is rapidly induced after deciduogenic stimulus. Egr1 knockdown can inhibit in vitro decidualization of cultured uterine stromal cells. Chromatin immunoprecipitation data show that Egr1 is recruited to the promoter of wingless-related murine mammary tumor virus integration site 4 (Wnt4). Collectively, our study presents for the first time that estrogen regulates Egr1 expression through LIF-STAT3 signaling pathway in mouse uterus, and Egr1 functions as a critical mediator of stromal cell decidualization by regulating Wnt4. PMID:25012664

  8. Improved algorithms in the CE-QUAL-W2 water-quality model for blending dam releases to meet downstream water-temperature targets

    USGS Publications Warehouse

    Rounds, Stewart A.; Buccola, Norman L.

    2015-01-01

    Water-quality models allow water resource professionals to examine conditions under an almost unlimited variety of potential future scenarios. The two-dimensional (longitudinal, vertical) water-quality model CE-QUAL-W2, version 3.7, was enhanced and augmented with new features to help dam operators and managers 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. The modified blending algorithm in version 3.7 of CE-QUAL-W2 allows the user to specify a time-series of target release temperatures, designate from 2 to 10 floating or fixed-elevation outlets for blending, impose minimum and maximum head and flow constraints for any blended outlet, and set priority designations for each outlet that allow the model to choose which outlets to use and how to balance releases among them. The modified model was tested with a variety of examples and against a previously calibrated model of Detroit Lake on the North Santiam River in northwestern Oregon, and the results compared well. These updates to the blending algorithms will allow more complicated dam-operation scenarios to be evaluated somewhat automatically with the model, with decreased need for multiple model runs or preprocessing of model inputs to fully characterize the operational constraints.

  9. A New Suggestion for the Radiation Target Volume After a Subtotal Gastrectomy in Patients With Stomach Cancer

    SciTech Connect

    Nam, Heerim; Lim, Do Hoon Kim, Sung; Kang, Won Ki; Sohn, Tae Sung; Noh, Jae Hyung; Kim, Yong Il; Park, Chan Hyung; Park, Chul Keun; Ahn, Yong Chan; Huh, Seung Jae

    2008-06-01

    Purpose: To compare treatment results between the use of two different radiation fields including and excluding remnant stomach and suggest new target volumes excluding remnant stomach after subtotal gastrectomy (STG) in patients with stomach cancer. Methods and Materials: We retrospectively analyzed 291 patients treated with adjuvant chemoradiotherapy after STG and D2 dissection at the Samsung Medical Center, Seoul, South Korea. Eighty-three patients registered from 1995 to 1997 underwent irradiation according to the INT 0116 protocol that recommended the inclusion of remnant stomach within the target volume (Group A). After this period, we excluded remnant stomach from the target volume for 208 patients (Group B). Median follow-up was 67 months. Results: Treatment failure developed in 93 patients (32.0%). Local and regional recurrence rates for Group A vs. Group B were 10.8% vs. 5.3% (p = not significant) and 9.6% vs. 6.3% (p = not significant), and recurrence rates for remnant stomach were 7.2% vs. 1.4% (p = 0.018), respectively. Overall and disease-free survival rates were not different between the two groups. Grade 3 or 4 vomiting and diarrhea developed more frequently in Group A than Group B (4.8% vs. 1.4% and 6.0% vs. 1.9%, respectively; p = 0.012; p < 0.001). Conclusion: Exclusion of remnant stomach from the radiation field had no effect on failure rates or survival, and a low complication rate occurred in patients treated excluding remnant stomach. We suggest that remnant stomach be excluded from the radiation target volume for patients with stomach cancer who undergo STG and D2 dissection.

  10. Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine.

    PubMed

    Cunha, Mauricio P; Budni, Josiane; Ludka, Fabiana K; Pazini, Francis L; Rosa, Julia Macedo; Oliveira, Ágatha; Lopes, Mark W; Tasca, Carla I; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

    2016-07-01

    Creatine has been proposed to exert beneficial effects in the management of depression, but the cell signaling pathways implicated in its antidepressant effects are not well established. This study investigated the involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. The acute treatment of mice with creatine (1 mg/kg, po) increased the Akt and P70S6K phosphorylation, and HO-1, GPx and PSD95 immunocontents. The pretreatment of mice with LY294002 (10 nmol/mouse, icv, PI3K inhibitor), wortmannin (0.1 μg/mouse, icv, PI3K inhibitor), ZnPP (10 μg/mouse, icv, HO-1 inhibitor), or rapamycin (0.2 nmol/mouse, icv, mTOR inhibitor) prevented the antidepressant-like effect of creatine (1 mg/kg, po) in the TST. In addition, the administration of subeffective dose of either the selective GSK3 inhibitor AR-A014418 (0.01 μg/mouse, icv), the nonselective GSK3 inhibitor lithium chloride (10 mg/kg, po), or the HO-1 inductor CoPP (0.01 μg/mouse, icv), in combination with a subeffective dose of creatine (0.01 mg/kg, po) reduced the immobility time in the TST as compared with either drug alone. No treatment caused significant changes in the locomotor activity of mice. These results indicate that the antidepressant-like effect of creatine in the TST depends on the activation of Akt, Nrf2/HO-1, GPx, and mTOR, and GSK3 inhibition. PMID:25943184

  11. Positive correlation between ADAR expression and its targets suggests a complex regulation mediated by RNA editing in the human brain

    PubMed Central

    Liscovitch, Noa; Bazak, Lily; Levanon, Erez Y; Chechik, Gal

    2014-01-01

    A-to-I RNA editing by adenosine deaminases acting on RNA is a post-transcriptional modification that is crucial for normal life and development in vertebrates. RNA editing has been shown to be very abundant in the human transcriptome, specifically at the primate-specific Alu elements. The functional role of this wide-spread effect is still not clear; it is believed that editing of transcripts is a mechanism for their down-regulation via processes such as nuclear retention or RNA degradation. Here we combine 2 neural gene expression datasets with genome-level editing information to examine the relation between the expression of ADAR genes with the expression of their target genes. Specifically, we computed the spatial correlation across structures of post-mortem human brains between ADAR and a large set of targets that were found to be edited in their Alu repeats. Surprisingly, we found that a large fraction of the edited genes are positively correlated with ADAR, opposing the assumption that editing would reduce expression. When considering the correlations between ADAR and its targets over development, 2 gene subsets emerge, positively correlated and negatively correlated with ADAR expression. Specifically, in embryonic time points, ADAR is positively correlated with many genes related to RNA processing and regulation of gene expression. These findings imply that the suggested mechanism of regulation of expression by editing is probably not a global one; ADAR expression does not have a genome wide effect reducing the expression of editing targets. It is possible, however, that RNA editing by ADAR in non-coding regions of the gene might be a part of a more complex expression regulation mechanism. PMID:25692240

  12. Positive correlation between ADAR expression and its targets suggests a complex regulation mediated by RNA editing in the human brain.

    PubMed

    Liscovitch, Noa; Bazak, Lily; Levanon, Erez Y; Chechik, Gal

    2014-01-01

    A-to-I RNA editing by adenosine deaminases acting on RNA is a post-transcriptional modification that is crucial for normal life and development in vertebrates. RNA editing has been shown to be very abundant in the human transcriptome, specifically at the primate-specific Alu elements. The functional role of this wide-spread effect is still not clear; it is believed that editing of transcripts is a mechanism for their down-regulation via processes such as nuclear retention or RNA degradation. Here we combine 2 neural gene expression datasets with genome-level editing information to examine the relation between the expression of ADAR genes with the expression of their target genes. Specifically, we computed the spatial correlation across structures of post-mortem human brains between ADAR and a large set of targets that were found to be edited in their Alu repeats. Surprisingly, we found that a large fraction of the edited genes are positively correlated with ADAR, opposing the assumption that editing would reduce expression. When considering the correlations between ADAR and its targets over development, 2 gene subsets emerge, positively correlated and negatively correlated with ADAR expression. Specifically, in embryonic time points, ADAR is positively correlated with many genes related to RNA processing and regulation of gene expression. These findings imply that the suggested mechanism of regulation of expression by editing is probably not a global one; ADAR expression does not have a genome wide effect reducing the expression of editing targets. It is possible, however, that RNA editing by ADAR in non-coding regions of the gene might be a part of a more complex expression regulation mechanism. PMID:25692240

  13. Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation

    PubMed Central

    Hausser, Jean; Syed, Afzal Pasha; Bilen, Biter; Zavolan, Mihaela

    2013-01-01

    Most of what is presently known about how miRNAs regulate gene expression comes from studies that characterized the regulatory effect of miRNA binding sites located in the 3′ untranslated regions (UTR) of mRNAs. In recent years, there has been increasing evidence that miRNAs also bind in the coding region (CDS), but the implication of these interactions remains obscure because they have a smaller impact on mRNA stability compared with miRNA-target interactions that involve 3′ UTRs. Here we show that miRNA-complementary sites that are located in both CDS and 3′-UTRs are under selection pressure and share the same sequence and structure properties. Analyzing recently published data of ribosome-protected fragment profiles upon miRNA transfection from the perspective of the location of miRNA-complementary sites, we find that sites located in the CDS are most potent in inhibiting translation, while sites located in the 3′ UTR are more efficient at triggering mRNA degradation. Our study suggests that miRNAs may combine targeting of CDS and 3′ UTR to flexibly tune the time scale and magnitude of their post-transcriptional regulatory effects. PMID:23335364

  14. 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.

    PubMed

    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. PMID:27408334

  15. Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function

    PubMed Central

    Kim, Byong Su; Savinova, Olga V.; Reedy, Mark V.; Martin, Janice; Lun, Yi; Gan, Lin; Smith, Richard S.; Tomarev, Stanislav I.; John, Simon W. M.; Johnson, Randy L.

    2001-01-01

    Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function. PMID:11604506

  16. PDGF beta targeting in cervical cancer cells suggest a fine-tuning of compensatory signalling pathways to sustain tumourigenic stimulation

    PubMed Central

    Tudoran, Oana Mihaela; Soritau, Olga; Balacescu, Loredana; Pop, Laura; Meurice, Guillaume; Visan, Simona; Lindberg, Staffan; Eniu, Alexandru; Langel, Ulo; Balacescu, Ovidiu; Berindan-Neagoe, Ioana

    2015-01-01

    The platelet-derived growth factor (PDGF) signalling pathway has been reported to play an important role in human cancers by modulating autocrine and paracrine processes such as tumour growth, metastasis and angiogenesis. Several clinical trials document the benefits of targeting this pathway; however, in cervical cancer the role of PDGF signalling in still unclear. In this study, we used siRNA against PDGF beta (PDGFBB) to investigate the cellular and molecular mechanisms of PDGFBB signalling in Ca Ski and HeLa cervical cancer cells. Our results show that PDGFBB inhibition in Ca Ski cells led to rapid alterations of the transcriptional pattern of 579 genes, genes that are known to have antagonistic roles in regulating tumour progression. Concomitantly, with the lack of significant effects on cervical cancer cells proliferation, apoptosis, migration or invasion, these findings suggests that cervical cancer cells shift between compensatory signalling pathways to maintain their behaviour. The observed autocrine effects were limited to cervical cancer cells ability to adhere to an endothelial cell (EC) monolayer. However, by inhibiting PDGFBB on cervical cells, we achieved reduced proliferation of ECs in co-culture settings and cellular aggregation in conditioned media. Because of lack of PDGF receptor expression on ECs, we believe that these effects are a result of indirect PDGFBB paracrine signalling mechanisms. Our results shed some light into the understanding of PDGFBB signalling mechanism in cervical cancer cells, which could be further exploited for the development of synergistic anti-tumour and anti-angiogenic therapeutic strategies. PMID:25311137

  17. Oligodendroglial Argonaute protein Ago2 associates with molecules of the Mbp mRNA localization machinery and is a downstream target of Fyn kinase

    PubMed Central

    Müller, Christina; Schäfer, Isabelle; Luhmann, Heiko J.; White, Robin

    2015-01-01

    Oligodendrocytes myelinate neuronal axons in the central nervous system (CNS) facilitating rapid transmission of action potentials by saltatory conduction. Myelin basic protein (MBP) is an essential component of myelin and its absence results in severe hypomyelination in the CNS of rodents. Mbp mRNA is not translated immediately after exit from the nucleus in the cytoplasm, but is transported to the plasma membrane in RNA transport granules in a translationally silenced state. We have previously identified the small non-coding RNA 715 (sncRNA715) as an inhibitor of Mbp translation associated with RNA granules. Argonaute (Ago) proteins and small RNAs form the minimal core of the RNA induced silencing complex and together recognize target mRNAs to be translationally inhibited or degraded. Recently, tyrosine phosphorylation of Ago2 was reported to be a regulator of small RNA binding. The oligodendroglial non-receptor tyrosine kinase Fyn is activated by neuronal signals and stimulates the translation of Mbp mRNA at the axon-glial contact site. Here we analyzed the expression of Ago proteins in oligodendrocytes, if they associate with Mbp mRNA transport granules and are tyrosine phosphorylated by Fyn. We show that all Ago proteins (Ago1-4) are expressed by oligodendrocytes and that Ago2 colocalizes with hnRNP A2 in granular cytoplasmic structures. Ago2 associates with hnRNP A2, Mbp mRNA, sncRNA715 and Fyn kinase and is tyrosine phosphorylated in response to Fyn activity. Our findings suggest an involvement of Ago2 in the translational regulation of Mbp. The identification of Ago proteins as Fyn targets will foster further research to understand in more molecular detail how Fyn activity regulates Mbp translation. PMID:26379499

  18. Oligodendroglial Argonaute protein Ago2 associates with molecules of the Mbp mRNA localization machinery and is a downstream target of Fyn kinase.

    PubMed

    Müller, Christina; Schäfer, Isabelle; Luhmann, Heiko J; White, Robin

    2015-01-01

    Oligodendrocytes myelinate neuronal axons in the central nervous system (CNS) facilitating rapid transmission of action potentials by saltatory conduction. Myelin basic protein (MBP) is an essential component of myelin and its absence results in severe hypomyelination in the CNS of rodents. Mbp mRNA is not translated immediately after exit from the nucleus in the cytoplasm, but is transported to the plasma membrane in RNA transport granules in a translationally silenced state. We have previously identified the small non-coding RNA 715 (sncRNA715) as an inhibitor of Mbp translation associated with RNA granules. Argonaute (Ago) proteins and small RNAs form the minimal core of the RNA induced silencing complex and together recognize target mRNAs to be translationally inhibited or degraded. Recently, tyrosine phosphorylation of Ago2 was reported to be a regulator of small RNA binding. The oligodendroglial non-receptor tyrosine kinase Fyn is activated by neuronal signals and stimulates the translation of Mbp mRNA at the axon-glial contact site. Here we analyzed the expression of Ago proteins in oligodendrocytes, if they associate with Mbp mRNA transport granules and are tyrosine phosphorylated by Fyn. We show that all Ago proteins (Ago1-4) are expressed by oligodendrocytes and that Ago2 colocalizes with hnRNP A2 in granular cytoplasmic structures. Ago2 associates with hnRNP A2, Mbp mRNA, sncRNA715 and Fyn kinase and is tyrosine phosphorylated in response to Fyn activity. Our findings suggest an involvement of Ago2 in the translational regulation of Mbp. The identification of Ago proteins as Fyn targets will foster further research to understand in more molecular detail how Fyn activity regulates Mbp translation. PMID:26379499

  19. Triptolide Induces Cell Apoptosis by Targeting H3K4me3 and Downstream Effector Proteins in KM3 Multiple Myeloma Cells.

    PubMed

    Wen, Lu; Chen, Yan; Zeng, Ling L; Zhao, Fei; Yi, Sha; Yang, Li J; Zhang, Ben P; Zhao, Jie; Zhao, Zi C; Zhang, Chun

    2015-01-01

    As the principal active ingredient in the Chinese herb Tripterygium wilfordii Hook.F (TwHF), triptolide has been shown to have very strong antitumor properties. The trimethylation of lysine 4 on histone H3 (H3K4me3) has been proposed to promote gene expression, and the accumulation of H3K4me3 at the transcriptional start sites of oncogenes is involved in carcinogenesis. To identify the association between the reduction of H3K4me3 and the apoptosis of MM cells induced by triptolide, we investigated the global patterns of H3K4me3 occupancy in the MM cell genome. Combined analyses using ChIP-on-chip and western blotting showed that H3K4me3 were highly enriched on the gene promoters of c-Myc and VEGFA and were associated with the up-regulation of both genes. Treatment of KM3 cells with triptolide and siRNA targeting ASH2L reduced the expression of c-Myc and VEGFA. These results suggest that triptolide can down-regulate c-Myc and VEGFA expression by blocking the accumulation of H3K4me3 on their promoters,and thus play an important role in anti-MM mechanism. PMID:26420049

  20. Upstream to downstream: a multiple-assessment-point approach for targeting non-point-source priority management areas at large watershed scale

    NASA Astrophysics Data System (ADS)

    Chen, L.; Zhong, Y.; Wei, G.; Shen, Z.

    2014-04-01

    The identification of priority management areas (PMAs) is essential for the control of non-point-source (NPS) pollution, especially for a large-scale watershed. However, previous studies have typically focused on small-scale catchments adjacent to specific assessment points; thus, the interactions between multiple river points remain poorly understood. In this study, a multiple-assessment-point PMA (MAP-PMA) framework was proposed by integrating the upstream sources and the downstream transport aspects of NPS pollution. Daning River watershed was taken as a case study in this paper, which has demonstrated that the integration of the upstream input changes was vital for the final PMAs map, especially for downstream areas. Contrary to conventional wisdom, this research recommended that the NPS pollutants could be best controlled among the upstream high-level PMAs when protecting the water quality of the entire watershed. The MAP-PMA framework provided a more cost-effective tool for the establishment of conservation practices, especially for a large-scale watershed.

  1. What Causes Reliance on English? Challenges and Instructional Suggestions in a Drive for Using a Target Language Only

    ERIC Educational Resources Information Center

    Bae, Gyseon; Kim, Eunju

    2008-01-01

    Given the raised graduation requirement of the proficiency Enhancement Program (PEP) to attain proficiency levels of "2+," "2+," and "2," the importance of target language use has been highly emphasized across language schools at Defense Language Institute Foreign Language Center (DLIFLC). This article discusses some of the challenges associated…

  2. Comparison of the gene expression profiles from normal and Fgfrl1 deficient mouse kidneys reveals downstream targets of Fgfrl1 signaling.

    PubMed

    Gerber, Simon D; Amann, Ruth; Wyder, Stefan; Trueb, Beat

    2012-01-01

    Fgfrl1 (fibroblast growth factor receptor-like 1) is a transmembrane receptor that is essential for the development of the metanephric kidney. It is expressed in all nascent nephrogenic structures and in the ureteric bud. Fgfrl1 null mice fail to develop the metanephric kidneys. Mutant kidney rudiments show a dramatic reduction of ureteric branching and a lack of mesenchymal-to-epithelial transition. Here, we compared the expression profiles of wildtype and Fgfrl1 mutant kidneys to identify genes that act downstream of Fgfrl1 signaling during the early steps of nephron formation. We detected 56 differentially expressed transcripts with 2-fold or greater reduction, among them many genes involved in Fgf, Wnt, Bmp, Notch, and Six/Eya/Dach signaling. We validated the microarray data by qPCR and whole-mount in situ hybridization and showed the expression pattern of candidate genes in normal kidneys. Some of these genes might play an important role during early nephron formation. Our study should help to define the minimal set of genes that is required to form a functional nephron. PMID:22432025

  3. Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-θ and its downstream pathways.

    PubMed

    Akber, Uroos; Na, Bo-Ra; Ko, Yoo-Seung; Ko, You-Seung; Lee, Hyun-Su; Kim, Hye-Ran; Kwon, Min-Sung; Park, Zee-Yong; Choi, Eun-Ju; Han, Weon-Cheol; Lee, Seung-Ho; Oh, Hyun-Mee; Jun, Chang-Duk

    2015-03-01

    Autoreactive T-cell responses have a crucial role in the pathology and clinical course of autoimmune diseases. Therefore, controlling the activation of these cells is an important strategy for developing therapies and therapeutics. Here, we identified that 4-hydroxy-3-methoxycinnamaldehyde (4H3MC) has a therapeutic potential for T-cell activation by modulating protein kinase C-θ (PKCθ) and its downstream pathways. Pre- and post-treatment with 4H3MC prevented IL-2 release from human transformed and untransformed T cells at the micromolar concentrations without any cytotoxic effects, in fact more efficiently than its structural analogue 4-hydroxycinnamic acid-a previously reported T-cell inhibitor. In silico analysis showed that 4H3MC is a potential inhibitor of PKC isotypes, including PKCθ-a crucial PKC isotype in T cells. Consistently, 4H3MC significantly blocked PKC activity in vitro and also inhibited the phosphorylation of PKCθ in T cells. 4H3MC had no effect on TCR-mediated membrane-proximal-signalling events such as phosphorylation of Zap70. Instead, it attenuated the phosphorylation of mitogen-activated protein kinases (ERK and p38) and promoter activities of NF-κB, AP-1 and NFAT. Taken together, our results provide the evidences that 4H3MC may have curative potential as a novel immune modulator in a broad range of immunopathological disorders by modulating PKCθ activity. PMID:25637768

  4. Comparison of the Gene Expression Profiles from Normal and Fgfrl1 Deficient Mouse Kidneys Reveals Downstream Targets of Fgfrl1 Signaling

    PubMed Central

    Gerber, Simon D.; Amann, Ruth; Wyder, Stefan; Trueb, Beat

    2012-01-01

    Fgfrl1 (fibroblast growth factor receptor-like 1) is a transmembrane receptor that is essential for the development of the metanephric kidney. It is expressed in all nascent nephrogenic structures and in the ureteric bud. Fgfrl1 null mice fail to develop the metanephric kidneys. Mutant kidney rudiments show a dramatic reduction of ureteric branching and a lack of mesenchymal-to-epithelial transition. Here, we compared the expression profiles of wildtype and Fgfrl1 mutant kidneys to identify genes that act downstream of Fgfrl1 signaling during the early steps of nephron formation. We detected 56 differentially expressed transcripts with 2-fold or greater reduction, among them many genes involved in Fgf, Wnt, Bmp, Notch, and Six/Eya/Dach signaling. We validated the microarray data by qPCR and whole-mount in situ hybridization and showed the expression pattern of candidate genes in normal kidneys. Some of these genes might play an important role during early nephron formation. Our study should help to define the minimal set of genes that is required to form a functional nephron. PMID:22432025

  5. Microbial Preservation in Sulfates in the Haughton Impact Structure Suggests Target in Search for Life on Mars

    NASA Technical Reports Server (NTRS)

    Parnell, J.; Osinski, G. R.; Lee, P.; Cockell, C. S.

    2005-01-01

    Microbes in Haughton Crater Sulfates: Impact craters are of high interest in planetary exploration because they are viewed as possible sites for evidence of life [1]. Hydrothermal systems in craters are particularly regarded as sites where primitive life could evolve. Evidence from the Miocene Haughton impact structure shows that crater hydrothermal deposits may also be a preferred site for subsequent colonization and hence possible extant life: Hydrothermal sulfates at Haughton are colonized by viable cyanobacteria [2]. The Haughton impact structure, Devon Island, Canadian High Arctic, is a 24 km-diameter crater of mid-Tertiary age. The structure preserves an exceptional record of impact-induced hydrothermal activity, including sulfide, and sulfate mineralization [3]. The target rocks excavated at the site included massive gypsum-bearing carbonate rocks of Ordovician age. Impact-remobilized sulfates occur as metre-scale masses of intergrown crystals of the clear form of gypsum selenite in veins and cavity fillings within the crater s impact melt breccia deposits [4]. The selenite is part of the hydrothermal assemblage as it was precipitated by cooling hot waters that were circulating as a result of the impact. Remobilization of the sulfate continues to the present day, such that it occurs in soil crusts (Fig. 1) including sandy beds with a gypsum cement. The sulfate-cemented beds make an interesting comparison with the sulfate-bearing sandy beds encountered by the Opportunity MER [5]. The selenite crystals are up to 0.3 m in width, of high purity, and transparent. They locally exhibit frayed margins where cleavage surfaces have separated. This exfoliation may be a response to freeze-thaw weathering. The selenite contains traces of rock detritus, newly precipitated gypsum, and microbial colonies. The rock detritus consists of sediment particles which penetrated the opened cleavages by up to 2cm from the crystal margins. Some of the detritus is cemented into place

  6. Targeting and valuing conservation investments in support of a water fund: linking upstream land management with downstream services in the Upper Tana catchment, Kenya

    NASA Astrophysics Data System (ADS)

    Bryant, B. P.; Droogers, P.; Hunink, J.; Vogl, A.; Wolny, S.

    2014-12-01

    We apply an integrated modeling framework to both target and value watershed management interventions in the Upper Tana watershed, which provides municipal water, irrigation water, and hydropower services to Nairobi and surrounding areas. The analysis begins by applying an index model approach that incorporates existing land use and land surface characteristics to prioritize the type and location of conservation investments in different subbasins, subject to budget constraints and stakeholder concerns (Resource Investment Optimization System -- RIOS). We then run the Soil and Water Assessment Tool (SWAT) using the RIOS-identified investment scenarios to produce spatially explicit scenarios that simulate changes in water yield and suspended sediment. Finally, we link those biophysical outputs to monetary and non-monetary human well-being metrics for multiple benefit streams, including: Reduced water treatment costs, increased hydropower production, and crop yield benefits for upstream farmers in the conservation area. The viability of a payment for watershed services scheme is discussed, with attention to the various components of value assessed and to dependencies on water management approaches. While other studies have examined links between land use and the provision of hydrologic services, this study is novel in that it presents an integrated analysis that targets interventions in a decision context and then relies on calibrated, process-based, biophysical models to demonstrate the return on those investments considering multiple (and sometimes competing) hydrological services, doing so at a sub-annual time-scale.

  7. Genomic Profiling of a Human Organotypic Model of AEC Syndrome Reveals ZNF750 as an Essential Downstream Target of Mutant TP63

    PubMed Central

    Zarnegar, Brian J.; Webster, Dan E.; Lopez-Pajares, Vanessa; Vander Stoep Hunt, Brook; Qu, Kun; Yan, Karen J.; Berk, David R.; Sen, George L.; Khavari, Paul A.

    2012-01-01

    The basis for impaired differentiation in TP63 mutant ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome is unknown. Human epidermis harboring AEC TP63 mutants recapitulated this impairment, along with downregulation of differentiation activators, including HOPX, GRHL3, KLF4, PRDM1, and ZNF750. Gene-set enrichment analysis indicated that disrupted expression of epidermal differentiation programs under the control of ZNF750 and KLF4 accounted for the majority of disrupted epidermal differentiation resulting from AEC mutant TP63. Chromatin immunoprecipitation (ChIP) analysis and ChIP-sequencing of TP63 binding in differentiated keratinocytes revealed ZNF750 as a direct target of wild-type and AEC mutant TP63. Restoring ZNF750 to AEC model tissue rescued activator expression and differentiation, indicating that AEC TP63-mediated ZNF750 inhibition contributes to differentiation defects in AEC. Incorporating disease-causing mutants into regenerated human tissue can thus dissect pathomechanisms and identify targets that reverse disease features. PMID:22922031

  8. EWS/FLI and its Downstream Target NR0B1 Interact Directly to Modulate Transcription and Oncogenesis in Ewing's Sarcoma

    PubMed Central

    Kinsey, Michelle; Smith, Richard; Iyer, Anita K.; McCabe, Edward R.B.; Lessnick, Stephen L.

    2009-01-01

    Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in frame, to the DNA binding domain-containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a co-repressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. While the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for Ewing's sarcoma development because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma. PMID:19920188

  9. Identification of putative pathogenic microRNA and its downstream targets in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.

    PubMed

    Mehrotra, Meenakshi; Medeiros, L Jeffrey; Luthra, Rajyalakshmi; Sargent, Rachel L; Yao, Hui; Barkoh, Bedia A; Singh, Rajesh; Patel, Keyur P

    2014-10-01

    Anaplastic large cell lymphomas (ALCL) are tumors of T/null-cell lineage characterized by uniform CD30 expression. The 2008 World Health Organization classification subdivided ALCLs into 2 groups: anaplastic lymphoma kinase (ALK)-positive (established entity) and ALK-negative (proposed new entity) ALCL. The genetic basis for the pathogenesis of newly categorized ALK- ALCL is poorly understood. In this study, we used microRNA microarray analysis to identify differentially expressed microRNAs in ALK+ and ALK- ALCL. ALK- ALCL showed significantly higher expression of miR-155 (0.888 ± 0.228) compared with ALK+ ALCL (0.0565 ± 0.009) on microarray and by quantitative real-time polymerase chain reaction in ALK- ALCL compared with ALK+ ALCL (P < .05) with a strong correlation between the 2 platforms (R = 0.9, P < .0003). A novel in situ hybridization method allows direct visualization of expression patterns and relative quantitation of miR-155 (mean score, 2.3 versus 1.3; P = .01) for the first time in tissue sections of ALCL. Among computationally predicted targets of miR-155, we identified ZNF652 (r = -0.57, P = .05), BACH1 (r = 0.88, P = .02), RBAK (r = 0.81, P = .05), TRIM32 (r = 0.92, P = .01), E2F2 (r = 0.81, P = .05), and TP53INP1 (r = -0.31, P = .03) as genes whose expression by quantitative real-time polymerase chain reaction correlated significantly with the level of miR-155 in ALCL tumor tissue. PMID:25128227

  10. Identification of Phosphotyrosine Binding Domain-Containing Proteins as Novel Downstream Targets of the EphA8 Signaling Function▿ †

    PubMed Central

    Shin, Jongdae; Gu, Changkyu; Park, Eunjeong; Park, Soochul

    2007-01-01

    Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-1b and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA-1b and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required for this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells. Taken together, our findings support a possible function for Anks family proteins as scaffolding proteins of the EphA8 signaling pathway. PMID:17875921

  11. The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma

    SciTech Connect

    Revet, Ingrid; Huizenga, Gerda; Chan, Alvin; Koster, Jan; Volckmann, Richard; Sluis, Peter van; Ora, Ingrid; Versteeg, Rogier; Geerts, Dirk

    2008-02-15

    Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was down-regulated. Western blot analysis showed that MSX1 induction caused cleavage of the NOTCH3 protein to its activated form, further confirming activation of the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Affymetrix micro-array analysis of a neuroblastic tumour series consisting of neuroblastomas and the more benign ganglioneuromas showed that MSX1, NOTCH3 and HEY1 are more highly expressed in ganglioneuromas. This suggests a block in differentiation of these tumours at distinct developmental stages or lineages.

  12. Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain

    PubMed Central

    2010-01-01

    Background The Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected. Results Using microarrays and quantitative PCR, the mRNA expression profiles of these two neuroanatomical regions were compared in postmortem brain tissue from RTT patients and normal controls. A subset of genes was differentially expressed in the frontal cortex of RTT brains, some of which are known to be associated with neurological disorders (clusterin and cytochrome c oxidase subunit 1) or are involved in synaptic vesicle cycling (dynamin 1). RNAi-mediated knockdown of MeCP2 in vitro, followed by further expression analysis demonstrated that the same direction of abnormal expression was recapitulated with MeCP2 knockdown, which for cytochrome c oxidase subunit 1 was associated with a functional respiratory chain defect. Chromatin immunoprecipitation (ChIP) analysis showed that MeCP2 associated with the promoter regions of some of these genes suggesting that loss of MeCP2 function may be responsible for their overexpression. Conclusions This study has shed more light on the subset of aberrantly expressed genes that result from MECP2 mutations. The mitochondrion has long been implicated in the pathogenesis of RTT, however it has not been at the forefront of RTT research interest since the discovery of MECP2 mutations. The functional consequence of the underexpression of cytochrome c oxidase subunit 1 indicates that this is an area that should be revisited. PMID:20420693

  13. View downstream of timber guide wall downstream from SE corner ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View downstream of timber guide wall downstream from SE corner of lock, view towards east - St. Lucie Canal, St. Lucie Lock No. 1, St. Lucie, Cross State Canal, Okeechobee Intracoastal Waterway, Stuart, Martin County, FL

  14. Comparative Analysis of mRNA Targets for Human PUF-Family Proteins Suggests Extensive Interaction with the miRNA Regulatory System

    PubMed Central

    Galgano, Alessia; Forrer, Michael; Jaskiewicz, Lukasz; Kanitz, Alexander; Zavolan, Mihaela; Gerber, André P.

    2008-01-01

    Genome-wide identification of mRNAs regulated by RNA-binding proteins is crucial to uncover post-transcriptional gene regulatory systems. The conserved PUF family RNA-binding proteins repress gene expression post-transcriptionally by binding to sequence elements in 3′-UTRs of mRNAs. Despite their well-studied implications for development and neurogenesis in metazoa, the mammalian PUF family members are only poorly characterized and mRNA targets are largely unknown. We have systematically identified the mRNAs associated with the two human PUF proteins, PUM1 and PUM2, by the recovery of endogenously formed ribonucleoprotein complexes and the analysis of associated RNAs with DNA microarrays. A largely overlapping set comprised of hundreds of mRNAs were reproducibly associated with the paralogous PUM proteins, many of them encoding functionally related proteins. A characteristic PUF-binding motif was highly enriched among PUM bound messages and validated with RNA pull-down experiments. Moreover, PUF motifs as well as surrounding sequences exhibit higher conservation in PUM bound messages as opposed to transcripts that were not found to be associated, suggesting that PUM function may be modulated by other factors that bind conserved elements. Strikingly, we found that PUF motifs are enriched around predicted miRNA binding sites and that high-confidence miRNA binding sites are significantly enriched in the 3′-UTRs of experimentally determined PUM1 and PUM2 targets, strongly suggesting an interaction of human PUM proteins with the miRNA regulatory system. Our work suggests extensive connections between the RBP and miRNA post-transcriptional regulatory systems and provides a framework for deciphering the molecular mechanism by which PUF proteins regulate their target mRNAs. PMID:18776931

  15. Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases.

    PubMed

    Satoh, Jun-Ichi; Kawana, Natsuki; Yamamoto, Yoji

    2013-01-01

    Nuclear respiratory factor 1 (NRF1) serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits, heme biosynthetic enzymes, and regulatory factors involved in the replication and transcription of mitochondrial DNA. Increasing evidence indicates that mitochondrial function is severely compromised in the brains of aging-related neurodegenerative diseases. To identify the comprehensive set of human NRF1 target genes potentially relevant to the pathogenesis of neurodegenerative diseases, we analyzed the NRF1 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset retrieved from the Encyclopedia of DNA Elements (ENCODE) project. Overall, we identified 2,470 highly stringent ChIP-Seq peaks on protein-coding genes in SK-N-SH human neuroblastoma cells. They were accumulated in the proximal promoter regions with an existence of the NRF1-binding consensus sequence. The set of ChIP-Seq-based NRF1 target genes included known NRF1 targets such as EIF2S1, EIF2S2, CYCS, FMR1, FXR2, E2F6, CD47, and TOMM34. By pathway analysis, the molecules located in the core pathways related to mitochondrial respiratory function were determined to be highly enriched in NRF1 target genes. Furthermore, we found that NRF1 target genes play a pivotal role in regulation of extra-mitochondrial biological processes, including RNA metabolism, splicing, cell cycle, DNA damage repair, protein translation initiation, and ubiquitin-mediated protein degradation. We identified a panel of neurodegenerative disease-related genes, such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) for Parkinson's disease, as well as PSENEN (Pen2) and MAPT (tau) for Alzheimer's disease, as previously unrecognized NRF1 targets. These results suggest a logical hypothesis that aberrant regulation of NRF1 and its targets might contribute to the

  16. Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases

    PubMed Central

    Satoh, Jun-ichi; Kawana, Natsuki; Yamamoto, Yoji

    2013-01-01

    Nuclear respiratory factor 1 (NRF1) serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits, heme biosynthetic enzymes, and regulatory factors involved in the replication and transcription of mitochondrial DNA. Increasing evidence indicates that mitochondrial function is severely compromised in the brains of aging-related neurodegenerative diseases. To identify the comprehensive set of human NRF1 target genes potentially relevant to the pathogenesis of neurodegenerative diseases, we analyzed the NRF1 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset retrieved from the Encyclopedia of DNA Elements (ENCODE) project. Overall, we identified 2,470 highly stringent ChIP-Seq peaks on protein-coding genes in SK-N-SH human neuroblastoma cells. They were accumulated in the proximal promoter regions with an existence of the NRF1-binding consensus sequence. The set of ChIP-Seq-based NRF1 target genes included known NRF1 targets such as EIF2S1, EIF2S2, CYCS, FMR1, FXR2, E2F6, CD47, and TOMM34. By pathway analysis, the molecules located in the core pathways related to mitochondrial respiratory function were determined to be highly enriched in NRF1 target genes. Furthermore, we found that NRF1 target genes play a pivotal role in regulation of extra-mitochondrial biological processes, including RNA metabolism, splicing, cell cycle, DNA damage repair, protein translation initiation, and ubiquitin-mediated protein degradation. We identified a panel of neurodegenerative disease-related genes, such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) for Parkinson’s disease, as well as PSENEN (Pen2) and MAPT (tau) for Alzheimer’s disease, as previously unrecognized NRF1 targets. These results suggest a logical hypothesis that aberrant regulation of NRF1 and its targets might contribute to the

  17. Possible target-related proteins and signal network of bufalin in A549 cells suggested by both iTRAQ-based and label-free proteomic analysis.

    PubMed

    Zhang, Dong-Mei; Feng, Li-Xing; Liu, Miao; Jin, Wen-Hai; Luo, Ji; Nie, Ai-Ying; Zhou, Yue; Li, Yin; Wu, Wan-Ying; Jiang, Bao-Hong; Yang, Min; Hu, Li-Hong; Guo, De-An; Liu, Xuan

    2016-03-01

    Bufalin (BF) exhibited antiproliferation and antimigration effects on human A549 lung cancer cells. To search its target-related proteins, protein expression profiles of BF-treated and control cells were compared using two quantitative proteomic methods, iTRAQ-based and label-free proteomic analysis. A total of 5428 proteins were identified in iTRAQ-based analysis while 6632 proteins were identified in label-free analysis. The number of common identified proteins of both methods was 4799 proteins. By application of 1.20-fold for upregulated and 0.83-fold for downregulated cutoff values, 273 and 802 differentially expressed proteins were found in iTRAQ-based and label-free analysis, respectively. The number of common differentially expressed proteins of both methods was 45 proteins. Results of bioinformational analysis using Metacore(TM) showed that the two proteomic methods were complementary and both suggested the involvement of oxidative stress and regulation of gene expression in the effects of BF, and fibronectin-related pathway was suggested to be an important pathway affected by BF. Western blotting assay results confirmed BF-induced change in levels of fibronectin and other related proteins. Overexpression of fibronectin by plasmid transfection ameliorated antimigration effects of BF. Results of the present study provided information about possible target-related proteins and signal network of BF. PMID:26787099

  18. DARHT-II Downstream Beam Transport Beamline

    SciTech Connect

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

    2000-08-01

    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 20-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 20-meter long region extending from the end of the accelerator to the bremsstrahlung target. Within this proposed transport line there are 15 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.

  19. Downstream in Mawrth Valles

    NASA Technical Reports Server (NTRS)

    2005-01-01

    [figure removed for brevity, see original site]

    The THEMIS VIS camera is capable of capturing color images of the Martian surface using five different color filters. In this mode of operation, the spatial resolution and coverage of the image must be reduced to accommodate the additional data volume produced from using multiple filters. To make a color image, three of the five filter images (each in grayscale) are selected. Each is contrast enhanced and then converted to a red, green, or blue intensity image. These three images are then combined to produce a full color, single image. Because the THEMIS color filters don't span the full range of colors seen by the human eye, a color THEMIS image does not represent true color. Also, because each single-filter image is contrast enhanced before inclusion in the three-color image, the apparent color variation of the scene is exaggerated. Nevertheless, the color variation that does appear is representative of some change in color, however subtle, in the actual scene. Note that the long edges of THEMIS color images typically contain color artifacts that do not represent surface variation.

    This false color image is from further downstream in Mawrth Valles than yesterday's image. The channel here is at the end of the vallis. This image was collected during the Northern Spring season.

    Image information: VIS instrument. Latitude 26.7, Longitude 340.2 East (19.8 West). 37 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages

  20. Limits of downstream hydraulic geometry

    NASA Astrophysics Data System (ADS)

    Wohl, Ellen

    2004-10-01

    Adjustments to flow width, depth, and velocity in response to changes in discharge are commonly characterized by using downstream hydraulic geometry relationships. The spatial limits of these relationships within a drainage basin have not been systematically quantified. Where the erosional resistance of the channel substrate is sufficiently large, hydraulic driving forces presumably will be unable to adjust channel form. Data sets from 10 mountain rivers in the United States, Panama, Nepal, and New Zealand are used in this study to explore the limits of downstream hydraulic geometry relationships. Where the ratio of stream power to sediment size (Ω/D84) exceeds 10,000 kg/s3, downstream hydraulic geometry is well developed; where the ratio falls below 10,000 kg/s3, downstream hydraulic geometry relationships are poorly developed. These limitations on downstream hydraulic geometry have important implications for channel engineering and simulations of landscape change.

  1. A common origin for the bacterial toxin-antitoxin systems parD and ccd, suggested by analyses of toxin/target and toxin/antitoxin interactions.

    PubMed

    Smith, Andrew B; López-Villarejo, Juan; Diago-Navarro, Elizabeth; Mitchenall, Lesley A; Barendregt, Arjan; Heck, Albert J; Lemonnier, Marc; Maxwell, Anthony; Díaz-Orejas, Ramón

    2012-01-01

    Bacterial toxin-antitoxin (TA) systems encode two proteins, a potent inhibitor of cell proliferation (toxin) and its specific antidote (antitoxin). Structural data has revealed striking similarities between the two model TA toxins CcdB, a DNA gyrase inhibitor encoded by the ccd system of plasmid F, and Kid, a site-specific endoribonuclease encoded by the parD system of plasmid R1. While a common structural fold seemed at odds with the two clearly different modes of action of these toxins, the possibility of functional crosstalk between the parD and ccd systems, which would further point to their common evolutionary origin, has not been documented. Here, we show that the cleavage of RNA and the inhibition of protein synthesis by the Kid toxin, two activities that are specifically counteracted by its cognate Kis antitoxin, are altered, but not inhibited, by the CcdA antitoxin. In addition, Kis was able to inhibit the stimulation of DNA gyrase-mediated cleavage of DNA by CcdB, albeit less efficiently than CcdA. We further show that physical interactions between the toxins and antitoxins of the different systems do occur and define the stoichiometry of the complexes formed. We found that CcdB did not degrade RNA nor did Kid have any reproducible effect on the tested DNA gyrase activities, suggesting that these toxins evolved to reach different, rather than common, cellular targets. PMID:23029540

  2. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis.

    PubMed

    Buj-Bello, Anna; Fougerousse, Françoise; Schwab, Yannick; Messaddeq, Nadia; Spehner, Danièle; Pierson, Christopher R; Durand, Muriel; Kretz, Christine; Danos, Olivier; Douar, Anne-Marie; Beggs, Alan H; Schultz, Patrick; Montus, Marie; Denèfle, Patrice; Mandel, Jean-Louis

    2008-07-15

    Myotubular myopathy (XLMTM, OMIM 310400) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small myofibers with frequent occurrence of central nuclei. Myotubularin is a ubiquitously expressed phosphoinositide phosphatase with a muscle-specific role in man and mouse that is poorly understood. No specific treatment exists to date for patients with myotubular myopathy. We have constructed an adeno-associated virus (AAV) vector expressing myotubularin in order to test its therapeutic potential in a XLMTM mouse model. We show that a single intramuscular injection of this vector in symptomatic Mtm1-deficient mice ameliorates the pathological phenotype in the targeted muscle. Myotubularin replacement in mice largely corrects nuclei and mitochondria positioning in myofibers and leads to a strong increase in muscle volume and recovery of the contractile force. In addition, we used this AAV vector to overexpress myotubularin in wild-type skeletal muscle and get insight into its localization and function. We show that a substantial proportion of myotubularin associates with the sarcolemma and I band, including triads. Myotubularin overexpression in muscle induces the accumulation of packed membrane saccules and presence of vacuoles that contain markers of sarcolemma and T-tubules, suggesting that myotubularin is involved in plasma membrane homeostasis of myofibers. This study provides a proof-of-principle that local delivery of an AAV vector expressing myotubularin can improve the motor capacities of XLMTM muscle and represents a novel approach to study myotubularin function in skeletal muscle. PMID:18434328

  3. Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors

    PubMed Central

    Karlsson, Hannah; Svensson, Emma; Gigg, Camilla; Jarvius, Malin; Olsson-Strömberg, Ulla; Savoldo, Barbara; Dotti, Gianpietro; Loskog, Angelica

    2015-01-01

    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. PMID:26700307

  4. Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors.

    PubMed

    Karlsson, Hannah; Svensson, Emma; Gigg, Camilla; Jarvius, Malin; Olsson-Strömberg, Ulla; Savoldo, Barbara; Dotti, Gianpietro; Loskog, Angelica

    2015-01-01

    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. PMID:26700307

  5. Prevalence of urogenital Chlamydia trachomatis increases significantly with level of urbanisation and suggests targeted screening approaches: results from the first national population based study in the Netherlands

    PubMed Central

    van Bergen, J; Gotz, H; Richardus, J; Hoebe, C; Broer, J; Coenen, A; t for

    2005-01-01

    Objectives: Chlamydia trachomatis (Chlamydia) is the most prevalent sexually transmitted bacterial infection and can cause considerable reproductive morbidity in women. Chlamydia screening programmes have been considered but policy recommendations are hampered by the lack of population based data. This paper describes the prevalence of Chlamydia in 15–29 year old women and men in rural and urban areas, as determined through systematic population based screening organised by the Municipal Public Health Services (MHS), and discusses the implications of this screening strategy for routine implementation. Methods: Stratified national probability survey according to "area address density" (AAD). 21 000 randomly selected women and men in four regions, aged 15–29 years received a home sampling kit. Urine samples were returned by mail and tested by polymerase chain reaction (PCR). Treatment was via the general practitioner, STI clinic, or MHS clinic. Results: 41% (8383) responded by sending in urine and questionnaire. 11% (2227) returned a refusal card. Non-responders included both higher and lower risk categories. Chlamydia prevalence was significantly lower in rural areas (0.6%, 95% CI 0.1 to 1.1) compared with very highly urbanised areas (3.2%, 95% CI 2.4 to 4.0). Overall prevalence was 2.0% (95% CI 1.7 to 2.3): 2.5% (95% CI 2.0 to 3.0%) in women and 1.5% (95% CI 1.1 to 1.8) in men. Of all cases 91% were treated. Infection was associated with degree of urbanisation, ethnicity, number of sex partners, and symptoms. Conclusion: This large, population based study found very low prevalence in rural populations, suggesting that nationwide systematic screening is not indicated in the Netherlands and that targeted approaches are a better option. Further analysis of risk profiles will contribute to determine how selective screening can be done. PMID:15681716

  6. Single-cell analyses of regulatory network perturbations using enhancer-targeting TALEs suggest novel roles for PU.1 during haematopoietic specification.

    PubMed

    Wilkinson, Adam C; Kawata, Viviane K S; Schütte, Judith; Gao, Xuefei; Antoniou, Stella; Baumann, Claudia; Woodhouse, Steven; Hannah, Rebecca; Tanaka, Yosuke; Swiers, Gemma; Moignard, Victoria; Fisher, Jasmin; Hidetoshi, Shimauchi; Tijssen, Marloes R; de Bruijn, Marella F T R; Liu, Pentao; Göttgens, Berthold

    2014-10-01

    Transcription factors (TFs) act within wider regulatory networks to control cell identity and fate. Numerous TFs, including Scl (Tal1) and PU.1 (Spi1), are known regulators of developmental and adult haematopoiesis, but how they act within wider TF networks is still poorly understood. Transcription activator-like effectors (TALEs) are a novel class of genetic tool based on the modular DNA-binding domains of Xanthomonas TAL proteins, which enable DNA sequence-specific targeting and the manipulation of endogenous gene expression. Here, we report TALEs engineered to target the PU.1-14kb and Scl+40kb transcriptional enhancers as efficient new tools to perturb the expression of these key haematopoietic TFs. We confirmed the efficiency of these TALEs at the single-cell level using high-throughput RT-qPCR, which also allowed us to assess the consequences of both PU.1 activation and repression on wider TF networks during developmental haematopoiesis. Combined with comprehensive cellular assays, these experiments uncovered novel roles for PU.1 during early haematopoietic specification. Finally, transgenic mouse studies confirmed that the PU.1-14kb element is active at sites of definitive haematopoiesis in vivo and PU.1 is detectable in haemogenic endothelium and early committing blood cells. We therefore establish TALEs as powerful new tools to study the functionality of transcriptional networks that control developmental processes such as early haematopoiesis. PMID:25252941

  7. DARHT-II Downstream Transport Beamline

    SciTech Connect

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

    2001-06-06

    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.

  8. May the remodeling of the Ca²⁺ toolkit in endothelial progenitor cells derived from cancer patients suggest alternative targets for anti-angiogenic treatment?

    PubMed

    Moccia, Francesco; Poletto, Valentina

    2015-09-01

    Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain the metastatic switch in a number of solid cancers, including breast cancer (BC) and renal cellular carcinoma (RCC). Preventing EPC mobilization causes tumor shrinkage. Novel anti-angiogenic treatments have been introduced in therapy to inhibit VEGFR-2 signaling; unfortunately, these drugs blocked tumor angiogenesis in pre-clinical murine models, but resulted far less effective in human patients. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis in cancer patients could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca²⁺ entry (SOCE) regulates the growth of human EPCs, and it is mediated by the interaction between the endoplasmic reticulum Ca²⁺-sensor, Stim1, and the plasmalemmal Ca²⁺ channels, Orai1 and TRPC1. EPCs do not belong to the neoplastic clone: thus, unlike tumor endothelium and neoplastic cells, they should not remodel their Ca²⁺ toolkit in response to tumor microenvironment. However, our recent work demonstrated that EPCs isolated from naïve RCC patients (RCC-EPCs) undergo a dramatic remodeling of their Ca²⁺ toolkit by displaying a remarkable drop in the endoplasmic reticulum Ca²⁺ content, by down-regulating the expression of inositol-1,4,5-receptors (InsP3Rs), and by up-regulating Stim1, Orai1 and TRPC1. Moreover, EPCs are dramatically less sensitive to VEGF stimulation both in terms of Ca²⁺ signaling and of gene expression when isolated from tumor patients. Conversely, the pharmacological abolition of SOCE suppresses proliferation in these cells. These results question the suitability of VEGFR-2 as a therapeutically relevant target for anti-angiogenic treatments and hint at Orai1 and TRPC1 as more promising alternatives. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID:25447551

  9. Chemical downstream etching of tungsten

    SciTech Connect

    Blain, M.G.; Jarecki, R.L.; Simonson, R.J.

    1998-07-01

    The downstream etching of tungsten and tungsten oxide has been investigated. Etching of chemical vapor deposited tungsten and e-beam deposited tungsten oxide samples was performed using atomic fluorine generated by a microwave discharge of argon and NF{sub 3}. Etching was found to be highly activated with activation energies approximated to be 6.0{plus_minus}0.5thinspkcal/mol and 5.4{plus_minus}0.4thinspkcal/mol for W and WO{sub 3}, respectively. In the case of F etching of tungsten, the addition of undischarged nitric oxide (NO) directly into the reaction chamber results in the competing effects of catalytic etch rate enhancement and the formation of a nearly stoichiometric WO{sub 3} passivating tungsten oxide film, which ultimately stops the etching process. For F etching of tungsten oxide, the introduction of downstream NO reduces the etch rate. {copyright} {ital 1998 American Vacuum Society.}

  10. Multiple myeloma-associated hDIS3 mutations cause perturbations in cellular RNA metabolism and suggest hDIS3 PIN domain as a potential drug target.

    PubMed

    Tomecki, Rafal; Drazkowska, Karolina; Kucinski, Iwo; Stodus, Krystian; Szczesny, Roman J; Gruchota, Jakub; Owczarek, Ewelina P; Kalisiak, Katarzyna; Dziembowski, Andrzej

    2014-01-01

    hDIS3 is a mainly nuclear, catalytic subunit of the human exosome complex, containing exonucleolytic (RNB) and endonucleolytic (PIN) active domains. Mutations in hDIS3 have been found in ∼10% of patients with multiple myeloma (MM). Here, we show that these mutations interfere with hDIS3 exonucleolytic activity. Yeast harboring corresponding mutations in DIS3 show growth inhibition and changes in nuclear RNA metabolism typical for exosome dysfunction. Construction of a conditional DIS3 knockout in the chicken DT40 cell line revealed that DIS3 is essential for cell survival, indicating that its function cannot be replaced by other exosome-associated nucleases: hDIS3L and hRRP6. Moreover, HEK293-derived cells, in which depletion of endogenous wild-type hDIS3 was complemented with exogenously expressed MM hDIS3 mutants, proliferate at a slower rate and exhibit aberrant RNA metabolism. Importantly, MM mutations are synthetically lethal with the hDIS3 PIN domain catalytic mutation both in yeast and human cells. Since mutations in PIN domain alone have little effect on cell physiology, our results predict the hDIS3 PIN domain as a potential drug target for MM patients with hDIS3 mutations. It is an interesting example of intramolecular synthetic lethality with putative therapeutic potential in humans. PMID:24150935

  11. Detection of Shigella by a PCR Assay Targeting the ipaH Gene Suggests Increased Prevalence of Shigellosis in Nha Trang, Vietnam

    PubMed Central

    Thiem, Vu Dinh; Sethabutr, Orntipa; von Seidlein, Lorenz; Van Tung, Tran; Canh, Do Gia; Chien, Bui Trong; Tho, Le Huu; Lee, Hyejon; Houng, Huo-Shu; Hale, Thomas L.; Clemens, John D.; Mason, Carl; Trach, Dang Duc

    2004-01-01

    Shigella spp. are exquisitely fastidious gram-negative organisms which frequently escape detection by traditional culture methods. To get a more complete understanding of the disease burden caused by Shigella in Nha Trang, Vietnam, real-time PCR was used to detect Shigella DNA. Randomly selected rectal swab specimens from 60 Shigella culture-positive patients and 500 Shigella culture-negative patients detected by population-based surveillance of patients seeking care for diarrhea were processed by real-time PCR. The target of the primer pair is the invasion plasmid antigen H gene sequence (ipaH), carried by all four Shigella species and enteroinvasive Escherichia coli. Shigella spp. could be isolated from the rectal swabs of 547 of 19,206 (3%) patients with diarrhea. IpaH was detected in 55 of 60 (93%) Shigella culture-positive specimens, whereas it was detected in 87 of 245 (36%) culture-negative patients free of dysentery (P < 0.001). The number of PCR cycles required to detect a PCR product was highest for culture-negative, nonbloody diarrheal specimens (mean number of cycles to detection, 36.6) and was lowest for children with culture-positive, bloody diarrheal specimens (mean number of cycles, 25.3) (P < 0.001). The data from real-time PCR amplification indicate that the culture-proven prevalence of Shigella among patients with diarrhea may underestimate the prevalence of Shigella infections. The clinical presentation of shigellosis may be directly related to the bacterial load. PMID:15131166

  12. Role of mTOR Downstream Effector Signaling Molecules in Francisella Tularensis Internalization by Murine Macrophages

    PubMed Central

    Edwards, Michael W.; Aultman, James A.; Harber, Gregory; Bhatt, Jay M.; Sztul, Elizabeth; Xu, Qingan; Zhang, Ping; Michalek, Suzanne M.; Katz, Jannet

    2013-01-01

    Francisella tularensis is an infectious, gram-negative, intracellular microorganism, and the cause of tularemia. Invasion of host cells by intracellular pathogens like Francisella is initiated by their interaction with different host cell membrane receptors and the rapid phosphorylation of different downstream signaling molecules. PI3K and Syk have been shown to be involved in F. tularensis host cell entry, and both of these signaling molecules are associated with the master regulator serine/threonine kinase mTOR; yet the involvement of mTOR in F. tularensis invasion of host cells has not been assessed. Here, we report that infection of macrophages with F. tularensis triggers the phosphorylation of mTOR downstream effector molecules, and that signaling via TLR2 is necessary for these events. Inhibition of mTOR or of PI3K, ERK, or p38, but not Akt signaling, downregulates the levels of phosphorylation of mTOR downstream targets, and significantly reduces the number of F. tularensis cells invading macrophages. Moreover, while phosphorylation of mTOR downstream effectors occurs via the PI3K pathway, it also involves PLCγ1 and Ca2+ signaling. Furthermore, abrogation of PLC or Ca2+ signaling revealed their important role in the ability of F. tularensis to invade host cells. Together, these findings suggest that F. tularensis invasion of primary macrophages utilize a myriad of host signaling pathways to ensure effective cell entry. PMID:24312679

  13. Targeting the Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with Novel Di-2-Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration and Cell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling.

    PubMed

    Wangpu, Xiongzhi; Lu, Jiaoyang; Xi, Ruxing; Yue, Fei; Sahni, Sumit; Park, Kyung Chan; Menezes, Sharleen; Huang, Michael L H; Zheng, Minhua; Kovacevic, Zaklina; Richardson, Des R

    2016-05-01

    Metastasis is a complex process that is regulated by multiple signaling pathways, with the focal adhesion kinase (FAK)/paxillin pathway playing a major role in the formation of focal adhesions and cell motility. N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor in many solid tumor types, including prostate and colon cancer. Considering the antimetastatic effect of NDRG1 and the crucial involvement of the FAK/paxillin pathway in cellular migration and cell-matrix adhesion, we assessed the effects of NDRG1 on this important oncogenic pathway. In the present study, NDRG1 overexpression and silencing models of HT29 colon cancer and DU145 prostate cancer cells were used to examine the activation of FAK/paxillin signaling and the formation of focal adhesions. The expression of NDRG1 resulted in a marked and significant decrease in the activating phosphorylation of FAK and paxillin, whereas silencing of NDRG1 resulted in an opposite effect. The expression of NDRG1 also inhibited the formation of focal adhesions as well as cell migration and cell-collagen adhesion. Incubation of cells with novel thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, that upregulate NDRG1 also resulted in decreased phosphorylation of FAK and paxillin. The ability of these thiosemicarbazones to inhibit cell migration and metastasis could be mediated, at least in part, through the FAK/paxillin pathway. PMID:26895766

  14. Genome-wide scan with nearly 700 000 SNPs in two Sardinian sub-populations suggests some regions as candidate targets for positive selection

    PubMed Central

    Piras, Ignazio Stefano; De Montis, Antonella; Calò, Carla Maria; Marini, Monica; Atzori, Manuela; Corrias, Laura; Sazzini, Marco; Boattini, Alessio; Vona, Giuseppe; Contu, Licinio

    2012-01-01

    This paper explores the genetic structure and signatures of natural selection in different sub-populations from the Island of Sardinia, exploiting information from nearly 700 000 autosomal SNPs genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The genetic structure of the Sardinian population and its position within the context of other Mediterranean and European human groups were investigated in depth by comparing our data with publicly available data sets. Principal components and admixture analyses suggest a clustering of the examined samples in two significantly differentiated sub-populations (Ogliastra and Southern Sardinia), as confirmed by AMOVA (FST=0.011; P<0.001). Differentiation of these sub-populations was still evident when they were pooled together with supplementary Sardinian samples from HGDP and compared with several other European, North-African and Near Eastern populations, confirming the uniqueness of the Sardinian genetic background. Moreover, by applying several statistical approaches aimed at assessing differences at the SNP level, the highest differentiated genomic regions between Ogliastra and Southern Sardinia were thus investigated via an extended haplotype homozygosity (EHH)-based test to point out potential selective sweeps. Using this approach, 40 genomic regions were detected, with significant differences between Ogliastra and Southern Sardinia. These regions were subsequently investigated using a long-range haplotype test, which found significant REHH values for SNPs rs11070188 and rs11070192 in the Ogliastra sub-population. In the light of these results and the overlap of the different computed statistics, the region encompassing these loci can be considered a strong candidate to have undergone selective pressure in Ogliastra. PMID:22535185

  15. Subsequent to suppression: Downstream comprehension consequences of noun/verb ambiguity in natural reading.

    PubMed

    Stites, Mallory C; Federmeier, Kara D

    2015-09-01

    We used eye tracking to investigate the downstream processing consequences of encountering noun/verb (NV) homographs (i.e., park) in semantically neutral but syntactically constraining contexts. Target words were followed by a prepositional phrase containing a noun that was plausible for only 1 meaning of the homograph. Replicating previous work, we found increased first fixation durations on NV homographs compared with unambiguous words, which persisted into the next sentence region. At the downstream noun, we found plausibility effects following ambiguous words that were correlated with the size of a reader's first fixation effect, suggesting that this effect reflects the recruitment of processing resources necessary to suppress the homograph's context-inappropriate meaning. Using these same stimuli, Lee and Federmeier (2012) found a sustained frontal negativity to the NV homographs, and, on the downstream noun, found a plausibility effect that was also positively correlated with the size of a reader's ambiguity effect. Together, these findings suggest that when only syntactic constraints are available, meaning selection recruits inhibitory mechanisms that can be measured in both first fixation slowdown and event-related potential ambiguity effects. PMID:25961358

  16. Subsequent to suppression: Downstream comprehension consequences of noun/verb ambiguity in natural reading

    PubMed Central

    Stites, Mallory C.; Federmeier, Kara D.

    2015-01-01

    We used eye-tracking to investigate the downstream processing consequences of encountering noun/verb (NV) homographs (i.e., park) in semantically neutral but syntactically constraining contexts. Target words were followed by a prepositional phrase containing a noun that was plausible for only one meaning of the homograph. Replicating previous work, we found increased first fixation durations on NV homographs compared to unambiguous words, which persisted into the next sentence region. At the downstream noun, we found plausibility effects following ambiguous words that were correlated with the size of a reader's first fixation effect, suggesting that this effect reflects the recruitment of processing resources necessary to suppress the homograph's context-inappropriate meaning. Using these same stimuli, Lee and Federmeier (2012) found a sustained frontal negativity to the NV homographs, and, on the downstream noun, found a plausibility effect that was also positively correlated with the size of a reader's ambiguity effect. Together, these findings suggest that when only syntactic constraints are available, meaning selection recruits inhibitory mechanisms that can be measured in both first fixation slowdown and ERP ambiguity effects. PMID:25961358

  17. Canine adenovirus downstream processing protocol.

    PubMed

    Puig, Meritxell; Piedra, Jose; Miravet, Susana; Segura, María Mercedes

    2014-01-01

    Adenovirus vectors are efficient gene delivery tools. A major caveat with vectors derived from common human adenovirus serotypes is that most adults are likely to have been exposed to the wild-type virus and exhibit active immunity against the vectors. This preexisting immunity limits their clinical success. Strategies to circumvent this problem include the use of nonhuman adenovirus vectors. Vectors derived from canine adenovirus type 2 (CAV-2) are among the best-studied representatives. CAV-2 vectors are particularly attractive for the treatment of neurodegenerative disorders. In addition, CAV-2 vectors have shown great promise as oncolytic agents in virotherapy approaches and as vectors for recombinant vaccines. The rising interest in CAV-2 vectors calls for the development of scalable GMP compliant production and purification strategies. A detailed protocol describing a complete scalable downstream processing strategy for CAV-2 vectors is reported here. Clarification of CAV-2 particles is achieved by microfiltration. CAV-2 particles are subsequently concentrated and partially purified by ultrafiltration-diafiltration. A Benzonase(®) digestion step is carried out between ultrafiltration and diafiltration operations to eliminate contaminating nucleic acids. Chromatography purification is accomplished in two consecutive steps. CAV-2 particles are first captured and concentrated on a propyl hydrophobic interaction chromatography column followed by a polishing step using DEAE anion exchange monoliths. Using this protocol, high-quality CAV-2 vector preparations containing low levels of contamination with empty viral capsids and other inactive vector forms are typically obtained. The complete process yield was estimated to be 38-45 %. PMID:24132487

  18. Ammonia downstream from HH 80 North

    NASA Technical Reports Server (NTRS)

    Girart, Jose M.; Rodriguez, Luis F.; Anglada, Guillem; Estalella, Robert; Torrelles, Jose, M.; Marti, Josep; Pena, Miriam; Ayala, Sandra; Curiel, Salvador; Noriega-Crespo, Alberto

    1994-01-01

    HH 80-81 are two optically visible Herbig-Haro (HH) objects located about 5 minutes south of their exciting source IRAS 18162-2048. Displaced symmetrically to the north of this luminous IRAS source, a possible HH counterpart was recently detected as a radio continuum source with the very large array (VLA). This radio source, HH 80 North, has been proposed to be a member of the Herbig-Haro class since its centimeter flux density, angular size, spectral index, and morphology are all similar to those of HH 80. However, no object has been detected at optical wavelengths at the position of HH 80 North, possibly because of high extinction, and the confirmation of the radio continuum source as an HH object has not been possible. In the prototypical Herbig-Haro objects HH 1 and 2, ammonia emission has been detected downstream of the flow in both objects. This detection has been intepreted as a result of an enhancement in the ammonia emission produced by the radiation field of the shock associated with the HH object. In this Letter we report the detection of the (1,1) and (2,2) inversion transitions of ammonia downstream HH 80 North. This detection gives strong suppport to the interpretation of HH 80 North as a heavily obscured HH object. In addition, we suggest that ammonia emission may be a tracer of embedded Herbig-Haro objects in other regions of star formation. A 60 micrometer IRAS source could be associated with HH 80 North and with the ammonia condensation. A tentative explanation for the far-infrared emission as arising in dust heated by their optical and UV radiation of the HH object is presented.

  19. Design of the DARHT-II Downstream Beamline

    SciTech Connect

    Westenskow, G A; Bertolini, L R; Chen, Y -J; Fessenden, T J; Paul, A C; Watson, J A

    2002-06-07

    This paper describes the 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. The principal element of the beam transport section is the fast deflector, or kicker system, used to generate four micropulses from the primary accelerator beam. Within this proposed transport line there are also several conventional solenoid, quadrupole and dipole magnets which transport and focus the beam to the target and to the beam dumps.

  20. TAL effectors and activation of predicted host targets distinguish Asian from African strains of the rice pathogen Xanthomonas oryzae pv. oryzicola while strict conservation suggests universal importance of five TAL effectors

    PubMed Central

    Wilkins, Katherine E.; Booher, Nicholas J.; Wang, Li; Bogdanove, Adam J.

    2015-01-01

    Xanthomonas oryzae pv. oryzicola (Xoc) causes the increasingly important disease bacterial leaf streak of rice (BLS) in part by type III delivery of repeat-rich transcription activator-like (TAL) effectors to upregulate host susceptibility genes. By pathogen whole genome, single molecule, real-time sequencing and host RNA sequencing, we compared TAL effector content and rice transcriptional responses across 10 geographically diverse Xoc strains. TAL effector content is surprisingly conserved overall, yet distinguishes Asian from African isolates. Five TAL effectors are conserved across all strains. In a prior laboratory assay in rice cv. Nipponbare, only two contributed to virulence in strain BLS256 but the strict conservation indicates all five may be important, in different rice genotypes or in the field. Concatenated and aligned, TAL effector content across strains largely reflects relationships based on housekeeping genes, suggesting predominantly vertical transmission. Rice transcriptional responses did not reflect these relationships, and on average, only 28% of genes upregulated and 22% of genes downregulated by a strain are up- and down- regulated (respectively) by all strains. However, when only known TAL effector targets were considered, the relationships resembled those of the TAL effectors. Toward identifying new targets, we used the TAL effector-DNA recognition code to predict effector binding elements in promoters of genes upregulated by each strain, but found that for every strain, all upregulated genes had at least one. Filtering with a classifier we developed previously decreases the number of predicted binding elements across the genome, suggesting that it may reduce false positives among upregulated genes. Applying this filter and eliminating genes for which upregulation did not strictly correlate with presence of the corresponding TAL effector, we generated testable numbers of candidate targets for four of the five strictly conserved TAL

  1. Downstream System for the Second Axis of the DARHT Facility

    SciTech Connect

    Chen, Y-J; Bertolini, L; Caporaso, G J; Chambers, F W; Cook, E G; Falabella, S; Goldin, F J; Guethlein, G; Ho, D D-M; McCarrick, J F; Nelson, S D; Neurath, R; Paul, A C; Pincosy, P A; Poole, B R; Richardson, R A; Sampayan, S; Wang, L-F; Watson, J A; Westenskow, G A; Weir, J T

    2002-07-15

    This paper presents the physics design of the DARHT-II downstream system, which consists of a diagnostic beam stop, a fast, high-precision kicker system and the x-ray converter target assembly. The beamline configuration, the transverse resistive wall instability and the ion hose instability modeling are presented. They also discuss elimination of spot size dilution during kicker switching and implementation of the foil-barrier scheme to minimize the backstreaming ion focusing effects. Finally, they present the target converter's configuration, and the simulated DARHT-II x-ray spot sizes and doses. Some experimental results, which support the physics design, are also presented.

  2. Density Fluctuations Upstream and Downstream of Interplanetary Shocks

    NASA Astrophysics Data System (ADS)

    Pitňa, A.; Šafránková, J.; Němeček, Z.; Goncharov, O.; Němec, F.; Přech, L.; Chen, C. H. K.; Zastenker, G. N.

    2016-03-01

    Interplanetary (IP) shocks as typical large-scale disturbances arising from processes such as stream-stream interactions or Interplanetary Coronal Mass Ejection (ICME) launching play a significant role in the energy redistribution, dissipation, particle heating, acceleration, etc. They can change the properties of the turbulent cascade on shorter scales. We focus on changes of the level and spectral properties of ion flux fluctuations upstream and downstream of fast forward oblique shocks. Although the fluctuation level increases by an order of magnitude across the shock, the spectral slope in the magnetohydrodynamic range is conserved. The frequency spectra upstream of IP shocks are the same as those in the solar wind (if not spoiled by foreshock waves). The spectral slopes downstream are roughly proportional to the corresponding slopes upstream, suggesting that the properties of the turbulent cascade are conserved across the shock thus, the shock does not destroy the shape of the spectrum as turbulence passes through it. Frequency spectra downstream of IP shocks often exhibit “an exponential decay” in the ion kinetic range that was earlier reported at electron scales in the solar wind or at ion scales in the interstellar medium. We suggest that the exponential shape of ion flux spectra in this range is caused by stronger damping of the fluctuations in the downstream region.

  3. Hypnosis, suggestion, and suggestibility: an integrative model.

    PubMed

    Lynn, Steven Jay; Laurence, Jean-Roch; Kirsch, Irving

    2015-01-01

    This article elucidates an integrative model of hypnosis that integrates social, cultural, cognitive, and neurophysiological variables at play both in and out of hypnosis and considers their dynamic interaction as determinants of the multifaceted experience of hypnosis. The roles of these variables are examined in the induction and suggestion stages of hypnosis, including how they are related to the experience of involuntariness, one of the hallmarks of hypnosis. It is suggested that studies of the modification of hypnotic suggestibility; cognitive flexibility; response sets and expectancies; the default-mode network; and the search for the neurophysiological correlates of hypnosis, more broadly, in conjunction with research on social psychological variables, hold much promise to further understanding of hypnosis. PMID:25928681

  4. Pyrvinium attenuates Hedgehog signaling downstream of smoothened.

    PubMed

    Li, Bin; Fei, Dennis Liang; Flaveny, Colin A; Dahmane, Nadia; Baubet, Valérie; Wang, Zhiqiang; Bai, Feng; Pei, Xin-Hai; Rodriguez-Blanco, Jezabel; Hang, Brian; Orton, Darren; Han, Lu; Wang, Baolin; Capobianco, Anthony J; Lee, Ethan; Robbins, David J

    2014-09-01

    The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. PMID:24994715

  5. Collisionless relaxation of downstream ion distributions in low-Mach number shocks

    SciTech Connect

    Gedalin, M.; Friedman, Y.; Balikhin, M.

    2015-07-15

    Collisionlessly formed downstream distributions of ions in low-Mach number shocks are studied. General expressions for the asymptotic value of the ion density and pressure are derived for the directly transmitted ions. An analytical approximation for the overshoot strength is suggested for the low-β case. Spatial damping scale of the downstream magnetic oscillations is estimated.

  6. THE TRANSCRIPTIONAL SIGNATURES OF CELLS FROM THE HUMAN PEYRONIE'S DISEASE PLAQUE AND THE ABILITY OF THESE CELLS TO GENERATE A PLAQUE IN A RAT MODEL SUGGEST POTENTIAL THERAPEUTIC TARGETS

    PubMed Central

    Gelfand, R; Vernet, D; Kovanecz, I; Rajfer, J; Gonzalez-Cadavid, NF

    2015-01-01

    Introduction The success of medical therapies for Peyronie's disease (PD) has not been optimal, possibly because many of them went directly to clinical application without sufficient preclinical scientific research. Previous studies revealed cellular and molecular pathways involved in the formation of the PD plaque, and in particular the role of the myofibroblast. Aims The current work aimed to determine under normal and fibrotic conditions what differentiates PD cells from tunica albuginea (TA) and corpora cavernosa (CC) cells, by defining their global transcriptional signatures and testing in vivo whether PD cells can generate a PD like plaque Main Outcomes Measures Fibroproliferative features of PD cells and identification of related key genes as novel targets to reduce plaque size Methods Human TA, PD, and CC cells were grown with TGFβ1 (TA+, PD+, CC+) or without it (TA−, PD−, CC−) and assayed by: a) immunofluorescence, western blot and RT/PCR for myofibroblast, smooth muscle cell and stem cell markers; b) collagen content; and c) DNA microarray analysis. The ability of PD+ cells to induce a PD like plaque in an immuno-suppressed rat model was assessed by Masson trichrome and Picrosirius Red. Results Upon TGFβ1stimulation, collagen levels were increased by myofibroblasts in the PD+ but not in the CC+ cells. The transcriptional signature of the PD− cells identified fibroproliferative, myogenic (myofibroblasts), inflammatory, and collagen turnover genes, that differentiate them from TA− or CC− cells, and respond to TGFβ1 with a PD+ fibrotic phenotype, by upregulation of IGF1, ACTG2, MYF5, ACTC1, PSTN, COL III, MMP3, and others. The PD+ cells injected into the TA of the rat induce a PD like plaque. Conclusions This suggests a novel combination therapy to eliminate a PD plaque, by targeting the identified genes to: a) improve collagenase action by stimulating endogenous MMPs specific to key collagen types, and b) counteract fibromatosis by inhibiting

  7. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms

    PubMed Central

    Harno, Erika; Cottrell, Elizabeth C.; Yu, Alice; DeSchoolmeester, Joanne; Gutierrez, Pablo Morentin; Denn, Mark; Swales, John G.; Goldberg, Fred W.; Bohlooly-Y, Mohammad; Andersén, Harriet; Wild, Martin J.; Turnbull, Andrew V.; Leighton, Brendan

    2013-01-01

    The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)–fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting “off-target” mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1–independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a “step-change” treatment for diabetes and/or obesity. PMID:24169553

  8. Open to Suggestion.

    ERIC Educational Resources Information Center

    Journal of Reading, 1987

    1987-01-01

    Offers (1) suggestions for improving college students' study skills; (2) a system for keeping track of parent, teacher, and community contacts; (3) suggestions for motivating students using tic tac toe; (4) suggestions for using etymology to improve word retention; (5) a word search grid; and (6) suggestions for using postcards in remedial reading…

  9. Downstream Hydraulic Geometry of Mountain Rivers

    NASA Astrophysics Data System (ADS)

    Wohl, E.

    2003-12-01

    The concept of downstream hydraulic geometry (DHG) was developed for fully alluvial rivers that are presumed to be capable of continually adjusting their dimensions to changes in bankfull discharge. Mountain rivers, although mostly formed in alluvium, may behave differently because discharges along the channel lack the competence to move coarse clasts introduced from colluvial processes or glaciation, or because discontinuous bedrock exposures limit channel adjustment. Consequently, the DHG of mountain rivers could reflect bankfull flows; larger magnitude, less frequent flows; or non-fluvial processes such as debris flows. The research summarized here was designed to test whether traditional DHG concepts apply to mountain rivers, and to determine when correlations between velocity, flow depth, or width, and bankfull discharge, are strongly developed. Rivers with strongly developed DHG are defined here as those with r2 values > 0.5 for at least two of the correlations. I hypothesize that a quantifiable threshold separates mountain rivers with well-developed DHG from those with poorly-developed DHG. This threshold can be expressed using a ratio of hydraulic driving forces to substrate resisting forces. As the ratio increases, the ability of bankfull flows to adjust channel dimensions should also increase. The hypothesis was tested using 8 datasets from mountain rivers in Alaska, Montana, Colorado, Panama, Nepal, and New Zealand. A ratio of either total stream power/D84, or unit stream power/D84, separates rivers with and without well-developed DHG. This approach is a simplification which ignores the presence of bedrock; the duration and frequency of flows as these affect stream power; and non-fluvial processes. However, the results suggest that mountain rivers with greater hydraulic driving forces are more likely to behave like fully alluvial rivers in terms of having well-developed DHG relations.

  10. Coupling of downstream RNA polymerase-promoter interactions with formation of catalytically competent transcription initiation complex

    PubMed Central

    Mekler, Vladimir; Minakhin, Leonid; Borukhov, Sergei; Mustaev, Arkady; Severinov, Konstantin

    2014-01-01

    Bacterial RNA polymerase (RNAP) makes extensive contacts with duplex DNA downstream of the transcription bubble in initiation and elongation complexes. We investigated the role of downstream interactions in formation of catalytically competent transcription initiation complex by measuring initiation activity of stable RNAP complexes with model promoter DNA fragments whose downstream ends extend from +3 to +21 relative to the transcription start site at +1. We found that DNA downstream of position +6 does not play a significant role in transcription initiation when RNAP-promoter interactions upstream of the transcription start site are strong and promoter melting region is AT-rich. Further shortening of downstream DNA dramatically reduces efficiency of transcription initiation. The boundary of minimal downstream DNA duplex needed for efficient transcription initiation shifted further away from the catalytic center upon increasing the GC content of promoter melting region or in the presence of bacterial stringent response regulators DksA and ppGpp. These results indicate that the strength of RNAP-downstream DNA interactions has to reach a certain threshold to retain the catalytically competent conformation of the initiation complex and that establishment of contacts between RNAP and downstream DNA can be coupled with promoter melting. The data further suggest that RNAP interactions with DNA immediately downstream of the transcription bubble are particularly important for initiation of transcription. We hypothesize that these active center-proximal contacts stabilize the DNA template strand in the active center cleft and/or position the RNAP clamp domain to allow RNA synthesis. PMID:25311862

  11. Selective Interactions between Vertebrate Polycomb Homologs and the SUV39H1 Histone Lysine Methyltransferase Suggest that Histone H3-K9 Methylation Contributes to Chromosomal Targeting of Polycomb Group Proteins

    PubMed Central

    Sewalt, Richard G. A. B.; Lachner, Monika; Vargas, Mark; Hamer, Karien M.; den Blaauwen, Jan L.; Hendrix, Thijs; Melcher, Martin; Schweizer, Dieter; Jenuwein, Thomas; Otte, Arie P.

    2002-01-01

    Polycomb group (PcG) proteins form multimeric chromatin-associated protein complexes that are involved in heritable repression of gene activity. Two distinct human PcG complexes have been characterized. The EED/EZH2 PcG complex utilizes histone deacetylation to repress gene activity. The HPC/HPH PcG complex contains the HPH, RING1, BMI1, and HPC proteins. Here we show that vertebrate Polycomb homologs HPC2 and XPc2, but not M33/MPc1, interact with the histone lysine methyltransferase (HMTase) SUV39H1 both in vitro and in vivo. We further find that overexpression of SUV39H1 induces selective nuclear relocalization of HPC/HPH PcG proteins but not of the EED/EZH2 PcG proteins. This SUV39H1-dependent relocalization concentrates the HPC/HPH PcG proteins to the large pericentromeric heterochromatin domains (1q12) on human chromosome 1. Within these PcG domains we observe increased H3-K9 methylation. Finally, we show that H3-K9 HMTase activity is associated with endogenous HPC2. Our findings suggest a role for the SUV39H1 HMTase and histone H3-K9 methylation in the targeting of human HPC/HPH PcG proteins to modified chromatin structures. PMID:12101246

  12. Identification of the target DNA sequence and characterization of DNA binding features of HlyU, and suggestion of a redox switch for hlyA expression in the human pathogen Vibrio cholerae from in silico studies

    PubMed Central

    Mukherjee, Debadrita; Pal, Aritrika; Chakravarty, Devlina; Chakrabarti, Pinak

    2015-01-01

    HlyU, a transcriptional regulator common in many Vibrio species, activates the hemolysin gene hlyA in Vibrio cholerae, the rtxA1 operon in Vibrio vulnificus and the genes of plp-vah1 and rtxACHBDE gene clusters in Vibrio anguillarum. The protein is also proposed to be a potential global virulence regulator for V. cholerae and V. vulnificus. Mechanisms of gene control by HlyU in V. vulnificus and V. anguillarum are reported. However, detailed elucidation of the interaction of HlyU in V. cholerae with its target DNA at the molecular level is not available. Here we report a 17-bp imperfect palindrome sequence, 5′-TAATTCAGACTAAATTA-3′, 173 bp upstream of hlyA promoter, as the binding site of HlyU. This winged helix-turn-helix protein binds necessarily as a dimer with the recognition helices contacting the major grooves and the β-sheet wings, the minor grooves. Such interactions enhance hlyA promoter activity in vivo. Mutations affecting dimerization as well as those in the DNA–protein interface hamper DNA binding and transcription regulation. Molecular dynamic simulations show hydrogen bonding patterns involving residues at the mutation sites and confirmed their importance in DNA binding. On binding to HlyU, DNA deviates by ∼68º from linearity. Dynamics also suggest a possible redox control in HlyU. PMID:25605793

  13. Philippines' downstream sector poised for growth

    SciTech Connect

    Not Available

    1992-05-11

    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.

  14. The Life of Suggestions

    ERIC Educational Resources Information Center

    Pearce, Cathie

    2010-01-01

    Using the notion of a suggestion, or rather charting the life of suggestions, this article considers the happenings of chance and embodiment as the "problems that got away." The life of suggestions helps us to ask how connectivities are made, how desire functions, and how "immanence" rather than "transcendence" can open up the politics and ethics…

  15. Suggestion and psychoanalytic technique.

    PubMed

    Levy, S T; Inderbitzin, L B

    2000-01-01

    The role of the analyst's suggestive influence on the course and outcome of psychoanalytic treatment is explored, and traditional and newer perspectives on analytic technique are contrasted. The intersubjective critique of the neutral, objective analyst in relation to suggestion is examined. The inevitable presence and need for suggestive factors in analysis, and the relationship of suggestion to transference susceptibility, are emphasized. The manner in which the analysis of suggestive factors is subsumed in transference analysis as part of traditional technique is highlighted. PMID:11059395

  16. Downstream prediction using a nonlinear prediction method

    NASA Astrophysics Data System (ADS)

    Adenan, N. H.; Noorani, M. S. M.

    2013-11-01

    The estimation of river flow is significantly related to the impact of urban hydrology, as this could provide information to solve important problems, such as flooding downstream. The nonlinear prediction method has been employed for analysis of four years of daily river flow data for the Langat River at Kajang, Malaysia, which is located in a downstream area. The nonlinear prediction method involves two steps; namely, the reconstruction of phase space and prediction. The reconstruction of phase space involves reconstruction from a single variable to the m-dimensional phase space in which the dimension m is based on optimal values from two methods: the correlation dimension method (Model I) and false nearest neighbour(s) (Model II). The selection of an appropriate method for selecting a combination of preliminary parameters, such as m, is important to provide an accurate prediction. From our investigation, we gather that via manipulation of the appropriate parameters for the reconstruction of the phase space, Model II provides better prediction results. In particular, we have used Model II together with the local linear prediction method to achieve the prediction results for the downstream area with a high correlation coefficient. In summary, the results show that Langat River in Kajang is chaotic, and, therefore, predictable using the nonlinear prediction method. Thus, the analysis and prediction of river flow in this area can provide river flow information to the proper authorities for the construction of flood control, particularly for the downstream area.

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

    NASA Technical Reports Server (NTRS)

    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.

  18. [Therapy and suggestion].

    PubMed

    Barrucand, D; Paille, F

    1986-12-01

    Therapy and suggestion are closely related. That is clear for the ancient time: primitive medicine gives a good place to the Word. In plant, animal or mineral remedies, the suggestion is clearly preponderant. Towards the end of the 19th century, the "Ecole de Nancy" sets up a real theory of the suggestion, and Bernheim, its leader, bases hypnosis, then psychotherapy on this concept. Thereafter Coué will bring up the "conscious autosuggestion". Today, despite the progress of scientific medicine, the part of suggestion is still very important in medical therapy (with or without drugs), or in chirurgical therapy; this part is also very important in psychotherapies, whatever has been said in this field. This has to be known and used consciously in the doctor-patient relation, which is always essential in the therapeutic effectiveness. PMID:3555209

  19. Transcription factor network downstream of protease activated receptors (PARs) modulating mouse bladder inflammation

    PubMed Central

    Saban, Ricardo; Simpson, Cindy; Davis, Carole A; Dozmorov, Igor; Maier, Julie; Fowler, Ben; Ihnat, Michael A; Hurst, Robert E; Wershil, Barry K; Saban, Marcia R

    2007-01-01

    Background All four PARs are present in the urinary bladder, and their expression is altered during inflammation. In order to search for therapeutic targets other than the receptors themselves, we set forth to determine TFs downstream of PAR activation in the C57BL/6 urinary bladders. Methods For this purpose, we used a protein/DNA combo array containing 345 different TF consensus sequences. Next, the TF selected was validated by EMSA and IHC. As mast cells seem to play a fundamental role in bladder inflammation, we determined whether c-kit receptor deficient (Kitw/Kitw-v) mice have an abrogated response to PAR stimulation. Finally, TFEB antibody was used for CHIP/Q-PCR assay and revealed up-regulation of genes known to be downstream of TFEB. Results TFEB, a member of the MiTF family of basic helix-loop-helix leucine zipper, was the only TF commonly up-regulated by all PAR-APs. IHC results confirm a correlation between inflammation and TFEB expression in C57BL/6 mice. In contrast, Kitw/Kitw-v mice did not exhibit inflammation in response to PAR activation. EMSA results confirmed the increased TFEB binding activity in C57BL/6 but not in Kitw/Kitw-v mice. Conclusion This is the first report describing the increased expression of TFEB in bladder inflammation in response to PAR activation. As TFEB belongs to a family of TFs essential for mast cell survival, our findings suggest that this molecule may influence the participation of mast cells in PAR-mediated inflammation and that targeting TFEB/MiTF activity may be a novel approach for the treatment of bladder inflammatory disorders. PMID:17705868

  20. Upstream water resource management to address downstream pollution concerns: A policy framework with application to the Nakdong River basin in South Korea

    NASA Astrophysics Data System (ADS)

    Yoon, Taeyeon; Rhodes, Charles; Shah, Farhed A.

    2015-02-01

    An empirical framework for assisting with water quality management is proposed that relies on open-source hydrologic data. Such data are measured periodically at fixed water stations and commonly available in time-series form. To fully exploit the data, we suggest that observations from multiple stations should be combined into a single long-panel data set, and an econometric model developed to estimate upstream management effects on downstream water quality. Selection of the model's functional form and explanatory variables would be informed by rating curves, and idiosyncrasies across and within stations handled in an error term by testing contemporary correlation, serial correlation, and heteroskedasticity. Our proposed approach is illustrated with an application to the Nakdong River basin in South Korea. Three alternative policies to achieve downstream BOD level targets are evaluated: upstream water treatment, greater dam discharge, and development of a new water source. Upstream water treatment directly cuts off incoming pollutants, thereby presenting the smallest variation in its downstream effects on BOD levels. Treatment is advantageous when reliability of water quality is a primary concern. Dam discharge is a flexible tool, and may be used strategically during a low-flow season. We consider development of a new water corridor from an extant dam as our third policy option. This turns out to be the most cost-effective way for securing lower BOD levels in the downstream target city. Even though we consider a relatively simple watershed to illustrate the usefulness of our approach, it can be adapted easily to analyze more complex upstream-downstream issues.

  1. Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters

    PubMed Central

    Lavender, Christopher A.; Hoffman, Jackson A.; Trotter, Kevin W.; Gilchrist, Daniel A.; Bennett, Brian D.; Burkholder, Adam B.; Fargo, David C.; Archer, Trevor K.

    2016-01-01

    Antisense transcription is a prevalent feature at mammalian promoters. Previous studies have primarily focused on antisense transcription initiating upstream of genes. Here, we characterize promoter-proximal antisense transcription downstream of gene transcription starts sites in human breast cancer cells, investigating the genomic context of downstream antisense transcription. We find extensive correlations between antisense transcription and features associated with the chromatin environment at gene promoters. Antisense transcription downstream of promoters is widespread, with antisense transcription initiation observed within 2 kb of 28% of gene transcription start sites. Antisense transcription initiates between nucleosomes regularly positioned downstream of these promoters. The nucleosomes between gene and downstream antisense transcription start sites carry histone modifications associated with active promoters, such as H3K4me3 and H3K27ac. This region is bound by chromatin remodeling and histone modifying complexes including SWI/SNF subunits and HDACs, suggesting that antisense transcription or resulting RNA transcripts contribute to the creation and maintenance of a promoter-associated chromatin environment. Downstream antisense transcription overlays additional regulatory features, such as transcription factor binding, DNA accessibility, and the downstream edge of promoter-associated CpG islands. These features suggest an important role for antisense transcription in the regulation of gene expression and the maintenance of a promoter-associated chromatin environment. PMID:27487356

  2. Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters.

    PubMed

    Lavender, Christopher A; Cannady, Kimberly R; Hoffman, Jackson A; Trotter, Kevin W; Gilchrist, Daniel A; Bennett, Brian D; Burkholder, Adam B; Burd, Craig J; Fargo, David C; Archer, Trevor K

    2016-08-01

    Antisense transcription is a prevalent feature at mammalian promoters. Previous studies have primarily focused on antisense transcription initiating upstream of genes. Here, we characterize promoter-proximal antisense transcription downstream of gene transcription starts sites in human breast cancer cells, investigating the genomic context of downstream antisense transcription. We find extensive correlations between antisense transcription and features associated with the chromatin environment at gene promoters. Antisense transcription downstream of promoters is widespread, with antisense transcription initiation observed within 2 kb of 28% of gene transcription start sites. Antisense transcription initiates between nucleosomes regularly positioned downstream of these promoters. The nucleosomes between gene and downstream antisense transcription start sites carry histone modifications associated with active promoters, such as H3K4me3 and H3K27ac. This region is bound by chromatin remodeling and histone modifying complexes including SWI/SNF subunits and HDACs, suggesting that antisense transcription or resulting RNA transcripts contribute to the creation and maintenance of a promoter-associated chromatin environment. Downstream antisense transcription overlays additional regulatory features, such as transcription factor binding, DNA accessibility, and the downstream edge of promoter-associated CpG islands. These features suggest an important role for antisense transcription in the regulation of gene expression and the maintenance of a promoter-associated chromatin environment. PMID:27487356

  3. A Comprehensive Profile of ChIP-Seq-Based Olig2 Target Genes in Motor Neuron Progenitor Cells Suggests the Possible Involvement of Olig2 in the Pathogenesis of Amyotrophic Lateral Sclerosis

    PubMed Central

    Satoh, Jun-ichi; Asahina, Naohiro; Kitano, Shouta; Kino, Yoshihiro

    2015-01-01

    BACKGROUND Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that primarily affects motor neurons in the cerebral cortex and the spinal cord. Recent evidence indicates that dysfunction of oligodendrocytes is implicated in the pathogenesis of ALS. The basic helix–loop–helix (bHLH) transcription factor Olig2 plays a pivotal role in the development of both motor neurons and oligodendrocytes in the progenitor of motor neuron (pMN) domain of the spinal cord, supporting evidence for the shared motor neuron/oligodendrocyte lineage. However, a comprehensive profile of Olig2 target genes in pMNs and oligodendrocyte progenitor cells (OPCs) with relevance to the pathogenesis of ALS remains to be characterized. METHODS By analyzing the ChIP-Seq datasets numbered SRP007566 and SRP015333 with the Strand NGS program, we identified genome-wide Olig2 target genes in pMNs and OPCs, followed by molecular network analysis using three distinct bioinformatics tools. RESULTS We identified 5966 Olig2 target genes in pMNs, including Nkx2.2, Pax6, Irx3, Ngn2, Zep2 (Cip1), Trp3, Mnx1 (Hb9), and Cdkn1a, and 1553 genes in OPCs. The genes closely related to the keyword “alternative splicing” were enriched in the set of 740 targets overlapping between pMNs and OPCs. Furthermore, approximately one-third of downregulated genes in purified motor neurons of presymptomatic mutant SOD1 transgenic mice and in lumbar spinal cord tissues of ALS patients corresponded to Olig2 target genes in pMNs. Molecular networks of Olig2 target genes indicate that Olig2 regulates a wide range of genes essential for diverse neuronal and glial functions. CONCLUSIONS These observations lead to a hypothesis that aberrant regulation of Olig2 function, by affecting biology of both motor neurons and oligodendrocytes, might be involved in the pathogenesis of ALS. PMID:26023283

  4. Downstream processing of biopharmaceutical proteins produced in plants

    PubMed Central

    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. PMID:24637706

  5. Data collection and documentation of flooding downstream of a dam failure in Mississippi

    USGS Publications Warehouse

    Van Wilson, Jr., K.

    2005-01-01

    On March 12, 2004, the Big Bay Lake dam failed, releasing water and affecting lives and property downstream in southern Mississippi. The dam is located near Purvis, Mississippi, on Bay Creek, which flows into Lower Little Creek about 1.9 miles downstream from the dam. Lower Little Creek flows into Pearl River about 16.9 miles downstream from the dam. Knowledge of the hydrology and hydraulics of floods caused by dam breaks is essential to the design of dams. A better understanding of the risks associated with possible dam failures may help limit the loss of life and property that often occurs downstream of a dam failure. The USGS recovered flood marks at the one crossing of Bay Creek and eight crossings of Lower Little Creek. Additional flood marks were also flagged at three other bridges crossing tributaries where backwater occurred. Flood marks were recovered throughout the stream reach of about 3/4 to 15 miles downstream of the dam. Flood marks that were flagged will be surveyed so that a flood profile can be documented downstream of the Big Bay Lake dam failure. Peak discharges are also to be estimated where possible. News reports stated that the peak discharge at the dam was about 67,000 cubic feet per second. Preliminary data suggest the peak discharge from the dam failure attenuated to about 13,000 cubic feet per second at Lower Little Creek at State Highway 43, about 15 miles downstream of the dam.

  6. Subsequent to Suppression: Downstream Comprehension Consequences of Noun/Verb Ambiguity in Natural Reading

    ERIC Educational Resources Information Center

    Stites, Mallory C.; Federmeier, Kara D.

    2015-01-01

    We used eye tracking to investigate the downstream processing consequences of encountering noun/verb (NV) homographs (i.e., park) in semantically neutral but syntactically constraining contexts. Target words were followed by a prepositional phrase containing a noun that was plausible for only 1 meaning of the homograph. Replicating previous work,…

  7. Plasma waves downstream of weak collisionless shocks

    NASA Technical Reports Server (NTRS)

    Coroniti, F. V.; Greenstadt, E. W.; Moses, S. L.; Smith, E. J.; Tsurutani, B. T.

    1993-01-01

    In September 1983 the International Sun Earth Explorer 3 (ISEE 3) International Cometary Explorer (ICE) spacecraft made a long traversal of the distant dawnside flank region of the Earth's magnetosphere and had many encounters with the low Mach number bow shock. These weak shocks excite plasma wave electric field turbulence with amplitudes comparable to those detected in the much stronger bow shock near the nose region. Downstream of quasi-perpendicular (quasi-parallel) shocks, the E field spectra exhibit a strong peak (plateau) at midfrequencies (1 - 3 kHz); the plateau shape is produced by a low-frequency (100 - 300 Hz) emission which is more intense behind downstream of two quasi-perpendicular shocks show that the low frequency signals are polarized parallel to the magnetic field, whereas the midfrequency emissions are unpolarized or only weakly polarized. A new high frequency (10 - 30 kHz) emission which is above the maximum Doppler shift exhibit a distinct peak at high frequencies; this peak is often blurred by the large amplitude fluctuations of the midfrequency waves. The high-frequency component is strongly polarized along the magnetic field and varies independently of the lower-frequency waves.

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

    PubMed

    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

    2006-08-01

    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. Promoters occupied by TAL1 were also frequently bound by the class I bHLH proteins E2A and HEB, suggesting that TAL1/E2A as well as TAL1/HEB heterodimers play a role in transformation of T-cell precursors. Using RNA interference, we demonstrated that TAL1 is required for the maintenance of the leukemic phenotype in Jurkat cells and showed that TAL1 binding can be associated with either repression or activation of genes whose promoters occupied by TAL1, E2A, and HEB. In addition, oligonucleotide microarray analysis of RNA from 47 primary T-ALL samples showed specific expression signatures involving TAL1 targets in TAL1-expressing compared with -nonexpressing human T-ALLs. Our results indicate that TAL1 may act as a bifunctional transcriptional regulator (activator and repressor) at the top of a complex regulatory network that disrupts normal T-cell homeostasis and contributes to leukemogenesis. PMID:16621969

  9. Learning Semantic Query Suggestions

    NASA Astrophysics Data System (ADS)

    Meij, Edgar; Bron, Marc; Hollink, Laura; Huurnink, Bouke; de Rijke, Maarten

    An important application of semantic web technology is recognizing human-defined concepts in text. Query transformation is a strategy often used in search engines to derive queries that are able to return more useful search results than the original query and most popular search engines provide facilities that let users complete, specify, or reformulate their queries. We study the problem of semantic query suggestion, a special type of query transformation based on identifying semantic concepts contained in user queries. We use a feature-based approach in conjunction with supervised machine learning, augmenting term-based features with search history-based and concept-specific features. We apply our method to the task of linking queries from real-world query logs (the transaction logs of the Netherlands Institute for Sound and Vision) to the DBpedia knowledge base. We evaluate the utility of different machine learning algorithms, features, and feature types in identifying semantic concepts using a manually developed test bed and show significant improvements over an already high baseline. The resources developed for this paper, i.e., queries, human assessments, and extracted features, are available for download.

  10. 7. VIEW DOWNSTREAM FROM THE NEWHALEM INTAKE WITH NO WATER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. VIEW DOWNSTREAM FROM THE NEWHALEM INTAKE WITH NO WATER BEING DIVERTED TO THE POWER TUNNEL, 1989. - Skagit Power Development, Newhalem Powerhouse & Dam, On Skagit River, 0.3 mile downstream from Newhalem, Newhalem, Whatcom County, WA

  11. 9. VIEW WEST TOWARD DOWNSTREAM SIDE OF SPILLWAY FROM NORTH ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    9. VIEW WEST TOWARD DOWNSTREAM SIDE OF SPILLWAY FROM NORTH SIDE OF DOWNSTREAM BANK OF DAM - Upper Doughty Dam, 200 feet west of Garden State Parkway, 1.7 miles west of Absecon, Egg Harbor City, Atlantic County, NJ

  12. Alfven waves and associated energetic ions downstream from Uranus

    SciTech Connect

    Zhang, Ming; Belcher, J.W.; Richardson, J.D. ); Smith, C.W. )

    1991-02-01

    The authors report the observation of low-frequency waves in the solar wind downstream from Uranus. These waves are observed by the Voyager spacecraft for more than 2 weeks after the encounter with Uranus and are present during this period whenever the interplanetary magnetic field is oriented such that the field lines intersect the Uranian bow shock. The magnetic field and velocity components transverse to the background field are strongly correlated, consistent with the interpretation that these waves are Alfvenic and/or fast-mode waves. The waves have a spacecraft frame frequency of about 10{sup {minus}3} Hz, and when first observed near the bow shock have an amplitude comparable to the background field. As the spacecraft moves farther from Uranus, the amplitude decays. The waves appear to propagate along the magnetic field lines outward from Uranus and are right-hand polarized. Theory suggests that these waves are generated in the upstream region by a resonant instability with a proton beam streaming along the magnetic field lines. The solar wind subsequently carries these waves downstream to the spacecraft location. These waves are associated with the presence of energetic (> 28 keV) ions observed by the low-energy charged particle instrument. These ions appear two days after the start of the wave activity and occur thereafter whenever the Alfven waves occur, increasing in intensity away from Uranus. The ions are argued to originate in the Uranian magnetosphere, but pitch-angle scattering in the upstream region is required to bring them downstream to the spacecraft location.

  13. 40 CFR 80.69 - Requirements for downstream oxygenate blending.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Requirements for downstream oxygenate... downstream oxygenate blending. The requirements of this section apply to all reformulated gasoline blendstock... annual compliance period; (D) A process for notifying oxygenate blenders and other downstream parties...

  14. Channel changes downstream from a dam

    USGS Publications Warehouse

    Hadley, R.F.; Emmett, W.W.

    1998-01-01

    A flood-control dam was completed during 1979 on Bear Creek, a small tributary stream to the South Platte River in the Denver, Colorado, area. Before and after dam closure, repetitive surveys between 1977 and 1992 at five cross sections downstream of the dam documented changes in channel morphology. During this 15-year period, channel width increased slightly, but channel depth increased by more than 40 percent. Within the study reach, stream gradient decreased and median bed material sizes coarsened from sand in the pools and fine gravel on the riffle to a median coarse gravel throughout the reach. The most striking visual change was from a sparse growth of streamside grasses to a dense growth of riparian woody vegetation.

  15. Downstream hydraulic geometry of alluvial rivers

    NASA Astrophysics Data System (ADS)

    Julien, P. Y.

    2015-03-01

    This article presents a three-level approach to the analysis of downstream hydraulic geometry. First, empirical concepts based on field observations of "poised" conditions in irrigation canals are examined. Second, theoretical developments have been made possible by combining basic relationships for the description of flow and sediment transport in alluvial rivers. Third, a relatively new concept of equivalent channel widths is presented. The assumption of equilibrium may describe a perpetual state of change and adjustments. The new concepts define the trade-offs between some hydraulic geometry parameters such as width and slope. The adjustment of river widths and slope typically follows a decreasing exponential function and recent developments indicate how the adjustment time scale can be quantified. Some examples are also presented to illustrate the new concepts presented and the realm of complex river systems.

  16. Turbulence decay downstream of an active grid

    NASA Astrophysics Data System (ADS)

    Bewley, Gregory; Bodenschatz, Eberhard

    2015-11-01

    A grid in a wind tunnel stirs up turbulence that has a certain large-scale structure. The moving parts in a so-called ``active grid'' can be programmed to produce different structures. We use a special active grid in which each of 129 paddles on the grid has its own position-controlled servomotor that can move independently of the others. We observe among other things that the anisotropy in the amplitude of the velocity fluctuations and in the correlation lengths can be set and varied with an algorithm that oscillates the paddles in a specified way. The variation in the anisotropies that we observe can be explained by our earlier analysis of anisotropic ``soccer ball'' turbulence (Bewley, Chang and Bodenschatz 2012, Phys. Fluids). We define the influence of this variation in structure on the downstream evolution of the turbulence. with Eberhard Bodenschatz and others.

  17. Downstream process options for the ABE fermentation.

    PubMed

    Friedl, Anton

    2016-05-01

    Butanol is a very interesting substance both for the chemical industry and as a biofuel. The classical distillation process for the removal of butanol is far too energy demanding, at a factor of 220% of the energy content of butanol. Alternative separation processes studied are hybrid processes of gas-stripping, liquid-liquid extraction and pervaporation with distillation and a novel adsorption/drying/desorption hybrid process. Compared with the energy content of butanol, the resulting energy demand for butanol separation and concentration of optimized hybrid processes is 11%-22% for pervaporation/distillation and 11%-17% for liquid-liquid extraction/distillation. For a novel adsorption/drying/desorption process, the energy demand is 9.4%. But all downstream process options need further proof of industrial applicability. PMID:27020411

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

    NASA Astrophysics Data System (ADS)

    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

  19. Alternative Activation Mechanisms of Protein Kinase B Trigger Distinct Downstream Signaling Responses.

    PubMed

    Balzano, Deborah; Fawal, Mohamad-Ali; Velázquez, Jose V; Santiveri, Clara M; Yang, Joshua; Pastor, Joaquín; Campos-Olivas, Ramón; Djouder, Nabil; Lietha, Daniel

    2015-10-01

    Protein kinase B (PKB/Akt) is an important mediator of signals that control various cellular processes including cell survival, growth, proliferation, and metabolism. PKB promotes these processes by phosphorylating many cellular targets, which trigger distinct downstream signaling events. However, how PKB is able to selectively target its substrates to induce specific cellular functions remains elusive. Here we perform a systematic study to dissect mechanisms that regulate intrinsic kinase activity versus mechanisms that specifically regulate activity toward specific substrates. We demonstrate that activation loop phosphorylation and the C-terminal hydrophobic motif are essential for high PKB activity in general. On the other hand, we identify membrane targeting, which for decades has been regarded as an essential step in PKB activation, as a mechanism mainly affecting substrate selectivity. Further, we show that PKB activity in cells can be triggered independently of PI3K by initial hydrophobic motif phosphorylation, presumably through a mechanism analogous to other AGC kinases. Importantly, different modes of PKB activation result in phosphorylation of distinct downstream targets. Our data indicate that specific mechanisms have evolved for signaling nodes, like PKB, to select between various downstream events. Targeting such mechanisms selectively could facilitate the development of therapeutics that might limit toxic side effects. PMID:26286748

  20. Epidermal Growth Factor Receptor-Targeted Photosensitizer Selectively Inhibits EGFR Signaling and Induces Targeted Phototoxicity In Ovarian Cancer Cells

    PubMed Central

    Abu-Yousif, Adnan O.; Moor, Anne C. E.; Zheng, Xiang; Savellano, Mark D.; Yu, Weiping; Selbo, Pål K.; Hasan, Tayyaba

    2012-01-01

    Targeted photosensitizer delivery to EGFR expressing cells was achieved in the present study using a high purity, targeted photoimmunoconjugate (PIC). When the PDT agent, benzoporphyin monoacid ring A (BPD) was coupled to an EGFR-targeting antibody (cetuximab), we observed altered cellular localization and selective phototoxicity of EGFR-positive cells, but no phototoxicity of EGFR-negative cells. Cetuximab in the PIC formulation blocked EGF-induced activation of the EGFR and downstream signaling pathways. Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of the antibody. PMID:22266098

  1. Downstream Processing of Synechocystis for Biofuel Production

    NASA Astrophysics Data System (ADS)

    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

  2. Downstream properties of magnetic flux transfer events. [in magnetosphere

    NASA Technical Reports Server (NTRS)

    Sibeck, D. G.; Siscoe, G. L.

    1984-01-01

    Attention is given to the downstream evolution of the field line tubes known as 'flux transfer events' (FTEs), whose magnetic field and plasma properties are distinct from those of the nearby unmerged magnetosheath and magnetosphere field lines. After the FTE has moved 200 earth radii down the tail, its drained portion reaches 25 earth radii radially outward from the tail boundary. It is suggested that most multiple crossings of the tail boundary observed by spacecraft are encounters with tailward-moving FTEs, thereby explaining both the behavior of boundary normals during multiple crossings and how the sign of the IMF causes the observed dawn-dusk asymmetries in the thickness of the magnetotail boundary layer.

  3. Plasma fluctuations in the magnetosheath downstream from Uranus

    NASA Technical Reports Server (NTRS)

    Richardson, John D.; Zhang, Ming; Belcher, John W.; Siscoe, George L.

    1990-01-01

    The Voyager plasma experiment observed large-amplitude plasma fluctuations in the Uranian magnetosheat downstream from the planet. This is a region that has not been well sampled in the earth's magnetosphere. These waves have periods of tens of minutes, are characterized by an anticorrelation between the plasma density and temperature, and are associated with deflections in the flow angle of the plasma. These fluctuations are observed only in regions where the magnetic field is rapidly varying. These waves have time and distance scales placing them in the MHD regime, but their characteristics are not compatible with any known solution of the MHD equations. It is suggested that these fluctuations are produced by the solar wind interaction with the magnetosphere at the bow shock, but the physics governing the production and propagation of these fluctuations is not understood.

  4. Tone generation by rotor-downstream strut interaction

    NASA Technical Reports Server (NTRS)

    Woodward, R. P.; Balombin, J. R.

    1983-01-01

    A JT15D fan stage was acoustically tested in the NASA Lewis anechoic chamber as part of the joint Lewis-Langley Research Center investigation of flight simulation techniques and flight effects using the JT15D engine as a common test vehicle. Suspected rotor-downstream support strut interaction was confirmed through the use of simulated support struts which were tested at three axial rotor-strut spacings. Tests were also performed with the struts removed. Inlet boundary layer suction in conjuction with an inflow control device was also explored. The removal of the boundary layer reduced the fan fundamental tone levels suggesting that the mounting and mating of such a device to the nacelle requires careful attention. With the same inflow control device installed good acoustic agreement was shown between the engine on an outdoor test stand and the fan in the anechoic chamber.

  5. Tone generation by rotor-downstream strut interaction

    NASA Technical Reports Server (NTRS)

    Woodward, R. P.; Balombin, J. R.

    1983-01-01

    A JT15D fan stage was acoustically tested in the NASA Lewis anechoic chamber as part of the joint Lewis-Langley Research Center investigation of flight simulation techniques and flight effects using the JT15D engine as a common test vehicle. Suspected rotor-downstream support strut interaction was confirmed through the use of simulated support struts which were tested at three axial rotor-strut spacings. Tests were also performed with the struts removed. Inlet boundary layer suction in conjunction with an inflow control device was also explored. The removal of the boundary layer reduced the fan fundamental tone levels suggesting that the mounting and mating of such a device to the nacelle requires careful attention. With the same inflow control device installed good acoustic agreement was shown between the engine on an outdoor test stand and the fan in the anechoic chamber.

  6. Distinct Signal Transduction Pathways Downstream of the (P)RR Revealed by Microarray and ChIP-chip Analyses

    PubMed Central

    Zaade, Daniela; Schmitz, Jennifer; Benke, Eileen; Klare, Sabrina; Seidel, Kerstin; Kirsch, Sebastian; Goldin-Lang, Petra; Zollmann, Frank S.; Unger, Thomas; Funke-Kaiser, Heiko

    2013-01-01

    The (pro)renin receptor ((P)RR) signaling is involved in different pathophysiologies ranging from cardiorenal end-organ damage via diabetic retinopathy to tumorigenesis. We have previously shown that the transcription factor promyelocytic leukemia zinc finger (PLZF) is an adaptor protein of the (P)RR. Furthermore, recent publications suggest that major functions of the (P)RR are mediated ligand-independently by its transmembrane and intracellular part, which acts as an accessory protein of V-ATPases. The transcriptome and recruitmentome downstream of the V-ATPase function and PLZF in the context of the (P)RR are currently unknown. Therefore, we performed a set of microarray and chromatin-immunoprecipitation (ChIP)-chip experiments using siRNA against the (P)RR, stable overexpression of PLZF, the PLZF translocation inhibitor genistein and the specific V-ATPase inhibitor bafilomycin to dissect transcriptional pathways downstream of the (P)RR. We were able to identify distinct and overlapping genetic signatures as well as novel real-time PCR-validated target genes of the different molecular functions of the (P)RR. Moreover, bioinformatic analyses of our data confirm the role of (P)RŔs signal transduction pathways in cardiovascular disease and tumorigenesis. PMID:23469216

  7. Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway.

    PubMed

    Cheng, Peng; Wang, Yun-Feng; Li, Gang; Yang, Sheng-sheng; Liu, Che; Hu, Hao; Jin, Gang; Hu, Xian-Gui

    2016-01-01

    Menin, the product of the Men1 gene, which is frequently mutated in pancreatic neuroendocrine tumors, acts as a chromatin-remodeling factor to modulate the transcription of cell cycle regulators by interacting with histone modification factors. However, the function of menin and its underlying mechanisms in pancreatic ductal adenocarcinoma remain unknown. Here, we found that menin inhibited pancreatic cancer cell growth in vitro and in vivo and that its expression was gradually lost during pancreatic carcinogenesis. Menin overexpression significantly activated the expression of the cyclin-dependent kinase (CDK) inhibitors p18 and p27, accompanied with a decrease in DNA methylation levels of p18 and p27 promoters. Mechanistically, we found that interaction of menin with DNA methyltransferase 1 (Dnmt1) competitively pulled down Dnmt1 from p18 and p27 promoters, leading to the downregulation of DNA methylation levels. Moreover, menin expression was suppressed by Dnmt1 downstream of the Hedgehog signaling pathway, and menin overexpression strongly antagonized the promotion effect of hedgehog signaling on pancreatic cancer cell proliferation. Taken together, the interaction between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of Hedgehog pathways with complex mutual modulation networks, suggesting that the Hedgehog/Dnmt1/menin axis is a potential molecular target for pancreatic cancer therapy. PMID:26454216

  8. ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination.

    PubMed

    Khair, Lyne; Guikema, Jeroen E J; Linehan, Erin K; Ucher, Anna J; Leus, Niek G J; Ogilvie, Colin; Lou, Zhenkun; Schrader, Carol E; Stavnezer, Janet

    2014-05-15

    Activation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C region genes. DSBs are necessary for CSR, but improper regulation of DSBs can lead to chromosomal translocations that can result in B cell lymphoma. The protein kinase ataxia telangiectasia mutated (ATM) is an important proximal regulator of the DNA damage response (DDR), and translocations involving S regions are increased in its absence. ATM phosphorylates H2AX, which recruits other DNA damage response (DDR) proteins, including mediator of DNA damage checkpoint 1 (Mdc1) and p53 binding protein 1 (53BP1), to sites of DNA damage. As these DDR proteins all function to promote repair and recombination of DSBs during CSR, we examined whether mouse splenic B cells deficient in these proteins would show alterations in S region DSBs when undergoing CSR. We find that in atm(-/-) cells Sμ DSBs are increased, whereas DSBs in downstream Sγ regions are decreased. We also find that mutations in the unrearranged Sγ3 segment are reduced in atm(-/-) cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm(-/-) cells Sμ DSBs accumulate as they lack a recombination partner. PMID:24729610

  9. Microbial production of scleroglucan and downstream processing

    PubMed Central

    Castillo, Natalia A.; Valdez, Alejandra L.; Fariña, Julia I.

    2015-01-01

    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 β-1,3-β-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 exopolysaccharide 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. PMID:26528259

  10. Upstream/downstream: Issues in environmental ethics

    SciTech Connect

    Scherer, D.

    1991-01-01

    Upstream/Downstream reminds us that there are four issues that are more or less distinctive to environmental ethics. First, and most distinctively, environmental issues involve the standing of nonhuman living things and systems. Thus, environmental politics is only partly a clash among the interest of the parties involved; it often involves actions on behalf of the existence rights of nonhuman life forms. Second, environmental ethics concern the intergenerational distribution of benefits more explicitly than do most other ethical issues, which brings out serious weaknesses in legal frameworks that rely on claims for damages. Third, the complexity and indirectness of many environmental impacts introduces a high degree of uncertainty and thus technical as well as ethical issues of prudent behavior. Specifically, where science may not fully reveal environmental risks, should development proceed; should analysis proceed if it is known to have a Pollyanna bias Fourth, insofar as environmental damage is typically done to common property, and thus its regulation is generally a matter for governmental regulation, the obligations of private actors to make sacrifices beyond what government requires is at issue - an issue that one would expect to be taken up at length in the other volumes.

  11. Microbial production of scleroglucan and downstream processing.

    PubMed

    Castillo, Natalia A; Valdez, Alejandra L; Fariña, Julia I

    2015-01-01

    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 β-1,3-β-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 exopolysaccharide 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. PMID:26528259

  12. Flow Structure and Turbulence Characteristics downstream of a Spanwise Suspended Linear Canopy through Laboratory Experiments

    NASA Astrophysics Data System (ADS)

    Qiao, Jundong; Delavan, Sarah

    2014-11-01

    Laboratory experiments were conducted to explore the mean flow structure and turbulence properties downstream of a spanwise suspended linear canopy in a 2-D open channel flow using the Particle Tracking Velocimetry technique. This canopy simulated the effect of one long-line structure of a mussel farm. Four experimental scenarios with the approach velocities 50, 80, 110, and 140 mm s-1 were under investigation. Three sub-layers formed downstream of the canopy. An internal canopy layer, where the time-averaged velocity decreases linearly with increasing distance downstream, a canopy mixing layer increasing in vertical extent with increasing distance downstream of the canopy, and an external canopy layer with higher velocity under the canopy, which may bring nutrients from the local ambient environment into this layer. The canopy turbulence results in upward momentum transport downstream of the canopy within a distance of 0.60 of the canopy depth and downward momentum transport beyond 1.20 of it. In the scenarios with relatively lower approach velocities 50 and 80 mm s1 , the wake turbulence results in upward momentum transport. The broader goal of this study is to offer guidelines for the design and site selection of more productive mussel farms. The results suggest that distance interval between the parallel long-lines in a mussel farm should be less than 0.6 times the height of a long-line dropper. Also, potential farm locations that are characterized with current velocity from 50 to 80 mm s1 are suggested.

  13. PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling

    SciTech Connect

    Yamada, Tamaki; Tsuda, Masumi; Ohba, Yusuke Kawaguchi, Hideaki; Totsuka, Yasunori; Shindoh, Masanobu

    2008-04-11

    Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer.

  14. CypA, a Gene Downstream of HIF-1α, Promotes the Development of PDAC

    PubMed Central

    Gao, Chuntao; Wang, Xiuchao; Zhao, Tiansuo; Liu, Jingcheng; Gao, Song; Zhao, Xiao; Ren, He; Hao, Jihui

    2014-01-01

    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. PMID:24662981

  15. 5. DOWNSTREAM ELEVATION OF BRIDGE AND SUBSTRUCTURE (with graduated meter ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. DOWNSTREAM ELEVATION OF BRIDGE AND SUBSTRUCTURE (with graduated meter pole); VIEW TO NORTH-NORTHEAST. - Auwaiakeakua Bridge, Spanning Auwaiakekua Gulch at Mamalahoa Highway, Waikoloa, Hawaii County, HI

  16. 1. GENERAL EXTERIOR VIEW LOOKING SOUTHEAST AT DOWNSTREAM FACE OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. GENERAL EXTERIOR VIEW LOOKING SOUTHEAST AT DOWNSTREAM FACE OF DAM/SPILLWAY. VIEW TAKEN FROM WASHINGTON SHORELINE. - Bonneville Project, Bonneville Dam, Columbia River, Bonneville, Multnomah County, OR

  17. 7. STONE PIER OF ORIGINAL WATERWHEEL INSTALLATION DOWNSTREAM FROM MILL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. STONE PIER OF ORIGINAL WATERWHEEL INSTALLATION DOWNSTREAM FROM MILL William E. Barrett, photographer, 1973 (copy negative) - Thomas Shepherd's Grist Mill, High Street Vicinity, Shepherdstown, Jefferson County, WV

  18. Serine-71 phosphorylation of Rac1 modulates downstream signaling.

    PubMed

    Schwarz, Janett; Proff, Julia; Hävemeier, Anika; Ladwein, Markus; Rottner, Klemens; Barlag, Britta; Pich, Andreas; Tatge, Helma; Just, Ingo; Gerhard, Ralf

    2012-01-01

    The Rho GTPases Rac1 and Cdc42 regulate a variety of cellular functions by signaling to different signal pathways. It is believed that the presence of a specific effector at the location of GTPase activation determines the route of downstream signaling. We previously reported about EGF-induced Ser-71 phosphorylation of Rac1/Cdc42. By using the phosphomimetic S71E-mutants of Rac1 and Cdc42 we investigated the impact of Ser-71 phosphorylation on binding to selected effector proteins. Binding of the constitutively active (Q61L) variants of Rac1 and Cdc42 to their specific interaction partners Sra-1 and N-WASP, respectively, as well as to their common effector protein PAK was abrogated when Ser-71 was exchanged to glutamate as phosphomimetic substitution. Interaction with their common effector proteins IQGAP1/2/3 or MRCK alpha was, however, hardly affected. This ambivalent behaviour was obvious in functional assays. In contrast to Rac1 Q61L, phosphomimetic Rac1 Q61L/S71E was not able to induce increased membrane ruffling. Instead, Rac1 Q61L/S71E allowed filopodia formation, which is in accordance with abrogation of the dominant Sra-1/Wave signalling pathway. In addition, in contrast to Rac1 transfected cells Rac1 S71E failed to activate PAK1/2. On the other hand, Rac1 Q61L/S71E was as effective in activation of NF-kappaB as Rac1 Q61L, illustrating positive signal transduction of phosphorylated Rac1. Together, these data suggest that phosphorylation of Rac1 and Cdc42 at serine-71 represents a reversible mechanism to shift specificity of GTPase/effector coupling, and to preferentially address selected downstream pathways. PMID:22970203

  19. Downstream cumulative effects of land use on freshwater communities

    NASA Astrophysics Data System (ADS)

    Kuglerová, L.; Kielstra, B. W.; Moore, D.; Richardson, J. S.

    2015-12-01

    Many streams and rivers are subject to disturbance from intense land use such as urbanization and agriculture, and this is especially obvious for small headwaters. Streams are spatially organized into networks where headwaters represent the tributaries and provide water, nutrients, and organic material to the main stems. Therefore perturbations within the headwaters might be cumulatively carried on downstream. Although we know that the disturbance of headwaters in urban and agricultural landscapes poses threats to downstream river reaches, the magnitude and severity of these changes for ecological communities is less known. We studied stream networks along a gradient of disturbance connected to land use intensity, from urbanized watersheds to watersheds placed in agricultural settings in the Greater Toronto Area. Further, we compared the patterns and processes found in the modified watershed to a control watershed, situated in a forested, less impacted landscape. Preliminary results suggest that hydrological modifications (flash floods), habitat loss (drainage and sewer systems), and water quality issues of small streams in urbanized and agricultural watersheds represent major disturbances and threats for aquatic and riparian biota on local as well as larger spatial scales. For example, communities of riparian plants are dominated by species typical of the land use on adjacent uplands as well as the dominant land use on the upstream contributing area, instead of riparian obligates commonly found in forested watersheds. Further, riparian communities in disturbed environments are dominated by invasive species. The changes in riparian communities are vital for various functions of riparian vegetation. Bank erosion control is suppressed, leading to severe channel transformations and sediment loadings in urbanized watersheds. Food sources for instream biota and thermal regimes are also changed, which further triggers alterations of in-stream biological communities

  20. The Mechanical Design for the DARHT-II Downstream Beam Transport Line

    NASA Astrophysics Data System (ADS)

    Westenskow, Glen

    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 20-MeV, 2000-Amperes, 2-msec linear induction accelerator designed to generate short bursts of x-rays for the purpose of radiographing dense objects. The down-stream beam transport line is approximately 20-meter long region extending from the end of the accelerator to the bremsstrahlung target. Within this proposed transport line there are 15 conventional solenoid, quadrupole and dipole magnets; as well as several speciality 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. Downstream development of baroclinic waves in the midlatitude jet induced by extratropical transition: A case study

    NASA Astrophysics Data System (ADS)

    Chen, Hua

    2015-04-01

    This study uses eddy kinetic energy analysis and a targeting method to investigate how an extratropical transition (ET) event induced downstream development (the modification of the midlatitude flow downstream of the ET system) in the midlatitude jet environment. The downstream development showed distinct characteristics of "coupling development" and being "boundary-trapped". Eddies (potential disturbances) first developed at the upper levels, and these triggered lower-level eddy development, with all eddies decaying away from the tropopause and the surface. Thereafter, a lower-level eddy caught up with the upper-level eddy ahead of it, and they coupled to form a cyclone extending through the whole troposphere. Vertical ageostrophic geopotential flux may be a crucial dynamic factor throughout the eddy's lower-level growth, boundary-trapping, and coupling development. Together with barotropic conversion, the ageostrophic geopotential fluxes that were transported from Hurricane Fabian (2003) to the midlatitudes by the outflow led to downstream ridge development in the upper-level jet. The strong downstream advection of eddy kinetic energy in the exit region of the jet streak triggered downstream trough development. The well-known ridge-trough couplet thus formed. The vertical ageostrophic fluxes that were transported downward from the developed upper-level systems converged near the surface and resulted in lower-level eddy growth. Baroclinic conversion was negligible near the boundaries, while it was the main source of eddy kinetic energy at mid-levels. In the upper-level jet, potential energy was converted to the mean kinetic energy of the jet, which in turn was converted to eddy kinetic energy through barotropic conversion.

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

    NASA Astrophysics Data System (ADS)

    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.

  3. Antibiotic Resistance in Aeromonas Upstream and Downstream of a Water Resource Recovery Facility

    PubMed Central

    Henderson, Samantha K.; Askew, Maegan L.; Risenhoover, Hollie G.; McAndrews, Chrystle R.; Kennedy, S. Dawn; Paine, C. Sue

    2014-01-01

    Aeromonas strains isolated from sediments upstream and downstream of a water resource recovery facility (WRRF) over a two-year time period were tested for susceptibility to thirteen antibiotics. Incidence of resistance to antibiotics, antibiotic resistance phenotypes, and diversity (based on resistance phenotypes) were compared in the two populations. At the beginning of the study, the upstream and downstream Aeromonas populations were different for incidence of antibiotic resistance (p < 0.01), resistance phenotypes (p < 0.005), and diversity. However, these differences declined over time and were not significant at the end of the study. These results (1) indicate that antibiotic resistance in Aeromonas in stream sediments fluctuates considerably over time and (2) suggest that WRRF effluent does not, when examined over the long term, affect antibiotic resistance in Aeromonas in downstream sediment. PMID:25327024

  4. Enhanced Magnetic Field Perturbations and Electric Currents Observed Downstream of the High Power Helicon

    NASA Astrophysics Data System (ADS)

    Race Roberson, B.; Winglee, Robert; Ziemba, Tim; Prager, James

    2010-11-01

    The high power helicon (HPH) is a compact plasma source that can generate downstream densities of 10^17-10^18 m-3 and directed ion energies greater than 20 eV that continue to increase tens of centimeters downstream of the source. In order to understand the coupling mechanism between the helicon antenna and the plasma outside the immediate source region, measurements were made in the plasma plume downstream from the thruster of the propagating wave magnetic field and the perturbation of the axial bulk field. This magnetic field perturbation (δB) peaks at more than 15 gauss in strength downstream of the plasma source and propagates tens of centimeters downstream, cancelling the base magnetic field as it propagates. Taking the curl of this measured magnetic perturbation and assuming azimuthal symmetry suggests a peak current density of 20 kA m-2. Data will be presented that relates the cancellation of the base magnetic field to the propagation of the helicon wave and the region where the plasma current system closes.

  5. Integrative Genomics Implicates EGFR as a Downstream Mediator in NKX2-1 Amplified Non-Small Cell Lung Cancer

    PubMed Central

    Clarke, Nicole; Biscocho, Jewison; Kwei, Kevin A.; Davidson, Jean M.; Sridhar, Sushmita; Gong, Xue; Pollack, Jonathan R.

    2015-01-01

    NKX2-1, encoding a homeobox transcription factor, is amplified in approximately 15% of non-small cell lung cancers (NSCLC), where it is thought to drive cancer cell proliferation and survival. However, its mechanism of action remains largely unknown. To identify relevant downstream transcriptional targets, here we carried out a combined NKX2-1 transcriptome (NKX2-1 knockdown followed by RNAseq) and cistrome (NKX2-1 binding sites by ChIPseq) analysis in four NKX2-1-amplified human NSCLC cell lines. While NKX2-1 regulated genes differed among the four cell lines assayed, cell proliferation emerged as a common theme. Moreover, in 3 of the 4 cell lines, epidermal growth factor receptor (EGFR) was among the top NKX2-1 upregulated targets, which we confirmed at the protein level by western blot. Interestingly, EGFR knockdown led to upregulation of NKX2-1, suggesting a negative feedback loop. Consistent with this finding, combined knockdown of NKX2-1 and EGFR in NCI-H1819 lung cancer cells reduced cell proliferation (as well as MAP-kinase and PI3-kinase signaling) more than knockdown of either alone. Likewise, NKX2-1 knockdown enhanced the growth-inhibitory effect of the EGFR-inhibitor erlotinib. Taken together, our findings implicate EGFR as a downstream effector of NKX2-1 in NKX2-1 amplified NSCLC, with possible clinical implications, and provide a rich dataset for investigating additional mediators of NKX2-1 driven oncogenesis. PMID:26556242

  6. The target of rapamycin (TOR) proteins

    PubMed Central

    Raught, Brian; Gingras, Anne-Claude; Sonenberg, Nahum

    2001-01-01

    Rapamycin potently inhibits downstream signaling from the target of rapamycin (TOR) proteins. These evolutionarily conserved protein kinases coordinate the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. The TOR proteins regulate (i) the initiation and elongation phases of translation, (ii) ribosome biosynthesis, (iii) amino acid import, (iv) the transcription of numerous enzymes involved in multiple metabolic pathways, and (v) autophagy. Intriguingly, recent studies have also suggested that TOR signaling plays a critical role in brain development, learning, and memory formation. PMID:11416184

  7. 1. VIEW OF DOWNSTREAM SIDE OF DIVERSION DAM ON THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. VIEW OF DOWNSTREAM SIDE OF DIVERSION DAM ON THE SNAKE RIVER, LOOKING NORTHEAST. NOTE HEADGATE STRUCTURE ON NORTH BANK, SPILLWAY ON LEFT SIDE OF DAM, AND SPLASH LOGS ON DOWNSTREAM SIDE OF DAM. - Snake River Ditch, Headgate on north bank of Snake River, Dillon, Summit County, CO

  8. 11. VIEW NORTH ALONG DOWNSTREAM BANK OF DAM FROM SOUTH ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    11. VIEW NORTH ALONG DOWNSTREAM BANK OF DAM FROM SOUTH SIDE OF CHANNEL ON DOWNSTREAM SIDE OF RESERVOIR - Upper Doughty Dam, 200 feet west of Garden State Parkway, 1.7 miles west of Absecon, Egg Harbor City, Atlantic County, NJ

  9. Downstream Transport System for the Second Axis of the Dual-Axis Radiographic Hydrodynamic Test Facility

    NASA Astrophysics Data System (ADS)

    Chen, Yu-Jiuan; Bertolini, Lou; Caporaso, George J.; Ho, Darwin D.-M.; McCarrick, James F.; Paul, Arthur C.; Pincosy, Philip A.; Poole, Brian R.; Wang, Li-Fang; Westenskow, Glen A.

    2002-12-01

    This paper presents physics design of the DARHT-II downstream system, which consists of a diagnostic beam stop, a novel, fast, high-precision kicker system and the x-ray converter target assembly. The beamline configuration and its beam parameter acceptance, the transverse resistive wall instability modeling, the ion hose instability in the presence of the background gas, and the simulations of beam spill are discussed. We also present the target converter assembly's configuration, and the simulated x-ray spot sizes and doses based on the radiation hydrodynamics code LASNEX and the Monte Carlo radiation transport code MCNP.

  10. Identification of novel targets of MYC whose transcription requires the essential MbII domain.

    PubMed

    Zhang, Xiao-yong; DeSalle, Lauren M; McMahon, Steven B

    2006-02-01

    The MYC oncoprotein is among the most potent regulators of cell cycle progression and malignant transformation in human cells. Current models suggest that much of MYC's role in these processes is related to its ability to regulate the transcription of downstream target genes that encode the ultimate effector proteins. In addition to its carboxy-terminal DNA binding and dimerization domains, an enigmatic motif in the amino terminus termed MbII is required for all of MYC's biological activities. In spite of historical observations demonstrating the absolute requirement for MbII in these biological functions, clues implicating this domain in target gene transcription have only recently appeared. Based on this emerging link between MbII and transcriptional activation, we hypothesized that the identification of individual MYC targets whose transactivation requires MbII would help define the essential downstream effectors of MYC in transformation and cell cycle progression. In hopes of directly identifying new MbII-dependent MYC target genes, an expression profiling screen was conducted. This screen resulted in our identification of ten novel downstream targets of MYC. As a proof of principle, we recently demonstrated using RNAi-mediated depletion that one of these targets, the metastasis regulator MTA1, is absolutely required for MYC mediated transformation. Here we report the identity of these previously uncharacterized MYC targets and discuss their potential roles in MYC function. In addition, we attempt to reconcile the historical and contemporary evidence linking MbII to transcriptional activation. PMID:16434883

  11. Downstream elements of mammalian pre-mRNA polyadenylation signals: primary, secondary and higher-order structures.

    PubMed

    Zarudnaya, Margarita I; Kolomiets, Iryna M; Potyahaylo, Andriy L; Hovorun, Dmytro M

    2003-03-01

    Primary, secondary and higher-order structures of downstream elements of mammalian pre-mRNA polyadenylation signals [poly(A) signals] are re viewed. We have carried out a detailed analysis on our database of 244 human pre-mRNA poly(A) signals in order to characterize elements in their downstream regions. We suggest that the downstream region of the mammalian pre-mRNA poly(A) signal consists of various simple elements located at different distances from each other. Thus, the downstream region is not described by any precise consensus. Searching our database, we found that approximately 80% of pre-mRNAs with the AAUAAA or AUUAAA core upstream elements contain simple downstream elements, consisting of U-rich and/or 2GU/U tracts, the former occurring approximately 2-fold more often than the latter. Approximately one-third of the pre-mRNAs analyzed here contain sequences that may form G-quadruplexes. A substantial number of these sequences are located immediately downstream of the poly(A) signal. A possible role of G-rich sequences in the polyadenylation process is discussed. A model of the secondary structure of the SV40 late pre-mRNA poly(A) signal downstream region is presented. PMID:12595544

  12. BMX acts downstream of PI3K to promote colorectal cancer cell survival and pathway inhibition sensitizes to the BH3 mimetic ABT-737.

    PubMed

    Potter, Danielle S; Kelly, Paul; Denneny, Olive; Juvin, Veronique; Stephens, Len R; Dive, Caroline; Morrow, Christopher J

    2014-02-01

    Evasion of apoptosis is a hallmark of cancer, and reversing this process by inhibition of survival signaling pathways is a potential therapeutic strategy. Phosphoinositide 3-kinase (PI3K) signaling can promote cell survival and is upregulated in solid tumor types, including colorectal cancer (CRC), although these effects are context dependent. The role of PI3K in tumorigenesis combined with their amenability to specific inhibition makes them attractive drug targets. However, we observed that inhibition of PI3K in HCT116, DLD-1, and SW620 CRC cells did not induce apoptotic cell death. Moreover, these cells were relatively resistant to the Bcl-2 homology domain 3 (BH3) mimetic ABT-737, which directly targets the Bcl-2 family of apoptosis regulators. To test the hypothesis that PI3K inhibition lowers the apoptotic threshold without causing apoptosis per se, PI3K inhibitors were combined with ABT-737. PI3K inhibition enhanced ABT-737-induced apoptosis by 2.3- to 4.5-fold and reduced expression levels of MCL-1, the resistance biomarker for ABT-737. PI3K inhibition enhanced ABT-737-induced apoptosis a further 1.4- to 2.4-fold in CRC cells with small interfering RNA-depleted MCL-1, indicative of additional sensitizing mechanisms. The observation that ABT-737-induced apoptosis was unaffected by inhibition of PI3K downstream effectors AKT and mTOR, implicated a novel PI3K-dependant pathway. To elucidate this, an RNA interference (RNAi) screen of potential downstream effectors of PI3K signaling was conducted, which demonstrated that knockdown of the TEC kinase BMX sensitized to ABT-737. This suggests that BMX is an antiapoptotic downstream effector of PI3K, independent of AKT. PMID:24709422

  13. Menopause Hastens Aging, Studies Suggest

    MedlinePlus

    ... gov/news/fullstory_160079.html Menopause Hastens Aging, Studies Suggest Researchers found it boosted cellular aging by ... it, can speed aging in women, two new studies suggest. "For decades, scientists have disagreed over whether ...

  14. Extraction and downstream processing of plant-derived recombinant proteins.

    PubMed

    Buyel, J F; Twyman, R M; Fischer, R

    2015-11-01

    Plants offer the tantalizing prospect of low-cost automated manufacturing processes for biopharmaceutical proteins, but several challenges must be addressed before such goals are realized and the most significant hurdles are found during downstream processing (DSP). In contrast to the standardized microbial and mammalian cell platforms embraced by the biopharmaceutical industry, there are many different plant-based expression systems vying for attention, and those with the greatest potential to provide inexpensive biopharmaceuticals are also the ones with the most significant drawbacks in terms of DSP. This is because the most scalable plant systems are based on the expression of intracellular proteins in whole plants. The plant tissue must therefore be disrupted to extract the product, challenging the initial DSP steps with an unusually high load of both particulate and soluble contaminants. DSP platform technologies can accelerate and simplify process development, including centrifugation, filtration, flocculation, and integrated methods that combine solid-liquid separation, purification and concentration, such as aqueous two-phase separation systems. Protein tags can also facilitate these DSP steps, but they are difficult to transfer to a commercial environment and more generic, flexible and scalable strategies to separate target and host cell proteins are preferable, such as membrane technologies and heat/pH precipitation. In this context, clarified plant extracts behave similarly to the feed stream from microbes or mammalian cells and the corresponding purification methods can be applied, as long as they are adapted for plant-specific soluble contaminants such as the superabundant protein RuBisCO. Plant-derived pharmaceutical proteins cannot yet compete directly with established platforms but they are beginning to penetrate niche markets that allow the beneficial properties of plants to be exploited, such as the ability to produce 'biobetters' with tailored

  15. 6. VIEW SHOWING DOWNSTREAM FACE AND TOE OF DAM, LOOKING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. VIEW SHOWING DOWNSTREAM FACE AND TOE OF DAM, LOOKING SOUTHWEST - High Mountain Dams in Upalco Unit, Kidney Lake Dam, Ashley National Forest, 4.7 miles North of Miners Gulch Campground, Mountain Home, Duchesne County, UT

  16. 5. VIEW SHOWING DOWNSTREAM FACE AND TOE OF DAM, LOOKING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. VIEW SHOWING DOWNSTREAM FACE AND TOE OF DAM, LOOKING SOUTHWEST - High Mountain Dams in Upalco Unit, Kidney Lake Dam, Ashley National Forest, 4.7 miles North of Miners Gulch Campground, Mountain Home, Duchesne County, UT

  17. 7. VIEW OF MAIN CANAL, LOOKING SOUTH, IMMEDIATELY DOWNSTREAM FROM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. VIEW OF MAIN CANAL, LOOKING SOUTH, IMMEDIATELY DOWNSTREAM FROM THE SNAKE RIVER VALLEY IRRIGATION DISTRICT, SECTION 34, T2N, R37E - Woodville Canal Company, West side of Snake River (River Mile 796), Woodville, Bingham County, ID

  18. Operating stability of hydroelectric stations with downstream surge tanks

    SciTech Connect

    Murav`ev, O.A.; Berlin, V.V.

    1995-10-01

    The possibilities for reducing the cross-sectional area of downstream surge tanks under the condition of providing stable regimes of the hydroelectric power plant are analyzed. Two calculation methods are described.

  19. Wave and particle evolution downstream of quasi-perpendicular shocks

    NASA Technical Reports Server (NTRS)

    Mckean, M. E.; Omidi, N.; Krauss-Varban, D.; Karimabadi, H.

    1995-01-01

    Distributions of ions heated in quasi-perpendicular bow shocks have large perpendicular temperature anisotropies that provide free energy for the growth of Alfven ion cyclotron (AIC) and mirror waves. These modes are often obsreved in the Earth's magnetosheath. Using two-dimensional hybrid simulations, we show that these waves are produced near the shock front and convected downstream rather than being produced locally downstream. The wave activity reduces the proton anisotropy to magnetosheath levels within a few tens of gyroradii of the shock but takes significantly longer to reduce the anisotropy of He(++) ions. The waves are primarily driven by proton anisotropy and the dynamics of the helium ions is controlled by the proton waves. Downstream of high Mach number shocks, mirror waves compete effectively with AIC waves. Downstream of low Mach number shocks, AIC waves dominate.

  20. 2. GENERAL EXTERIOR VIEW LOOKING WEST, SHOWING CHANNEL DOWNSTREAM FROM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. GENERAL EXTERIOR VIEW LOOKING WEST, SHOWING CHANNEL DOWNSTREAM FROM NAVIGATION LOCK #1; MOVABLE BRIDGE IS VISIBLE IN LEFT FOREGROUND. - Bonneville Project, Navigation Lock No. 1, Oregon shore of Columbia River near first Powerhouse, Bonneville, Multnomah County, OR

  1. 9. DETAIL EXTERIOR VIEW LOOKING SOUTHEAST, SHOWING DOWNSTREAM MITER GATES ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    9. DETAIL EXTERIOR VIEW LOOKING SOUTHEAST, SHOWING DOWNSTREAM MITER GATES FOR NAVIGATION LOCK #1. - Bonneville Project, Navigation Lock No. 1, Oregon shore of Columbia River near first Powerhouse, Bonneville, Multnomah County, OR

  2. 27. Evening view of downstream face of Pleasant Dam under ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    27. Evening view of downstream face of Pleasant Dam under construction. Part of construction camp housing is visible in foreground. Photographer unknown, 1927. Source: MWD. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  3. DOWNSTREAM LOCK GATE DETAIL VIEW WITH DOG HOUSE. NOTE CONTROL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DOWNSTREAM LOCK GATE DETAIL VIEW WITH DOG HOUSE. NOTE CONTROL ARM AND GEAR FOR GATE. LOOKING NORTHWEST. - Illinois Waterway, Dresden Island Lock and Dam , 7521 North Lock Road, Channahon, Will County, IL

  4. 22. DOWNSTREAM DETAIL OF PIER NO. 3, TRUSS TOWER AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    22. DOWNSTREAM DETAIL OF PIER NO. 3, TRUSS TOWER AND CANTILEVER ARMS. VIEW TO NORTHEAST. - MacArthur Bridge, Spanning Mississippi River on Highway 34 between IA & IL, Burlington, Des Moines County, IA

  5. 24. DOWNSTREAM DETAIL OF PIER NO. 2 AND THROUGH AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    24. DOWNSTREAM DETAIL OF PIER NO. 2 AND THROUGH AND DECK TRUSS END PANELS. VIEW TO NORTHEAST. - MacArthur Bridge, Spanning Mississippi River on Highway 34 between IA & IL, Burlington, Des Moines County, IA

  6. 12. VIEW OF DOWNSTREAM ELEVATION, LOOKING SOUTHEAST. PIER OF OLD ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. VIEW OF DOWNSTREAM ELEVATION, LOOKING SOUTHEAST. PIER OF OLD BRIDGE IS IN FOREGROUND - Chili Bar Bridge, Spanning South Fork of American River at State Highway 193, Placerville, El Dorado County, CA

  7. 10. VIEW WEST TOWARD DOWNSTREAM SIDE OF SPILLWAY FROM UNDERSIDE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. VIEW WEST TOWARD DOWNSTREAM SIDE OF SPILLWAY FROM UNDERSIDE OF GARDEN STATE PARKWAY ABUTMENT - Upper Doughty Dam, 200 feet west of Garden State Parkway, 1.7 miles west of Absecon, Egg Harbor City, Atlantic County, NJ

  8. EVALUATING THE EFFECT OF UPSTREAM WATERSHED ACTIVITIES TO DOWNSTREAM STREAMFLOW

    EPA Science Inventory

    Linking the impacts of upstream activities such as urban development to changes in downstream streamflow is critical to achieving a balance between economic development and environmental protection as a basis for sustainable watershed development. This paper presents a modeling a...

  9. 14. Credit PED. Downstream elevation, near completion, showing tail race ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. Credit PED. Downstream elevation, near completion, showing tail race and trestle used to carry excavated rock and construction materials across tail race. Photo c. 1909. - Dam No. 4 Hydroelectric Plant, Potomac River, Martinsburg, Berkeley County, WV

  10. 10. OBLIQUE VIEW OF BRIDGE, LOOKING EAST OF DOWNSTREAM SIDE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. OBLIQUE VIEW OF BRIDGE, LOOKING EAST OF DOWNSTREAM SIDE OF BRIDGE FROM YOLO COUNTY SIDE OF THE SACRAMENTO RIVER - Sacramento River Bridge, Spanning Sacramento River at California State Highway 275, Sacramento, Sacramento County, CA

  11. 4. DOWNSTREAM ELEVATION. DETAIL OF BUTTRESS ADDITION ON NORTHEAST WING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. DOWNSTREAM ELEVATION. DETAIL OF BUTTRESS ADDITION ON NORTHEAST WING WALL. - Core Creek County Bridge, Spanning Core Creek, approximately 1 mile South of State Route 332 (Newtown Bypass), Newtown, Bucks County, PA

  12. 10. Downstream face of Mormon Flat Dam under construction. Cement ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. Downstream face of Mormon Flat Dam under construction. Cement storage shed is at center right. Photographer unknown, September 1924. Source: Salt River Project. - Mormon Flat Dam, On Salt River, Eastern Maricopa County, east of Phoenix, Phoenix, Maricopa County, AZ

  13. 23. DOWNSTREAM VIEW OF COMPLETED OUTLET CONTROL STRUCTURE.... Volume XIX, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    23. DOWNSTREAM VIEW OF COMPLETED OUTLET CONTROL STRUCTURE.... Volume XIX, No. 8, April 12, 1940. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  14. 28. DOWNSTREAM VIEW OF ROCK PAVING OPERATIONS ON LEFT BANK ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    28. DOWNSTREAM VIEW OF ROCK PAVING OPERATIONS ON LEFT BANK OF OUTLET CHANNEL.... Volume XVI, No. 18, September 29, 1939. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  15. 18. GENERAL VIEW OF THE OUTLET STRUCTURE LOOKING DOWNSTREAM AT ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. GENERAL VIEW OF THE OUTLET STRUCTURE LOOKING DOWNSTREAM AT WEST ABUTMENT.... Volume XVI, No. 13, July 26, 1939. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  16. 8. EMPTY LOCK CHAMBER FROM DOWNSTREAM (WEST) END, WITH VISITORS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. EMPTY LOCK CHAMBER FROM DOWNSTREAM (WEST) END, WITH VISITORS CENTER (LEFT) AND LOCKMASTER'S HOUSE ON NORTH BANK. VIEW TO NORTHEAST. - Starved Rock Locks & Dam, Illinois Waterway River mile 231, Peru, La Salle County, IL

  17. 6. DOWNSTREAM SIDE OF LOWER MITER GATES WITH FULL LOCK ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. DOWNSTREAM SIDE OF LOWER MITER GATES WITH FULL LOCK CHAMBER, VISITORS, AND LOCKMASTER'S HOUSE IN BACKGROUND. VIEW TO NORTHEAST. - Starved Rock Locks & Dam, Illinois Waterway River mile 231, Peru, La Salle County, IL

  18. View of Lake Sabrina Dam downstream face from parking lot ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of Lake Sabrina Dam downstream face from parking lot showing concrete outlet structure on tow of dam at left edge of photo, view southeast - Bishop Creek Hydroelectric System, Plant 2, Lake Sabrina Dam, Bishop Creek, Bishop, Inyo County, CA

  19. 14. VIEW OF DAM SITE, LOOKING SOUTH (DOWNSTREAM). MIXING PLANT ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. VIEW OF DAM SITE, LOOKING SOUTH (DOWNSTREAM). MIXING PLANT IS VISIBLE AT RIGHT, COFFER DAM IS UPSTREAM OF PLACING TOWER. EAST DOME IS VISIBLE AT LEFT OF TOWER, c. 1927 - Coolidge Dam, Gila River, Peridot, Gila County, AZ

  20. 34. DOWNSTREAM VIEW OF COOLIDGE DAM COMPLETED. POWER HOUSE, INTAKE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    34. DOWNSTREAM VIEW OF COOLIDGE DAM COMPLETED. POWER HOUSE, INTAKE TOWERS, WEST SPILLWAY CHANNEL AND DECORATIVE EAGLES ALL CLEARLY VISIBLE, c. 1928 - Coolidge Dam, Gila River, Peridot, Gila County, AZ

  1. 54. Downstream face of Agua Fria project's diversion dam showing ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    54. Downstream face of Agua Fria project's diversion dam showing initial masonry construction and poured concrete capping. Photographer Mark Durben, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  2. 7. Contextual view to eastnortheast showing downstream (west) side of ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. Contextual view to east-northeast showing downstream (west) side of bridge in setting, depicting dense riparian nature of area. - Stanislaus River Bridge, Atchison, Topeka & Santa Fe Railway at Stanislaus River, Riverbank, Stanislaus County, CA

  3. VIEW OF DOWNSTREAM SIDE OF TUMALO DIVERSION DAM AND SPILLWAY, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF DOWNSTREAM SIDE OF TUMALO DIVERSION DAM AND SPILLWAY, WITH FISH LADDER TO RIGHT OF VIEW. FROM WEST BANK OF TUMALO CREEK. LOOKING SOUTHWEST - Tumalo Irrigation District, Tumalo Project, West of Deschutes River, Tumalo, Deschutes County, OR

  4. VIEW OF BLAKELY ROAD ACROSS TUMALO DAM, DOWNSTREAM SIDE TO ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF BLAKELY ROAD ACROSS TUMALO DAM, DOWNSTREAM SIDE TO LEFT AND RESERVOIR SIDE TO RIGHT. LOOKING WEST - Tumalo Irrigation District, Tumalo Project, West of Deschutes River, Tumalo, Deschutes County, OR

  5. VIEW OF HIGHLINE DROP ON THE HIGHLINE LATERAL CANAL DOWNSTREAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF HIGHLINE DROP ON THE HIGHLINE LATERAL CANAL DOWNSTREAM FROM BULLCREEK DAM AND BRIDGE. LOOKING SOUTHEAST - Tumalo Irrigation District, Tumalo Project, West of Deschutes River, Tumalo, Deschutes County, OR

  6. VIEW OF DOWNSTREAM SIDE OF BULL CREEK DAM AND BRIDGE, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF DOWNSTREAM SIDE OF BULL CREEK DAM AND BRIDGE, WITH LATER HEADGATE ADDITION THROUGH SPILLWAY. LOOKING WEST - Tumalo Irrigation District, Tumalo Project, West of Deschutes River, Tumalo, Deschutes County, OR

  7. View of downstream face of Grand Coulee Dam (from just ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of downstream face of Grand Coulee Dam (from just below No. 3 Powerhouse), looking southwest. - Columbia Basin Project, Grand Coulee Dam & Franklin D. Roosevelt Lake, Across Columbia River, Southeast of Town of Grand Coulee, Grand Coulee, Grant County, WA

  8. Detail of downstream face of dam showing water being discharged ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail of downstream face of dam showing water being discharged through diversion tube. - Columbia Basin Project, Grand Coulee Dam & Franklin D. Roosevelt Lake, Across Columbia River, Southeast of Town of Grand Coulee, Grand Coulee, Grant County, WA

  9. 5. VIEW SHOWING THE DOWNSTREAM SIDE OF SWAN FALLS DAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. VIEW SHOWING THE DOWNSTREAM SIDE OF SWAN FALLS DAM AND POWER HOUSE, LOOKING UPSTREAM TO SOUTH FROM THE A MOUND OF DEBRIS ABOUT THIRTY TO FORTY FEET ABOVE THE RIVER - Swan Falls Dam, Snake River, Kuna, Ada County, ID

  10. 32. Otter Lake Dam. View from downstream show how the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. Otter Lake Dam. View from downstream show how the dam blends into its environment. Looking east-northeast. - Blue Ridge Parkway, Between Shenandoah National Park & Great Smoky Mountains, Asheville, Buncombe County, NC

  11. 27. DETAIL VIEW OF CONCRETE MONOLITH CONSTRUCTION AT DOWNSTREAM END ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    27. DETAIL VIEW OF CONCRETE MONOLITH CONSTRUCTION AT DOWNSTREAM END OF WEST MAIN LOCK WALL, LOOKiNG SOUTHEAST - Upper Mississippi River 9-Foot Channel Project, Lock & Dam 26R, Alton, Madison County, IL

  12. 23. INTAKE DIVERSION DAM UNDER CONSTRUCTION, FACING NORTHWEST AND DOWNSTREAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    23. INTAKE DIVERSION DAM UNDER CONSTRUCTION, FACING NORTHWEST AND DOWNSTREAM Photographer: Walter J. Lubken, September 17, 1906 - Roosevelt Power Canal & Diversion Dam, Parallels Salt River, Roosevelt, Gila County, AZ

  13. 15. INSIDE VIEW OF FLUME, LOOKING DOWNSTREAM, LEFT FORK TO ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    15. INSIDE VIEW OF FLUME, LOOKING DOWNSTREAM, LEFT FORK TO SETTLING BASIN, SHOWING RIGHT FORK WITH GATE IN PLACE AND A FEW NEEDLES IN PLACE - Electron Hydroelectric Project, Along Puyallup River, Electron, Pierce County, WA

  14. 14. INSIDE VIEW OF FLUME, LOOKING DOWNSTREAM TOWARD SETTLING BASIN, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. INSIDE VIEW OF FLUME, LOOKING DOWNSTREAM TOWARD SETTLING BASIN, SHOWING RIGHT FORK TO BYPASS, LEFT FORK TO BASIN - Electron Hydroelectric Project, Along Puyallup River, Electron, Pierce County, WA

  15. MAIN CANAL HEADWORKS, FROM DOWNSTREAM (TO RIGHT), NOTE SAND AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    MAIN CANAL HEADWORKS, FROM DOWNSTREAM (TO RIGHT), NOTE SAND AND SILT SLUICE GATE FOR DIVERSION DAM ON LEFT, VIEW TO NORTHWEST - Salmon Creek Diversion Dam, Main Canal Headworks, Salmon Creek, Okanogan, Okanogan County, WA

  16. 25. GENERAL EXTERIOR VIEW LOOKING WEST, SHOWING FISH LADDER DOWNSTREAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    25. GENERAL EXTERIOR VIEW LOOKING WEST, SHOWING FISH LADDER DOWNSTREAM FROM THE DAM/SPILLWAY ON THE WASHINGTON SHORE. - Bonneville Project, Bonneville Dam, Columbia River, Bonneville, Multnomah County, OR

  17. 2. GENERAL EXTERIOR VIEW LOOKING SOUTH, SHOWING DOWNSTREAM FACE OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. GENERAL EXTERIOR VIEW LOOKING SOUTH, SHOWING DOWNSTREAM FACE OF DAM/SPILLWAY; PARKING LOT/WORK AREA ON WASHINGTON SHORE IS VISIBLE IN FOREGROUND. - Bonneville Project, Bonneville Dam, Columbia River, Bonneville, Multnomah County, OR

  18. 29. VIEW OF STONE BUILDING, ABOUT ONE MILE DOWNSTREAM OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    29. VIEW OF STONE BUILDING, ABOUT ONE MILE DOWNSTREAM OF DAM, USED TO STORE EXPLOSIVES DURING THE CONSTRUCTION OF HORSE MESA - Horse Mesa Dam, Salt River, 65 miles East of Phoenix, Phoenix, Maricopa County, AZ

  19. 3. VIEW OF DIABLO CANYON LOOKING DOWNSTREAM FROM THE VALVE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. VIEW OF DIABLO CANYON LOOKING DOWNSTREAM FROM THE VALVE HOUSE AT ELEVATION 1044, 1989. - Skagit Power Development, Diablo Dam, On Skagit River, 6.9 miles upstream from Newhalem, Newhalem, Whatcom County, WA

  20. View of downstream debris field at the Merry Generator House, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of downstream debris field at the Merry Generator House, showing possible concrete generator seats, looking south - Arthur Holmes Merry Generator House, Signal Lake North of Range Road, Fort Gordon, Richmond County, GA

  1. 2. DOWNSTREAM VIEW OF THE SOUTH CHANNEL DAM, LOOKING WEST. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. DOWNSTREAM VIEW OF THE SOUTH CHANNEL DAM, LOOKING WEST. - Washington Water Power Company Post Falls Power Plant, South Channel Dam, West of intersection of Spokane & Fourth Streets, Post Falls, Kootenai County, ID

  2. VIEW LOOKING SOUTH SOUTHWEST AT THE DOWNSTREAM ENTRANCE INTO LOCK ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW LOOKING SOUTH SOUTHWEST AT THE DOWNSTREAM ENTRANCE INTO LOCK 67. NOTE THE BEDDING TIMBERS AT BASE OF STONE WORK. THEY ARE EXPOSED ONLY AT LOW WATER. - New York State Barge Canal, Lockport Locks, Richmond Avenue, Lockport, Niagara County, NY

  3. 70. Downstream view of Waddell Dam spillway and taintor gates. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    70. Downstream view of Waddell Dam spillway and taintor gates. Photographer Mark Durben. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  4. 42. View of emergency spillway excavation looking downstream from spillway. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    42. View of emergency spillway excavation looking downstream from spillway. Photographer unknown, 1929. Source: ADWR. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  5. 28. View of construction shops looking west and downstream. Photographer ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    28. View of construction shops looking west and downstream. Photographer unknown, October 29, 1926. Source: MWD. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  6. 57. Downstream side of left section of diversion dam. Photographer ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    57. Downstream side of left section of diversion dam. Photographer Mark Durben, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  7. 55. Downstream face of diversion dam looking northwest. Photographer Mark ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    55. Downstream face of diversion dam looking northwest. Photographer Mark Durben, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  8. 51. Downstream end of diversion tunnel around east end of ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    51. Downstream end of diversion tunnel around east end of Humbug Creek Diversion Dam. Photographer James Eastwood, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  9. 49. Downstream face of Humbug Creek Diversion Dam with sluice ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    49. Downstream face of Humbug Creek Diversion Dam with sluice opening at center. Photographer James Eastwood, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  10. 69. View of downstream face from west or right abutment. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    69. View of downstream face from west or right abutment. Photographer Mark Durben. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  11. 40. Reservoir behind Pleasant Dam, looking downstream, spillway is at ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    40. Reservoir behind Pleasant Dam, looking downstream, spillway is at right. Photographer unknown, c. late 1920s. Source: MWD. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  12. 65. Close up view of downstream face of arch, buttress ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    65. Close up view of downstream face of arch, buttress ties and roadway support work. Photographer Mark Durben. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  13. 76. PALMDALE WATER COMPANY, LITTLEROCK DAM, EASTWOOD MULTIPLEARCHED TYPE: DOWNSTREAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    76. PALMDALE WATER COMPANY, LITTLEROCK DAM, EASTWOOD MULTIPLE-ARCHED TYPE: DOWNSTREAM ELEVATION, SHEET 3; OCTOBER 2, 1919. Littlerock Water District files. - Little Rock Creek Dam, Little Rock Creek, Littlerock, Los Angeles County, CA

  14. Downstream influence scaling of turbulent flow past expansion corners

    NASA Technical Reports Server (NTRS)

    Lu, Frank K.; Chung, Kung-Ming

    1992-01-01

    Previous studies of the high-speed viscous inviscid interaction between a turbulent boundary layer and an expansion at a convex corner have noted that surface pressure decreases toward the downstream inviscid value yielded by a Prandtl-Meyer expansion. A downstream influence on the corner is presently identified which is based on the mean surface pressure distribution; a scaling law is proposed for this distance.

  15. Modeling Neutral Densities Downstream of a Gridded Ion Thruster

    NASA Technical Reports Server (NTRS)

    Soulas, George C.

    2010-01-01

    The details of a model for determining the neutral density downstream of a gridded ion thruster are presented. An investigation of the possible sources of neutrals emanating from and surrounding a NEXT ion thruster determined that the most significant contributors to the downstream neutral density include discharge chamber neutrals escaping through the perforated grids, neutrals escaping from the neutralizer, and vacuum facility background neutrals. For the neutral flux through the grids, near- and far-field equations are presented for rigorously determining the neutral density downstream of a cylindrical aperture. These equations are integrated into a spherically-domed convex grid geometry with a hexagonal array of apertures for determining neutral densities downstream of the ion thruster grids. The neutrals escaping from an off-center neutralizer are also modeled assuming diffuse neutral emission from the neutralizer keeper orifice. Finally, the effect of the surrounding vacuum facility neutrals is included and assumed to be constant. The model is used to predict the neutral density downstream of a NEXT ion thruster with and without neutralizer flow and a vacuum facility background pressure. The impacts of past simplifying assumptions for predicting downstream neutral densities are also examined for a NEXT ion thruster.

  16. Against the flow: chemical detection of downstream predators in running waters

    PubMed Central

    Dahl, J.; Nilsson, P. A.; Petersson, L. B.

    1998-01-01

    In running waters, chemical cues have generally been assumed to always come from upstream locations. Here, we present field and laboratory evidence that Gammarus pulex can use chemical cues from downstream predators to adaptively adjust drifting behaviour. In the field, significantly fewer Gammarus migrated into stream enclosures where brown trout (Salmo trutta) were present than into control enclosures. In a subsequent laboratory experiment, Gammarus actively avoided live trout and trout chemicals placed downstream in an artificial stream, whereas no effects were found in response to control or visual cues. We suggest that the mechanism explaining the ability of Gammarus to detect downstream predators is use of backflows, which locally transport fish chemicals against the main flow. Such backflows are both created by the Gammarus itself and by surrounding substrate heterogeneity. These results profoundly affect the way in which we view the chemical environment of running waters and have important implications for empirical and theoretical work evaluating predator effects in running waters, as they demonstrate that prey immigration rates can depend on downstream predator densities.

  17. Propagation characteristics of waves upstream and downstream of quasi-parallel shocks

    NASA Technical Reports Server (NTRS)

    Krauss-Varban, D.; Omidi, N.

    1993-01-01

    The propagation characteristics of waves upstream and downstream of quasi-parallel shocks are investigated by using 2D hybrid simulations. At low Alfven Mach numbers, M(A) below about 2, the shock is initially associated with upstream phase-standing whistlers. At later times, backstreaming ions excite longer-wavelength whistlers via the right-hand resonant ion/ion instability. These waves propagate along the magnetic field at a group velocity no smaller than the upstream flow speed, so that the waves remain in the upstream region. At higher MA (above about 3), these waves are convected back into the shock, causing its reformation and downstream perturbations. Shock transmitted waves mode-convert into Alfven/ion-cyclotron waves which have a wave vector along the shock normal (pointing upstream) and convect downstream. The 2D simulation results confirm our earlier suggestion that the upstream waves should be field aligned, and that their convection into the downstream is associated with linear mode conversion into the Alfven/ion-cyclotron branch.

  18. Investigation of downstream and sideline subsonic jet noise using Large Eddy Simulation

    NASA Astrophysics Data System (ADS)

    Bogey, Christophe; Bailly, Christophe

    2006-02-01

    The sound fields radiated by Mach number 0.6 and 0.9, circular jets with Reynolds numbers varying from 1.7×103 to 4×105 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].

  19. Ultrasonic observation of blood disturbance in a stenosed tube: effects of flow acceleration and turbulence downstream.

    PubMed

    Nam, Kweon-Ho; Paeng, Dong-Guk; Choi, Min Joo; Shung, K Kirk

    2008-01-01

    Red blood cell (RBC) aggregation is known to be highly dependent on hemodynamic parameters such as shear rate, flow turbulence and flow acceleration under pulsatile flow. The effects of all three hemodynamic parameters on RBC aggregation and echogenicity of porcine whole blood were investigated downstream of an eccentric stenosis in a mock flow loop using B-mode images with Doppler spectrograms of a commercial ultrasonic system. A hyperechoic parabolic profile appeared downstream during flow acceleration, yielding another piece of evidence suggesting that the enhancement of rouleaux formation may be caused by flow acceleration. It was also found that echogenicity increased locally at a distance of three tube diameters downstream from the stenosis. The local increase of echogenicity is thought to be mainly due to flow turbulence. The hypoechoic "black hole" was also seen at the center of the tube downstream of the stenosis where blood flow was disturbed, and this may be caused by the compound effect of flow turbulence and shear rate. PMID:17900794

  20. Onecut1 and Onecut2 transcription factors operate downstream of Pax6 to regulate horizontal cell development.

    PubMed

    Klimova, Lucie; Antosova, Barbora; Kuzelova, Andrea; Strnad, Hynek; Kozmik, Zbynek

    2015-06-01

    Genetic studies of the last decades strongly indicated that generation of particular retinal cell types is governed by gene regulatory networks of transcription factors and their target genes. The paired and homeodomain transcription factor Pax6 plays a pivotal role in retinal development as its inactivation in the retinal progenitor cell population leads to abolished differentiation of all retinal cell types. However, until now, only a few transcription factors operating downstream of Pax6 responsible for generation of individual retinal cell types have been identified. In this study, we identified two transcription factors of the Onecut family, Onecut1 and Onecut2, as Pax6 downstream-acting factors. Onecut1 and Onecut2 were previously shown to be expressed in developing horizontal cells, retinal ganglion cells and cone photoreceptors; however, their role in differentiation of these cell types is poorly understood. In this study, we show that the horizontal cell genesis is severely disturbed in Onecut-deficient retinae. In single Onecut1 and Onecut2 mutants, the number of horizontal cells is dramatically reduced while horizontal cells are completely missing in the Onecut1/Onecut2 compound mutant. Analysis of genes involved in the horizontal cell genesis such as Foxn4, Ptf1a, Prox1 and Lim1 showed that although horizontal cells are initially formed, they are not maintained in Onecut-deficient retinae. Taken together, this study suggests the model in which Pax6 regulates the maintenance of horizontal cells through the activation of Onecut1 and Onecut2 transcription factors. PMID:25794677

  1. Gas phase oxidation downstream of a catalytic combustor

    NASA Technical Reports Server (NTRS)

    Tien, J. S.; Anderson, D. N.

    1979-01-01

    Effect of the length available for gas-phase reactions downstream of the catalytic reactor on the emission of CO and unburned hydrocarbons was investigated. A premixed, prevaporized propane/air feed to a 12/cm/diameter catalytic/reactor test section was used. The catalytic reactor was made of four 2.5 cm long monolithic catalyst elements. Four water cooled gas sampling probes were located at positions between 0 and 22 cm downstream of the catalytic reactor. Measurements of unburned hydrocarbon, CO, and CO2 were made. Tests were performed with an inlet air temperature of 800 K, a reference velocity of 10 m/s, pressures of 3 and 600,000 Pa, and fuel air equivalence ratios of 0.14 to 0.24. For very lean mixtures, hydrocarbon emissions were high and CO continued to be formed downstream of the catalytic reactor. At the highest equivalence ratios tested, hydrocarbon levels were much lower and CO was oxidized to CO2 in the gas phase downstream. To achieve acceptable emissions, a downstream region several times longer than the catalytic reactor could be required.

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

    USGS Publications Warehouse

    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.

  3. Modeling downstream fining in sand-bed rivers. I: Formulation

    USGS Publications Warehouse

    Wright, S.; Parker, G.

    2005-01-01

    In this paper a numerical modeling formulation is presented for simulation of the development of the longitudinal profile and bed sediment distribution in sand-bed rivers. The objective of the model application, which is presented in the companion paper (Wright and Parker, 2005), is to study the development of two characteristics of large, low-slope, sand-bed rivers: (1) a downstream decrease in bed slope (i.e. concave upward longitudinal profile) and (2) a downstream decrease in characteristic bed sediment diameter (e.g. the median bed surface size D50). Three mechanisms that lead to an upward concave profile and downstream fining are included in the modeling formulation: (1) a delta prograding into standing water at the downstream boundary, (2) sea-level rise, and (3) tectonic subsidence. In the companion paper (Wright and Parker, 2005) the model is applied to simulate the development of the longitudinal profile and downstream fining in sand-bed rivers flowing into the ocean during the past 5000 years of relatively slow sea-level rise. ?? 2005 International Association of Hydraulic Engineering and Research.

  4. Biotic integrity of the Boise River upstream and downstream from two municipal wastewater treatment facilities, Boise, Idaho, 1995-96

    USGS Publications Warehouse

    Mullins, William H.

    1999-01-01

    Aquatic biological communities were used to assess the biotic integrity of the Boise River upstream and downstream from the Lander Street and West Boise municipal wastewater treatment facilities (WTFs) in Boise, Idaho. Samples of epilithic periphyton, benthic macroinvertebrates, and fish were collected in late February and early March 1995, in late October 1996, and in early December 1996. Epilithic periphyton biomass, expressed as chlorophyll-a and ash-free dry weight, declined substantially between 1995 and 1996. Chlorophyll-a concentrations were higher at sites downstream from WTFs in both years, but differences in concentrations between sites upstream and downstream from WTFs were not statistically significant. High withinsite variance suggests that greater sampling intensity would improve statistical comparison. Index of Biotic Integrity (IBI) scores calculated for benthic macroinvertebrates were higher for the sites upstream from WTFs in 1995 and were the same for all sites in 1996. Similarly, IBI scores calculated for fish were higher for the sites upstream from WTFs in 1995, were higher for the site upstream from the Lander Street WTF in 1996, and were the same for sites upstream and downstream from the West Boise WTF in 1996. Two species of sculpin (Cottus) were abundant at the site upstream from both WTFs but were absent at all other sites downstream from WTFs in 1995 and composed only 2 percent of the total number of fish collected downstream from the Lander Street WTF in 1996.

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

    PubMed Central

    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

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

    PubMed

    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. PMID:27158753

  7. Rotor wake mixing effects downstream of a compressor rotor

    NASA Technical Reports Server (NTRS)

    Ravindranath, A.; Lakshminarayana, B.

    1981-01-01

    An experimental study of rotor wake was conducted in the trailing-edge and near-wake regions of a moderately loaded compressor rotor blade using a rotating triaxial hot-wire probe in a rotating frame of reference. The flow-field was surveyed very close to the trailing-edge as well as inside the annulus- and hub-wall boundary layers. The large amount of data acquired during this program has been analyzed to discern the decay effects as well as the spanwise variation of three components of velocity, three components of intensities and three components of shear stresses. The data set also include extensive information on the variation of the flow properties downstream. The other derived quantities include wake momentum thickness and deviation angles at various spanwise and downstream locations. These data are presented and interpreted, with emphasis on the downstream mixing as well as endwall-wake interaction effects.

  8. Experimental investigation of unsteady fan flow interaction with downstream struts

    NASA Technical Reports Server (NTRS)

    Ng, W. F.; Obrien, W. F.; Olsen, T. L.

    1986-01-01

    In the present study of the unsteady pressure field produced on fan rotor blades by interaction with downstream struts, a single stage, low speed axial-flow fan was instrumented with blade-mounted high frequency pressure transducers. In addition, stationary pressure problems were used to map out the flowfield. Fluctuating pressure measurements are presented for blade midspan and 85-percent span on both the suction and pressure surfaces of the rotor blades at several positions of the downstream struts, and for two different flow coefficients. The strut is found to produce an effect on the unsteady pressure field on the rotor blades; this effect exceeds that due to the stator at design rotor-stator-strut spacing, but it rapidly declines as the struts are moved downstream.

  9. Critical effects of downstream boundary conditions on vortex breakdown

    NASA Technical Reports Server (NTRS)

    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.

  10. Interaction of fan rotor flow with downstream struts

    NASA Technical Reports Server (NTRS)

    Obrien, W. F., Jr.; Reimers, S. L.; Richardson, S. W.

    1983-01-01

    The detailed unsteady pressure field produced on the rotor blades of an axial-flow fan by interaction with downstream struts was investigated. The experimental arrangement was similar to that found in the fan casings of turbofan aircraft engines. Acoustically significant pressure fluctuations were measured on both thy suction and pressure sides of the rotor blades for several positions of the downstream struts. The level of the observed interaction decreased with increased spacing of the struts behind the rotor. An inviscid flow analysis for the disturbance level is compared with trends of the measured results.

  11. Transition duct with divided upstream and downstream portions

    SciTech Connect

    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.

  12. Laminar flow heat transfer downstream from U-bends

    NASA Astrophysics Data System (ADS)

    Abdelmessih, Amanie Nassif

    1987-05-01

    The laminar flow heat transfer downstream from the unheated, vertical bends in horizontal U-tubes with electrically heated straight tube sections was investigated. For each test section, local axial and peripheral wall temperatures were measured and the local peripheral heat transfer coefficients at the various locations were calculated. The investigation permitted a better understanding of the interaction of the primary, secondary and tertiary flow patterns, i.e., the combination of forced and natural convection with the centrifugal effects. Also, a correlation was developed, which predicts the heat transfer coefficient downstream from an unheated U-bend, and which can be extended to straight tubes.

  13. Microbial Sulfate Reduction Enhances Arsenic Mobility Downstream of Zerovalent-Iron-Based Permeable Reactive Barrier.

    PubMed

    Kumar, Naresh; Couture, Raoul-Marie; Millot, Romain; Battaglia-Brunet, Fabienne; Rose, Jérôme

    2016-07-19

    We assessed the potential of zerovalent-iron- (Fe(0)) based permeable reactive barrier (PRB) systems for arsenic (As) remediation in the presence or absence of microbial sulfate reduction. We conducted long-term (200 day) flow-through column experiments to investigate the mechanisms of As transformation and mobility in aquifer sediment (in particular, the PRB downstream linkage). Changes in As speciation in the aqueous phase were monitored continuously. Speciation in the solid phase was determined at the end of the experiment using X-ray absorption near-edge structure (XANES) spectroscopy analysis. We identified thio-As species in solution and AsS in solid phase, which suggests that the As(V) was reduced to As(III) and precipitated as AsS under sulfate-reducing conditions and remained as As(V) under abiotic conditions, even with low redox potential and high Fe(II) content (4.5 mM). Our results suggest that the microbial sulfate reduction plays a key role in the mobilization of As from Fe-rich aquifer sediment under anoxic conditions. Furthermore, they illustrate that the upstream-downstream linkage of PRB affects the speciation and mobility of As in downstream aquifer sediment, where up to 47% of total As initially present in the sediment was leached out in the form of mobile thio-As species. PMID:27309856

  14. 10 Suggestions for Enhancing Lecturing

    ERIC Educational Resources Information Center

    Heitzmann, Ray

    2010-01-01

    Criticism of the lecture method remains a staple of discussion and writing in academia--and most of the time it's deserved! Those interested in improving this aspect of their teaching might wish to consider some or all of the following suggestions for enhancing lectures. These include: (1) Lectures must start with a "grabber"; (2) Lectures must be…

  15. A MAPK cascade downstream of ERECTA receptor-like protein kinase regulates Arabidopsis inflorescence architecture by promoting localized cell proliferation.

    PubMed

    Meng, Xiangzong; Wang, Huachun; He, Yunxia; Liu, Yidong; Walker, John C; Torii, Keiko U; Zhang, Shuqun

    2012-12-01

    Spatiotemporal-specific cell proliferation and cell differentiation are critical to the formation of normal tissues, organs, and organisms. The highly coordinated cell differentiation and proliferation events illustrate the importance of cell-cell communication during growth and development. In Arabidopsis thaliana, ERECTA (ER), a receptor-like protein kinase, plays important roles in promoting localized cell proliferation, which determines inflorescence architecture, organ shape, and size. However, the downstream signaling components remain unidentified. Here, we report a mitogen-activated protein kinase (MAPK; or MPK) cascade that functions downstream of ER in regulating localized cell proliferation. Similar to an er mutant, loss of function of MPK3/MPK6 or their upstream MAPK kinases (MAPKKs; or MKKs), MKK4/MKK5, resulted in shortened pedicels and clustered inflorescences. Epistasis analysis demonstrated that the gain of function of MKK4 and MKK5 transgenes could rescue the loss-of-function er mutant phenotype at both morphological and cellular levels, suggesting that the MPK3/MPK6 cascade functions downstream of the ER receptor. Furthermore, YODA (YDA), a MAPKK kinase, was shown to be upstream of MKK4/MKK5 and downstream of ER in regulating inflorescence architecture based on both gain- and loss-of-function data. Taken together, these results suggest that the YDA-MKK4/MKK5-MPK3/MPK6 cascade functions downstream of the ER receptor in regulating localized cell proliferation, which further shapes the morphology of plant organs. PMID:23263767

  16. Anthranilic Acid: A Potential Biomarker and Treatment Target for Schizophrenia

    PubMed Central

    Oxenkrug, Gregory; van der Hart, Marieke; Roeser, Julien; Summergrad, Paul

    2016-01-01

    Dysregulation of Trp-Kyn pathway is the most recent hypothesis of mechanisms of schizophrenia. In particular, over-production of kynurenic acid (KYNA), one of the three immediate downstream metabolites of kynurenine (Kyn) along tryptophan (Trp): Kyn pathway, has been considered as a new target for therapeutic intervention in schizophrenia. Up-regulation of KYNA formation was suggested to occur at the expense of down-regulated production of 3-hydroxyKyn (3-HK), the second immediate downstream metabolite of Kyn. We were interested to assess the third immediate downstream Kyn metabolite, anthranilic acid (AA). Serum AA concentrations were evaluated in schizophrenia patients and control subjects by HPLC-mass spectrometry method. We found 2-fold increase of AA and 3-fold decrease of 3-HK concentrations in serum of schizophrenia patients. Up regulated formation of AA might contribute to mechanisms of schizophrenia considering experimental evidences of AA augmentation of autoimmune processes in rat and mice; clinical findings of AA elevation in rheumatoid arthritis and type 1 diabetes, autoimmune diseases diametrical to schizophrenia; and involvement of autoimmunity in development of schizophrenia. Present data warrant further studies of AA as biological marker in, at least, a subgroup (associated with autoimmune mechanisms) of schizophrenia patients and as a new target for therapeutic intervention. PMID:27042691

  17. Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells

    PubMed Central

    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

    2015-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.04640.001 PMID:26284497

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

    USGS Publications Warehouse

    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

  19. 16. Detail, lower chord connection point on downstream side at ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    16. Detail, lower chord connection point on downstream side at end panel showing lower chord eye bars, vertical tension eye bar, original and supplemental floor beams, turnbuckled lower laterals. View to northwest. - Dry Creek Bridge, Spanning Dry Creek at Cook Road, Ione, Amador County, CA

  20. 1. LOOKING DOWNSTREAM (NORTHEAST) ALONG WINTER'S RUN TOWARD THE MITCHELL'S ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. LOOKING DOWNSTREAM (NORTHEAST) ALONG WINTER'S RUN TOWARD THE MITCHELL'S MILL BRIDGE, SHOWING THE SETTING OF THE BRIDGE. CARRS MILL ROAD APPROACHES THE BRIDGE FROM THE SOUTH, ON THE RIGHT. - Mitchell's Mill Bridge, Spanning Winter's Run on Carrs Mill Road, west of Bel Air, Bel Air, Harford County, MD

  1. Modeling downstream fining in sand-bed rivers. II: Application

    USGS Publications Warehouse

    Wright, S.; Parker, G.

    2005-01-01

    In this paper the model presented in the companion paper, Wright and Parker (2005) is applied to a generic river reach typical of a large, sand-bed river flowing into the ocean in order to investigate the mechanisms controlling longitudinal profile development and downstream fining. Three mechanisms which drive downstream fining are studied: a delta prograding into standing water, sea-level rise, and tectonic subsidence. Various rates of sea-level rise (typical of the late Holocene) and tectonic subsidence are modeled in order to quantify their effects on the degree of profile concavity and downstream fining. Also, several other physical mechanisms which may affect fining are studied, including the relative importance of the suspended versus bed load, the effect of the loss of sediment overbank, and the influence of the delta bottom slope. Finally, sensitivity analysis is used to show that the grain-size distribution at the interface between the active layer and substrate has a significant effect on downstream fining. ?? 2005 International Association of Hydraulic Engineering and Research.

  2. 1. CONTEXTUAL VIEW, LOOKING DOWNSTREAM (NORTHERLY) OF THE CONCRETE ARCH ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. CONTEXTUAL VIEW, LOOKING DOWNSTREAM (NORTHERLY) OF THE CONCRETE ARCH ('ONE-WAY BRIDGE') THAT PROVIDES PRIVATE (WWP) ACCESS TO THE MIDDLE CHANNEL OF THE POST FALLS POWER PLANT. - Washington Water Power Company Post Falls Power Plant, Concrete Arch Bridge, West of intersection of Spokane & Fourth Streets, Post Falls, Kootenai County, ID

  3. 1. CONTEXTUAL VIEW OF THE POST FALLS POWERHOUSE LOOKING DOWNSTREAM. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. CONTEXTUAL VIEW OF THE POST FALLS POWERHOUSE LOOKING DOWNSTREAM. POWER PLANT AND INTAKE GATES ARE IN THE LEFT FOREGROUND, AND THE ATTACHED 'OLD SWITCHING BUILDING' (NOW ABANDONED) IS IN THE RIGHT BACKGROUND, LOOKING NORTHWEST. - Washington Water Power Company Post Falls Power Plant, Middle Channel Powerhouse & Dam, West of intersection of Spokane & Fourth Streets, Post Falls, Kootenai County, ID

  4. 1. CONTEXTUAL VIEW FROM DOWNSTREAM OF BRIDGE IN ITS SETTING, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. CONTEXTUAL VIEW FROM DOWNSTREAM OF BRIDGE IN ITS SETTING, LOOKING NORTH-NORTHEAST FROM PIONEER BRIDGE (BUSINESS ROUTE 80). CAPITOL BANK OF COMMERCE BUILDING IS AT EXTREME RIGHT. - Sacramento River Bridge, Spanning Sacramento River at California State Highway 275, Sacramento, Sacramento County, CA

  5. 1. GENERAL EXTERIOR VIEW LOOKING SOUTHWEST, SHOWING DOWNSTREAM END OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. GENERAL EXTERIOR VIEW LOOKING SOUTHWEST, SHOWING DOWNSTREAM END OF NAVIGATION LOCK #1 WITH CHAMBER FILLED; THE CONTROL HOUSE IS ON RIGHT; VIEW IS TAKEN FROM ROOF OF POWERHOUSE #1. - Bonneville Project, Navigation Lock No. 1, Oregon shore of Columbia River near first Powerhouse, Bonneville, Multnomah County, OR

  6. 8. Chandler Falls, looking downstream, and downhill from the edge ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. Chandler Falls, looking downstream, and downhill from the edge of the mesa (from south). Penstock and foundation of the hydropower plant visible on left. Photographer: Mark Durben, February 1989. Source: SRPA - Tempe Canal, South Side Salt River in Tempe, Mesa & Phoenix, Tempe, Maricopa County, AZ

  7. 6. VIEW SOUTHWEST OF DOWNSTREAM FACE OF DAM WITH SPILLWAY ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. VIEW SOUTHWEST OF DOWNSTREAM FACE OF DAM WITH SPILLWAY SECTION TO LEFT AND NON-OVERFLOW SECTION TO RIGHT - Middle Creek Hydroelectric Dam, On Middle Creek, West of U.S. Route 15, 3 miles South of Selinsgrove, Selinsgrove, Snyder County, PA

  8. 9. OBLIQUE OF DOWNSTREAM SIDE OF BRIDGE, LOOKING EAST FROM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    9. OBLIQUE OF DOWNSTREAM SIDE OF BRIDGE, LOOKING EAST FROM YOLO COUNTY SIDE OF THE SACRAMENTO RIVER. VESSEL MOORED AT RIGHT IS DELTA KING, WHICH HAS SINCE BEEN REFURBISHED AND MOVED UPSTREAM OF BRIDGE TO PERMANENT MOORING. CAPITOL BANK OF COMMERCE BUILDING IS BEHIND VESSEL. - Sacramento River Bridge, Spanning Sacramento River at California State Highway 275, Sacramento, Sacramento County, CA

  9. 8. Detail view of downstream side, looking south. Buttresses, struttie ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. Detail view of downstream side, looking south. Buttresses, strut-tie beams, and arch-rings are shown. The white discoloration on the concrete is the result of efflorescence. - Little Rock Creek Dam, Little Rock Creek, Littlerock, Los Angeles County, CA

  10. 2. EXTERIOR VIEW OF DOWNSTREAM SIDE OF COTTAGE 191 TAKEN ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. EXTERIOR VIEW OF DOWNSTREAM SIDE OF COTTAGE 191 TAKEN FROM ROOF OF GARAGE 393. CAMERA FACING SOUTHEAST. COTTAGE 181 AND CHILDREN'S PLAY AREA VISIBLE ON EITHER SIDE OF ROOF. GRAPE ARBOR IN FOREGROUND. - Swan Falls Village, Cottage 191, Snake River, Kuna, Ada County, ID

  11. 52. THE DOWNSTREAM FACE OF ROOSEVELT DAM. THE ROOSEVELT POWER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    52. THE DOWNSTREAM FACE OF ROOSEVELT DAM. THE ROOSEVELT POWER HOUSE IS LOCATED AT THE CENTER OF THE PHOTO WITH THE TRANSFORMER HOUSE LOCATED AT THE RIGHT. THE NORTH SPILLWAY IS AT THE FAR LEFT AND SOUTH SPILLWAY AT THE FAR RIGHT Photographer: Mark Durben, 1984 - Roosevelt Power Canal & Diversion Dam, Parallels Salt River, Roosevelt, Gila County, AZ

  12. 27. A DOWNSTREAM VIEW FROM THE LOWER END OF THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    27. A DOWNSTREAM VIEW FROM THE LOWER END OF THE OUTLET CONDUIT, SHOWING STILLING BASIN BAFFLE PIERS.... Volume XVII, No. 17, November 29, 1939. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  13. 17. VIEW EASTERLY ALONG DOWNSTREAM END OF THE SPILLWAY, SHOWING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    17. VIEW EASTERLY ALONG DOWNSTREAM END OF THE SPILLWAY, SHOWING CELL WALL CONSTRUCTION IN THE CRIB CUTOFF.... Volume XX, No. 4, August 3, 1940. - Prado Dam, Spillway, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  14. 3. DOWNSTREAM AERIAL VIEW OF THE DIVERSION CHANNEL AND CONTROL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. DOWNSTREAM AERIAL VIEW OF THE DIVERSION CHANNEL AND CONTROL WORKS. THE OUTLET CONTROL TOWER AND THE PIER FOR THE SERVICE BRIDGE ARE SHOWN COMPLETED.... Volume XVIII, No. 11, January 18, 1940. - Prado Dam, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  15. 20. DOWNSTREAM VIEW OF THE INTAKE STRUCTURE, SHOWING THE SLIDE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    20. DOWNSTREAM VIEW OF THE INTAKE STRUCTURE, SHOWING THE SLIDE GATES FOR THE CONTROLLED OUTLET, IN POSITION FOR INSTALLATION.... Volume XVII, No. 15, November 13, 1939. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  16. 20. VIEW FROM DOWNSTREAM SIDE OF DAM SHOWING BUTTS OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    20. VIEW FROM DOWNSTREAM SIDE OF DAM SHOWING BUTTS OF LOGS PROJECTING BETWEEN CROSS LOGS. FREQUENTLY WHOLE TREES WERE USED IN CONSTRUCTING THESE DAMS. THE BRANCHES WERE PLACED UPSTREAM AND COVERED WITH EARTH AND STONE TO ANCHOR THEM. Photographed November 6, 1935. - Forge Creek Dam-John Cable Mill, Townsend, Blount County, TN

  17. 3. View of Potomac River looking downstream from the Great ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. View of Potomac River looking downstream from the Great Falls of the Potomac. Reduction of stream in width during low water, is clearly shown by exposed beach on left side and indisputable normal water height markings shown on right side of photograph. Mr. Horyduzak, photographer, 1943. - Potowmack Company: Great Falls Canal & Locks, Great Falls, Fairfax County, VA

  18. 13. OVERALL VIEW OF DOWNSTREAM FACE OF LIFT GATE SECTION ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    13. OVERALL VIEW OF DOWNSTREAM FACE OF LIFT GATE SECTION (FROM EDGE OF COFFERDAM) WITH BOILERHOUSE AND TAINTER GATE SECTION IN BACKGROUND TO THE RIGHT. VIEW TO SOUTHEAST. - Starved Rock Locks & Dam, Illinois Waterway River mile 231, Peru, La Salle County, IL

  19. 60. PANORAMIC VIEW OF DOWNSTREAM FACE. No date, but believed ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    60. PANORAMIC VIEW OF DOWNSTREAM FACE. No date, but believed to be just subsequent to construction. Photograph by C.G. Duffey, Long Beach, California. (38' x 11' framed print). - Little Rock Creek Dam, Little Rock Creek, Littlerock, Los Angeles County, CA

  20. 44. View of log boom (downstream) protecting fish screens at ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    44. View of log boom (downstream) protecting fish screens at Dingle Basin, looking northeast from south side of basin. Photo by Brian C. Morris, Puget Power, 1989. - Puget Sound Power & Light Company, White River Hydroelectric Project, 600 North River Avenue, Dieringer, Pierce County, WA

  1. 46. View of downstream face of fish screens at Dingle ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    46. View of downstream face of fish screens at Dingle Basin, looking southeast from north side of basin. Photo by Brian C. Morris, Puget Power, 1989. - Puget Sound Power & Light Company, White River Hydroelectric Project, 600 North River Avenue, Dieringer, Pierce County, WA

  2. 51. Photocopy of photograph, October 16, 1942. VIEW, LOOKING DOWNSTREAM, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    51. Photocopy of photograph, October 16, 1942. VIEW, LOOKING DOWNSTREAM, OF POWER HOUSE DURING FLOOD. (Courtesy of the Potomac Edison Company Library (Hagerstown, MD), Historical Data Files, Dam NO. 5 listing) - Dam No. 5 Hydroelectric Plant, On Potomac River, Hedgesville, Berkeley County, WV

  3. 5. DETAIL OF THE DOWNSTREAM SIDE OF THE GATES SHOWING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. DETAIL OF THE DOWNSTREAM SIDE OF THE GATES SHOWING REINFORCEMENT AND THE TOP EDGE OF THE UPSTREAM MASONRY WALL OF THE HISTORIC OUTLET WORKS TAKEN FROM THE SOUTHERN EMBANKMENT. VIEW LOOKING NORTH. - Twin Lakes Dam & Outlet Works, Beneath Twin Lakes Reservoir, T11S, R80W, S22, Twin Lakes, Lake County, CO

  4. 4. DOWNSTREAM VIEW OF HISTORIC OUTLET WORKS TAKEN FROM THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. DOWNSTREAM VIEW OF HISTORIC OUTLET WORKS TAKEN FROM THE NORTH BANK OF THE CHANNEL BETWEEN THE OLD WORKS AND TWIN LAKES DAM. VIEW LOOKING WEST. - Twin Lakes Dam & Outlet Works, Beneath Twin Lakes Reservoir, T11S, R80W, S22, Twin Lakes, Lake County, CO

  5. 6. DETAIL VIEW OF THE MASONRY FACING ON THE DOWNSTREAM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. DETAIL VIEW OF THE MASONRY FACING ON THE DOWNSTREAM SIDE OF THE HISTORIC OUTLET WORKS. VIEW LOOKING NORTHEAST. - Twin Lakes Dam & Outlet Works, Beneath Twin Lakes Reservoir, T11S, R80W, S22, Twin Lakes, Lake County, CO

  6. 3. DOWNSTREAM VIEW OF HISTORIC OUTLET WORKS TAKEN FROM THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. DOWNSTREAM VIEW OF HISTORIC OUTLET WORKS TAKEN FROM THE SOUTH SIDE OF THE CHANNEL BETWEEN THE OLD WORKS AND TWIN LAKES DAM. VIEW LOOKING NORTHWEST - Twin Lakes Dam & Outlet Works, Beneath Twin Lakes Reservoir, T11S, R80W, S22, Twin Lakes, Lake County, CO

  7. View of Flume Bridge #5 from FS 502 looking downstream ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of Flume Bridge #5 from FS 502 looking downstream (south). Bridge is on the left side of the photograph. This is similar to other flume bridges in the system and is the only photograph representing these features. - Childs-Irving Hydroelectric Project, Childs System, Flume Bridge No. 5, Forest Service Road 708/502, Camp Verde, Yavapai County, AZ

  8. 1. Contextual view of bridge in setting, from downstream, view ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Contextual view of bridge in setting, from downstream, view to south from edge of bluff east of Rawson Road. Bridge visible among trees at left center. - Red Bank Creek Bridge, Spanning Red Bank Creek at Rawson Road, Red Bluff, Tehama County, CA

  9. Distant view from downstream of lock with southeast machinery house, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Distant view from downstream of lock with southeast machinery house, SF 109, and timber guide wall on left, exterior view of closed lower lock gates and hydro-electric power house and dam in background, view towards west - St. Lucie Canal, St. Lucie Lock No. 1, St. Lucie, Cross State Canal, Okeechobee Intracoastal Waterway, Stuart, Martin County, FL

  10. DESCHUTES. WICKIUP DAM OUTLET WORKS. LOOKING DOWNSTREAM THROUGH VALVE HOUSE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DESCHUTES. WICKIUP DAM OUTLET WORKS. LOOKING DOWNSTREAM THROUGH VALVE HOUSE SUNSTRUCTURE. Photocopy of historic photograph (original photograph on file at National Archives, Rocky Mountain Region, Denver, CO). Unknown USBR photographer, August 5, 1940 - Wickiup Dam, Outlet Works, Deschutes River, La Pine, Deschutes County, OR

  11. DESCHUTES. WICKIUP DAM OUTLET WORKS. LOOKING DOWNSTREAM; AFTER COMPLETION OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DESCHUTES. WICKIUP DAM OUTLET WORKS. LOOKING DOWNSTREAM; AFTER COMPLETION OF MONTAG & SONS CONTRACT. Photocopy of historic photograph (original photograph on file at National Archives, Rocky Mountain Region, Denver, CO). Unknown USBR photographer, November 24, 1940 - Wickiup Dam, Outlet Works, Deschutes River, La Pine, Deschutes County, OR

  12. DESCHUTES PROJECT VIEW OF DOWNSTREAM FACE OF WICKIUP DAM, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DESCHUTES PROJECT - VIEW OF DOWNSTREAM FACE OF WICKIUP DAM, VALVE HOUSE AND STILLING BASIN OF OUTLET WORKS. Photocopy of historic photograph (original photograph on file at National Archives, Rocky Mountain Region, Denver, CO). Unknown USBR photographer, August 31, 1943 - Wickiup Dam, Outlet Works, Deschutes River, La Pine, Deschutes County, OR

  13. DESCHUTES PROJECT – WICKIUP DAM – ROCKFILL ON DOWNSTREAM FACE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DESCHUTES PROJECT – WICKIUP DAM – ROCKFILL ON DOWNSTREAM FACE OF DAM. Photocopy of historic photographs (original photograph on file at National Archives, Rocky Mountain Region, Denver, CO). Unknown USBR Photographer, Ocotber 1, 1942 - Wickiup Dam, Deschutes River, La Pine, Deschutes County, OR

  14. View of downstream face of Grand Coulee Dam (from hillside ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of downstream face of Grand Coulee Dam (from hillside north of No. 3 Powerhouse), looking southwest. - Columbia Basin Project, Grand Coulee Dam & Franklin D. Roosevelt Lake, Across Columbia River, Southeast of Town of Grand Coulee, Grand Coulee, Grant County, WA

  15. 5. AERATOR VIEW FROM DOWNSTREAM. FLUSH VALVE AT RIGHT OPENS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. AERATOR VIEW FROM DOWNSTREAM. FLUSH VALVE AT RIGHT OPENS TO CLEAR THE SYSTEM ABOVE THE SILT AND DEBRIS AND TO STOP THE FLOW OF WATER INTO THE SYSTEM DOWN LINE. BOX FLUME CONTINUES DOWN LINE TO SEDIMENTATION CHAMBER. - Kalaupapa Water Supply System, Waikolu Valley to Kalaupapa Settlement, Island of Molokai, Kalaupapa, Kalawao County, HI

  16. 7. SEDIMENTATION CHAMBER AT 520', CONSTRUCTED 19371938, VIEWED FROM DOWNSTREAM. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. SEDIMENTATION CHAMBER AT 520', CONSTRUCTED 1937-1938, VIEWED FROM DOWNSTREAM. DEBRIS REMOVED FROM TOP PLANKS FOR CLARITY. ONE OF TWO SPILLWAYS SEEN AT RIGHT. FLUSH VALVE SEEN AT LOWER LEFT AND WRENCH FOR VALVES IS PROPPED AGAINST CHAMBER. - Kalaupapa Water Supply System, Waikolu Valley to Kalaupapa Settlement, Island of Molokai, Kalaupapa, Kalawao County, HI

  17. LOOKING DOWNSTREAM FROM KACHESS DAM CREST, 1910 RIVER CUTOFF CHANNEL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    LOOKING DOWNSTREAM FROM KACHESS DAM CREST, 1910 RIVER CUTOFF CHANNEL WITH CRIB STRUCTURE IN CENTER. BRIDGE FOOTING CRIB STRUCTURE AT RIGHT (Upstream face of Kachess Dam in foreground) - Kachess Dam, Cutoff Channel and Crib Structures, Kachess River, 1.5 miles north of Interstate 90, Easton, Kittitas County, WA

  18. 40 CFR 80.69 - Requirements for downstream oxygenate blending.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... blending. 80.69 Section 80.69 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.69 Requirements for downstream oxygenate blending. The requirements of this section apply to all reformulated gasoline...

  19. 40 CFR 80.69 - Requirements for downstream oxygenate blending.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... blending. 80.69 Section 80.69 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.69 Requirements for downstream oxygenate blending. The requirements of this section apply to all reformulated gasoline...

  20. 40 CFR 80.69 - Requirements for downstream oxygenate blending.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... blending. 80.69 Section 80.69 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.69 Requirements for downstream oxygenate blending. The requirements of this section apply to all reformulated gasoline...

  1. 8. View of gabeon west wall added downstream from the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. View of gabeon west wall added downstream from the lower dam. Photograph taken from east side of Millstone Creek. VIEW SOUTH - Loleta Recreation Area, Lower Dam, 6 miles Southeast of interesection of State Route 24041 & State Route 66, Loleta, Elk County, PA

  2. 4. VIEW OF DOWNSTREAM FACE OF DAM, WITH SCARS FROM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. VIEW OF DOWNSTREAM FACE OF DAM, WITH SCARS FROM EARTH MOVING TO CONSTRUCT DAM IN FOREGROUND, LOOKING NORTHWEST - High Mountain Dams in Upalco Unit, Five Point Lake Dam, Ashley National Forest, 12 miles Northwest of Swift Creek Campground, Mountain Home, Duchesne County, UT

  3. 14. DETAIL EXTERIOR VIEW LOOKING EAST AT DOWNSTREAM SIDE OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. DETAIL EXTERIOR VIEW LOOKING EAST AT DOWNSTREAM SIDE OF NORTH END OF DAM/SPILLWAY; GANTRY CRANE ABOVE MOVABLE STONEY GATE IS VISIBLE IN CENTER BACKGROUND; FISH LADDER ON WASHINGTON SHORE IS VISIBLE IN FOREGROUND. - Bonneville Project, Bonneville Dam, Columbia River, Bonneville, Multnomah County, OR

  4. 5. Downstream elevation, view to southeast. Dark stains on side ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. Downstream elevation, view to southeast. Dark stains on side of main girder are from deck drain scuppers, marking deck level within the girders. Compare this view and CA-126-7 to CA-126-19 for indication of severity of siltation of Salt River channel has silted. - Salt River Bridge, Spanning Salt River at Dillon Road, Ferndale, Humboldt County, CA

  5. 23. The Salt River, downstream, from atop Mormon Flat Dam. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    23. The Salt River, downstream, from atop Mormon Flat Dam. HEFU generator deck is at center bottom. Photographer Mark Durben, 1988. Source: Salt River Project. - Mormon Flat Dam, On Salt River, Eastern Maricopa County, east of Phoenix, Phoenix, Maricopa County, AZ

  6. 2. View from the Minnesota bank looking downstream (northnorthwest) at ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. View from the Minnesota bank looking downstream (north-northwest) at bridge's southwest elevation; the bridge approach is missing - Enloe Bridge No. 90021, Spanning Red River of North between Minnesota & North Dakota on County State Aid Highway 28, Wolverton, Wilkin County, MN

  7. 59. Downstream view of Waddell Dam showing buttress ties, crane, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    59. Downstream view of Waddell Dam showing buttress ties, crane, housing over penstock outlet (left) and storage building (right). Photographer Mark Durben, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  8. 53. Humbug Creek looking downstream from Humbug Diversion Dam. Retaining ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    53. Humbug Creek looking downstream from Humbug Diversion Dam. Retaining wall for canal is visible beginning at left center. Photographer James Eastwood, 1986. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  9. 71. Close up view of downstream view of four large ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    71. Close up view of downstream view of four large taintor gates and section for sector gate (now removed). Photographer Mark Durben. Source: Salt River Project. - Waddell Dam, On Agua Fria River, 35 miles northwest of Phoenix, Phoenix, Maricopa County, AZ

  10. 12. Close up view of construction on the downstream face. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. Close up view of construction on the downstream face. Track at lower center conveyed aggregate from the stream bed to the mixing plant. Photographer unknown, October 15, 1924. Source: Salt River Project. - Mormon Flat Dam, On Salt River, Eastern Maricopa County, east of Phoenix, Phoenix, Maricopa County, AZ

  11. 1. FITZ WATERWHEEL IN DOWNSTREAM LOCATION SHOWING ELEVATED HEADRACE AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. FITZ WATERWHEEL IN DOWNSTREAM LOCATION SHOWING ELEVATED HEADRACE AND ENDLESS-WIRE POWER TRANSMISSION TO MILL. LOOKING SOUTH. Photocopied July 1972 from photograph owned by Silas Starry, c. 1735 - Thomas Shepherd's Grist Mill, High Street Vicinity, Shepherdstown, Jefferson County, WV

  12. 2. WINTER VIEW OF WATERWHEEL IN DOWNSTREAM LOCATION SHOWING ELEVATED ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. WINTER VIEW OF WATERWHEEL IN DOWNSTREAM LOCATION SHOWING ELEVATED HEADRACE AND ENDLESS-WIRE POWER TRANSMISSION TO MILL Photocopied July 1972 from photograph owned by Silas Starry, c. 1735 - Thomas Shepherd's Grist Mill, High Street Vicinity, Shepherdstown, Jefferson County, WV

  13. VIEW OF DOWNSTREAM SIDE OF CHECK DAM, CONCRETE SPILLWAY WITH ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF DOWNSTREAM SIDE OF CHECK DAM, CONCRETE SPILLWAY WITH MORTARED ROCK WALLS, AND CIPPOLETTI WEIR ON TUMALO RESERVOIR FEED CANAL NEAR COLLINS ROAD (IN BACKGROUND). LOOKING NORTHEAST - Tumalo Irrigation District, Tumalo Project, West of Deschutes River, Tumalo, Deschutes County, OR

  14. Downstream-migrating fluvial point bars in the rock record

    NASA Astrophysics Data System (ADS)

    Ghinassi, Massimiliano; Ielpi, Alessandro; Aldinucci, Mauro; Fustic, Milovan

    2016-04-01

    Classical models developed for ancient fluvial point bars are based on the assumption that meander bends invariably increase their radius as meander-bend apices migrate in a direction transverse to the channel-belt axis (i.e., meander bend expansion). However, many modern meandering rivers are also characterized by down-valley migration of the bend apex, a mechanism that takes place without a significant change in meander radius and wavelength. Downstream-migrating fluvial point bars (DMFPB) are the dominant architectural element of these types of meander belts. Yet they are poorly known from ancient fluvial-channel belts, since their disambiguation from expansional point bars often requires fully-3D perspectives. This study aims to review DMFPB deposits spanning in age from Devonian to Holocene, and to discuss their main architectural and sedimentological features from published outcrop, borehole and 3D-seismic datasets. Fluvial successions hosting DMFPB mainly accumulated in low accommodation conditions, where channel belts were affected by different degrees of morphological (e.g., valleys) or tectonic (e.g., axial drainage of shortening basins) confinement. In confined settings, bends migrate downstream along the erosion-resistant valley flanks and little or no floodplain deposits are preserved. Progressive floor aggradation (e.g., valley filling) allow meander belts with DMFPB to decrease their degree of confinement. In less confined settings, meander bends migrate downstream mainly after impinging against older, erosion-resistant channel fill mud. By contrast, tectonic confinement is commonly associated with uplifted alluvial plains that prevented meander-bend expansion, in turn triggering downstream translation. At the scale of individual point bars, translational morphodynamics promote the preservation of downstream-bar deposits, whereas the coarser-grained upstream and central beds are less frequently preserved. However, enhanced preservation of upstream

  15. Methylation of Hg downstream from the Bonanza Hg mine, Oregon

    USGS Publications Warehouse

    Gray, John E.; Hines, Mark E.; Krabbenhoft, David P.; Thoms, Bryn

    2012-01-01

    Speciation of Hg and conversion to methyl-Hg were evaluated in stream sediment, stream water, and aquatic snails collected downstream from the Bonanza Hg mine, Oregon. Total production from the Bonanza mine was >1360t of Hg, during mining from the late 1800s to 1960, ranking it as an intermediate sized Hg mine on an international scale. The primary objective of this study was to evaluate the distribution, transport, and methylation of Hg downstream from a Hg mine in a coastal temperate climatic zone. Data shown here for methyl-Hg, a neurotoxin hazardous to humans, are the first reported for sediment and water from this area. Stream sediment collected from Foster Creek flowing downstream from the Bonanza mine contained elevated Hg concentrations that ranged from 590 to 71,000ng/g, all of which (except the most distal sample) exceeded the probable effect concentration (PEC) of 1060ng/g, the Hg concentration above which harmful effects are likely to be observed in sediment-dwelling organisms. Concentrations of methyl-Hg in stream sediment collected from Foster Creek varied from 11 to 62ng/g and were highly elevated compared to regional baseline concentrations (0.11-0.82ng/g) established in this study. Methyl-Hg concentrations in stream sediment collected in this study showed a significant correlation with total organic C (TOC, R2=0.62), generally indicating increased methyl-Hg formation with increasing TOC in sediment. Isotopic-tracer methods indicated that several samples of Foster Creek sediment exhibited high rates of Hg-methylation. Concentrations of Hg in water collected downstream from the mine varied from 17 to 270ng/L and were also elevated compared to baselines, but all were below the 770ng/L Hg standard recommended by the USEPA to protect against chronic effects to aquatic wildlife. Concentrations of methyl-Hg in the water collected from Foster Creek ranged from 0.17 to 1.8ng/L, which were elevated compared to regional baseline sites upstream and downstream

  16. The Role of Headwater Streams in Downstream Water Quality1

    PubMed Central

    Alexander, Richard B; Boyer, Elizabeth W; Smith, Richard A; Schwarz, Gregory E; Moore, Richard B

    2007-01-01

    Knowledge of headwater influences on the water-quality and flow conditions of downstream waters is essential to water-resource management at all governmental levels; this includes recent court decisions on the jurisdiction of the Federal Clean Water Act (CWA) over upland areas that contribute to larger downstream water bodies. We review current watershed research and use a water-quality model to investigate headwater influences on downstream receiving waters. Our evaluations demonstrate the intrinsic connections of headwaters to landscape processes and downstream waters through their influence on the supply, transport, and fate of water and solutes in watersheds. Hydrological processes in headwater catchments control the recharge of subsurface water stores, flow paths, and residence times of water throughout landscapes. The dynamic coupling of hydrological and biogeochemical processes in upland streams further controls the chemical form, timing, and longitudinal distances of solute transport to downstream waters. We apply the spatially explicit, mass-balance watershed model SPARROW to consider transport and transformations of water and nutrients throughout stream networks in the northeastern United States. We simulate fluxes of nitrogen, a primary nutrient that is a water-quality concern for acidification of streams and lakes and eutrophication of coastal waters, and refine the model structure to include literature observations of nitrogen removal in streams and lakes. We quantify nitrogen transport from headwaters to downstream navigable waters, where headwaters are defined within the model as first-order, perennial streams that include flow and nitrogen contributions from smaller, intermittent and ephemeral streams. We find that first-order headwaters contribute approximately 70% of the mean-annual water volume and 65% of the nitrogen flux in second-order streams. Their contributions to mean water volume and nitrogen flux decline only marginally to about 55% and

  17. Detecting floodplain inundation based on the upstream-downstream relationship

    NASA Astrophysics Data System (ADS)

    Zhao, Tongtiegang; Shao, Quanxi

    2015-11-01

    The rise in river stage (water depth) can lead to disastrous floodplain inundation. On the basis of hydraulic simulation data, this study proposes novel data-analytical methods to infer the threshold river stage and detect floodplain inundation. A quasi-Muskingum model is derived from the classical Muskingum model to characterise the relationship between upstream and downstream river stages. Based on this model, F-test and modified Akaike information criterion AICc are introduced to test if there is a change of the upstream-downstream relationship. Furthermore, a bootstrap-based calibration-validation experiment is set up to evaluate the performance of the quasi-Muskingum model. The proposed methods are applied to a case study of the 1991 and 2001 floods in the Flinders and Norman Rivers in Northern Australia. The results show that floodplain inundation does change the upstream-downstream relationship as it drastically alters the stage-discharge relationship. To combine the quasi-Muskingum model with F-test and AICc facilitates an efficient approach to detect the change and infer the threshold river stage. The analytical testing is in concert with visual examination - the time when the river stage becomes higher than the detected threshold coincides with the beginning of floodplain inundation. Despite the change, the quasi-Muskingum model effectively captures the upstream-downstream relationship and requires a small number of samples in calibration. This study highlights the effectiveness of the data-analytical methods in dealing with the change of the upstream-downstream relationship.

  18. Suggestions for Popularizing Civil Aviation

    NASA Technical Reports Server (NTRS)

    1926-01-01

    The public generally is taking very little interest in the progress of Civil Aviation, and the time has come to educate the public in aeronautics and to make them realize the far-reaching importance of air transport. Briefly, the whole problem resolves itself into discovering and applying means for bringing some of the many aspects and effects of civil aviation into the everyday lives of the public. The report suggests three principal groups of methods: (1) Bring aviation into daily contact with the public. (2) Bring the public into daily contact with aviation. (3) General publicity.

  19. ED-based screening programs for hepatitis C (HCV) highlight significant opportunity to identify patients, prevent downstream costs/complications.

    PubMed

    2014-01-01

    New data suggest there is a huge opportunity for EDs to identify patients with the hepatitis C virus (HCV) and link them into care before downstream complications lead to higher medical costs and adverse outcomes. Early results from a pilot study at the University of Alabama Medical Center in Birmingham show that at least 12% of the targeted baby boomer population being screened for HCV in the ED is testing positive for HCV, with confirmatory tests showing that about 9% of the screened population is infected with the disease. Both the Centers for Disease Control in Atlanta and the US Preventive Services Task Force recommend one-time HCV screening for patients who were born between 1945 and 1965. Public health experts say 75% of HCV infections occur in patients born during the baby boomer years, and that roughly half of them are unaware of their HCV status. Researchers at UAB report that so many patients are testing positive for HCV that demand for care can quickly overwhelm the health system if new primary care/specialty resources are not identified. Administrators of ED-based HCV screening programs in both Birmingham and Houston note that EDs with existing screening programs for HIV should have the easiest time implementing HCV screening. They also stress that patients are more accepting of HCV screening, and that the counseling process is easier. PMID:24432549

  20. miR-326 Is Downstream of Sonic Hedgehog Signaling and Regulates the Expression of Gli2 and Smoothened

    PubMed Central

    Jiang, Zhihua; Cushing, Leah; Lü, Jining

    2014-01-01

    Sonic hedgehog (Shh) is expressed and secreted from the embryonic lung epithelium and acts on the adjacent mesenchymal cells via its receptor Patched (Ptch)/Smoothened (Smo) and transcriptional effectors Gli proteins. Genetic studies showed that the Shh pathway plays critical roles in mouse lung development. However, little is known about microRNAs (miRNAs) downstream of Shh in embryonic lungs. Here we profiled miRNAs in embryonic lung cultures treated with cyclopamine, a specific Smo antagonist or with Smo agonist by next-generation of sequencing. We then performed functional screening to examine whether some of these miRNAs can modulate the induction of Gli-responsive luciferase by Shh treatment. These analyses revealed that expression of miR-326 and its host gene, Arrestin β1, is selectively enriched in embryonic lung mesenchymal cells and is specifically influenced by Shh activity. Furthermore, functional analyses showed that miR-326 acts as a negative modulator for Shh signaling by directly targeting Smo and Gli2. Together, these findings suggest a novel miR-326–negative feedback loop in regulating the activity of Shh signaling. PMID:24617895

  1. miR-326 is downstream of Sonic hedgehog signaling and regulates the expression of Gli2 and smoothened.

    PubMed

    Jiang, Zhihua; Cushing, Leah; Ai, Xingbin; Lü, Jining

    2014-08-01

    Sonic hedgehog (Shh) is expressed and secreted from the embryonic lung epithelium and acts on the adjacent mesenchymal cells via its receptor Patched (Ptch)/Smoothened (Smo) and transcriptional effectors Gli proteins. Genetic studies showed that the Shh pathway plays critical roles in mouse lung development. However, little is known about microRNAs (miRNAs) downstream of Shh in embryonic lungs. Here we profiled miRNAs in embryonic lung cultures treated with cyclopamine, a specific Smo antagonist or with Smo agonist by next-generation of sequencing. We then performed functional screening to examine whether some of these miRNAs can modulate the induction of Gli-responsive luciferase by Shh treatment. These analyses revealed that expression of miR-326 and its host gene, Arrestin β1, is selectively enriched in embryonic lung mesenchymal cells and is specifically influenced by Shh activity. Furthermore, functional analyses showed that miR-326 acts as a negative modulator for Shh signaling by directly targeting Smo and Gli2. Together, these findings suggest a novel miR-326-negative feedback loop in regulating the activity of Shh signaling. PMID:24617895

  2. Revision of Suggested State Regulations.

    PubMed

    Winston, John P

    2016-02-01

    It is the mission of the Conference of Radiation Control Program Directors (CRCPD) to promote radiological health in all aspects and phases of implementation and to create a seamless and coherent regulatory structure across the United States. CRCPD currently has 25 committees charged with the development of Suggested State Regulations (SSRs) for everything from transportation and waste disposal to tanning and medical therapy. The SR-F Committee is responsible for the suggested regulations of the equipment and processes used in medical diagnostic and interventional x-ray procedures. Several states are required by law to adopt the SSR verbatim, making it vital that they are kept current. The current revision of SR-F brought together representatives from the state radiation control programs, the Food and Drug Administration, the American Association of Physicists in Medicine, American College of Radiology, and industry. Through the course of two meetings and multiple conference calls, the Committee finalized an updated draft. The CRCPD process for the development of SSR is well established and includes internal and external peer review, review by the state Director Members, approval by the Board of Directors, and concurrence from relevant federal agencies. Once final, an SSR allows a state radiation control program to proceed through the state's own regulatory process with a vetted set of regulations, making this difficult process more efficient and effective. PMID:26717174

  3. Enhanced diamagnetic perturbations and electric currents observed downstream of the high power helicon

    NASA Astrophysics Data System (ADS)

    Roberson, B. Race; Winglee, Robert; Prager, James

    2011-05-01

    The high power helicon (HPH) is capable of producing a high density plasma (1017-1018 m-3) and directed ion energies greater than 20 eV that continue to increase tens of centimeters downstream of the thruster. In order to understand the coupling mechanism between the helicon antenna and the plasma outside the immediate source region, measurements were made in the plasma plume downstream from the thruster of the propagating wave magnetic field and the perturbation of the axial bulk field using a type `R' helicon antenna. This magnetic field perturbation (ΔB) peaks at more than 15 G in strength downstream of the plasma source, and is 3-5 times larger than those previously reported from HPH. Taking the curl of this measured magnetic perturbation and assuming azimuthal symmetry suggests that this magnetic field is generated by a (predominantly) azimuthal current ring with a current density on the order of tens of kA m-2. At this current density the diamagnetic field is intense enough to cancel out the B0 axial magnetic field near the source region. The presence of the diamagnetic current is important as it demonstrates modification of the vacuum fields well beyond the source region and signifies the presence of a high density, collimated plasma stream. This diamagnetic current also modifies the propagation of the helicon wave, which facilitates a better understanding of coupling between the helicon wave and the resultant plasma acceleration.

  4. Transport of perfluoroalkyl substances (PFAS) from an arctic glacier to downstream locations: implications for sources.

    PubMed

    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. PMID:23376515

  5. Acoustical interaction between vibrating lips, downstream air column, and upstream airways in trombone performance.

    PubMed

    Fréour, Vincent; Scavone, Gary P

    2013-11-01

    This paper presents experimental results on the acoustical influence of the vocal tract in trombone performance. The experimental approach makes use of measurements at the interface between the player and instrument, allowing a relative comparison between upstream airways and the downstream air column impedances, as well as an estimation of the phase of the impedance of the upstream and downstream systems. Measurements were conducted over the full traditional range of playing, during sustained tones with varying dynamic, as well as in special effects such as pitch bending. Subjects able to play over the full range demonstrated significant upstream influence in the higher register of the instrument. These players were categorized in two groups according to their ability to control the phase of the upstream impedance and their ability to generate powerful downstream acoustic energy. Sustained tones played with varying dynamics showed a general tendency of a decrease in vocal-tract support with increase in loudness. Although pitch bends did not involve significant upstream influence at f0, results suggest modification of the lip behavior during bending. Vocal-tract tuning at tone transitions was also investigated and found to potentially contribute to slur articulations. PMID:24180797

  6. Enhanced diamagnetic perturbations and electric currents observed downstream of the high power helicon

    SciTech Connect

    Roberson, B. Race; Winglee, Robert; Prager, James

    2011-05-15

    The high power helicon (HPH) is capable of producing a high density plasma (10{sup 17}-10{sup 18} m{sup -3}) and directed ion energies greater than 20 eV that continue to increase tens of centimeters downstream of the thruster. In order to understand the coupling mechanism between the helicon antenna and the plasma outside the immediate source region, measurements were made in the plasma plume downstream from the thruster of the propagating wave magnetic field and the perturbation of the axial bulk field using a type 'R' helicon antenna. This magnetic field perturbation ({Delta}B) peaks at more than 15 G in strength downstream of the plasma source, and is 3-5 times larger than those previously reported from HPH. Taking the curl of this measured magnetic perturbation and assuming azimuthal symmetry suggests that this magnetic field is generated by a (predominantly) azimuthal current ring with a current density on the order of tens of kA m{sup -2}. At this current density the diamagnetic field is intense enough to cancel out the B{sub 0} axial magnetic field near the source region. The presence of the diamagnetic current is important as it demonstrates modification of the vacuum fields well beyond the source region and signifies the presence of a high density, collimated plasma stream. This diamagnetic current also modifies the propagation of the helicon wave, which facilitates a better understanding of coupling between the helicon wave and the resultant plasma acceleration.

  7. Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth-suppressor gene

    PubMed Central

    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 (P<0.05), while phytosterols significantly induced growth-suppression (P<0.05) and apoptosis. Cell cycle analysis showed that contrary to cholesterol, phytosterols 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

  8. Formation of inversely graded, downstream-dipping, low-angle cross-stratification by antidunes

    SciTech Connect

    Clifton, T.R.

    1987-05-01

    Antidunes migrating upstream during aggradation produce a distinctive internal structure that results from the upstream climb of the bed form. This structure differs markedly from the upstream-dipping foresets usually ascribed to antidunes. Most studies on antidune internal structures focus on equilibrium conditions where there is no net deposition and preservation potential of structures is limited. Experiments where aggradation was induced in small coastal streams show that upstream-climbing antidunes produce low-angle, downstream-dipping, cross-stratification 1-10 mm thick. The stratification results from grain size and density segregation between the antidune trough and crest. Studies show that small, dense grains form a lag in the antidune trough while coarser, less-dense grains accumulate at the crest. The grain segregation causes inverse grading within the stratification as the antidune body and crest pass over the finer grained lag in the trough. Upstream-dipping foresets are not commonly formed by this process as there is no avalanching of grains over the bed form. Temporal variations in flow velocity may produce upstream-dipping foresets bounded by the downstream-dipping cross-stratification, but these features are subtle. The studies above suggest that antidune cross-stratification may be more common in fluvial deposits than previously thought. Deposits along the Toutle River in southern Washington show numerous examples of inversely graded, downstream-dipping, low-angle (up to 15) cross-stratification 1-5 cm thick, quite similar to antidune cross-stratification produced experimentally. Local upstream-dipping cross-stratification bounded by the downstream-dipping strata strengthens the interpretation.

  9. Osa-containing Brahma chromatin remodeling complexes are required for the repression of Wingless target genes

    PubMed Central

    Collins, Russell T.; Treisman, Jessica E.

    2000-01-01

    The Wingless signaling pathway directs many developmental processes in Drosophila by regulating the expression of specific downstream target genes. We report here that the product of the trithorax group gene osa is required to repress such genes in the absence of the Wingless signal. The Wingless-regulated genes nubbin, Distal-less, and decapentaplegic and a minimal enhancer from the Ultrabithorax gene are misexpressed in osa mutants and repressed by ectopic Osa. Osa-mediated repression occurs downstream of the up-regulation of Armadillo but is sensitive both to the relative levels of activating Armadillo/Pangolin and repressing Groucho/Pangolin complexes present and to the responsiveness of the promoter to Wingless. Osa functions as a component of the Brahma chromatin-remodeling complex; other components of this complex are likewise required to repress Wingless target genes. These results suggest that altering the conformation of chromatin is an important mechanism by which Wingless signaling activates gene expression. PMID:11124806

  10. Building false memories without suggestions.

    PubMed

    Foster, Jeffrey L; Garry, Maryanne

    2012-01-01

    People can come to remember doing things they have never done. The question we asked in this study is whether people can systematically come to remember performing actions they never really did, in the absence of any suggestion from the experimenter. People built LEGO vehicles, performing some steps but not others. For half the people, all the pieces needed to assemble each vehicle were laid out in order in front of them while they did the building; for the other half, the pieces were hidden from view. The next day, everyone returned for a surprise recognition test. People falsely and confidently remembered having carried out steps they did not; those who saw all the pieces while they built each vehicle were more likely to correctly remember performing steps they did perform but equally likely to falsely remember performing steps they did not. We explain our results using the source monitoring framework: People used the relationships between actions to internally generate the missing, related actions, later mistaking that information for genuine experience. PMID:22774684

  11. Further study of the effect of the downstream plasma condition on accelerator grid erosion in an ion thruster

    NASA Technical Reports Server (NTRS)

    Peng, Xiaohang; Ruyten, Wilhelmus M.; Keefer, Dennis

    1992-01-01

    Further numerical results are presented of earlier particle-in-cell/Monte Carlo calculations of accelerator grid erosion in an ion thruster. A comparison between numerical and experimental results suggests that the accelerator grid impingement is primarily due to ions created far downstream from the accelerator grid. In particular, for the same experimental conditions as those of Monheiser and Wilbur at Colorado State University, it is found that a downstream plasma density of 2 x 10 exp 14/cu m is required to give the same ratio of accelerator grid impingement current to beam current (5 percent). For this condition, a potential hill is found in the downstream region of 2.5 V.

  12. Spatial Response of Epilithic Diatom Communities to Downstream Nutrient Increases.

    PubMed

    Schuch, Marilia; Oliveira, Maria Angelica; Lobo, Eduardo A

    2015-06-01

    To monitor water quality and investigate relationships between downstream nutrient increases and diatom communities in the Pardo River Basin, Brazil, water and diatom samples were collected between 2005 and 2009. There were significant differences in diatom community composition among all river zones, with the greatest differences found between the upper and lower reaches. Significant changes were detected in relative abundances of diatom species and spatial structuring was evident. Dissolved oxygen, phosphates, turbidity, Eicherichia coli, and total dissolved solids were the most important variables shaping diatom communities, characterizing an organic pollution and eutrophication gradient. However, the hypothesis of sensitive species prevailing upstream and their gradual downstream replacement for more tolerant species was not confirmed because shifts in relative abundances of the same group of species in both the upper and lower reaches of the rivers were identified. PMID:26459823

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

    SciTech Connect

    Wensing, Lislaine A.; Campos, Alexandre H.

    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)

  14. Identification of Tox chromatin binding properties and downstream targets by DamID-Seq.

    PubMed

    de Jesus Domingues, António Miguel; Artegiani, Benedetta; Dahl, Andreas; Calegari, Federico

    2016-03-01

    In recent years, DNA adenine methyltransferase identification (DamID) has emerged as a powerful tool to profile protein-DNA interaction on a genome-wide scale. While DamID has been primarily combined with microarray analyses, which limits the spatial resolution and full potential of this technique, our group was the first to combine DamID with sequencing (DamID-Seq) for characterizing the binding loci and properties of a transcription factor (Tox) (sequencing data available at NCBI's Gene Expression Omnibus under the accession number GSE64240). Our approach was based on the combination and optimization of several bioinformatics tools that are here described in detail. Analysis of Tox proximity to transcriptional start sites, profiling on enhancers and binding motif has allowed us to identify this transcription factor as an important new regulator of neural stem cells differentiation and newborn neurons maturation during mouse cortical development. Here we provide a valuable resource to study the role of Tox as a novel key determinant of mammalian somatic stem cells during development of the nervous and lymphatic system, in which this factor is known to be active, and describe a useful pipeline to perform DamID-Seq analyses for any other transcription factor. PMID:26981424

  15. Fn14, a Downstream Target of the TGF-β Signaling Pathway, Regulates Fibroblast Activation

    PubMed Central

    Yang, Min; Lai, Wen; Ye, Litong; Chen, Jing; Hou, Xinghua; Ding, Hong; Zhang, Wenwei; Wu, Yueheng; Liu, Xiaoying; Huang, Shufang; Yu, Xiyong; Xiao, Dingzhang

    2015-01-01

    Fibrosis, the hallmark of human injuries and diseases such as serious burns, is characterized by excessive collagen synthesis and myofibroblast accumulation. Transforming growth factor-β (TGF-β), a potent inducer of collagen synthesis, has been implicated in fibrosis in animals. In addition to TGF-β, fibroblast growth factor-inducible molecule 14 (Fn14) has been reported to play an important role in fibrotic diseases, such as cardiac fibrosis. However, the function and detailed regulatory mechanism of Fn14 in fibrosis are unclear. Here, we investigated the effect of Fn14 on the activation of human dermal fibroblasts. In normal dermal fibroblasts, TGF-β signaling increased collagen production and Fn14 expression. Furthermore, Fn14 siRNA blocked extracellular matrix gene expression; even when TGF-β signaling was activated by TGF-β1, fibroblast activation remained blocked in the presence of Fn14 siRNA. Overexpressing Fn14 increased extracellular matrix gene expression. In determining the molecular regulatory mechanism, we discovered that SMAD4, an important TGF-β signaling co-mediator, bound to the Fn14 promoter and activated Fn14 transcription. Taken together, these results indicate that the TGF-β signaling pathway activates Fn14 expression through the transcription factor SMAD4 and that activated Fn14 expression increases extracellular matrix synthesis and fibroblast activation. Therefore, Fn14 may represent a promising approach to preventing the excessive accumulation of collagen or ECM in skin fibrosis. PMID:26625141

  16. Dynamics of wakes downstream of wind turbine towers

    NASA Technical Reports Server (NTRS)

    Snyder, M. H.; Wentz, W. H., Jr.

    1981-01-01

    The near field wakes downstream of circular cylinders and of 12 sided cylinders were surveyed in a wind tunnel. Local velocity and velocity deficit diagrams are presented. The variation of turbulence in the wake was surveyed and the frequency of the periodic component of wake motion was determined. Differences between wakes of circular cylinders and of 12 sided cylinders are discussed. Also effects of strakes, orientation of the 12 sided cylinders, and rounding of the corners are noted.

  17. Influence of sediment storage on downstream delivery of contaminated sediment

    USGS Publications Warehouse

    Malmon, D.V.; Reneau, S.L.; Dunne, T.; Katzman, D.; Drakos, P.G.

    2005-01-01

    Sediment storage in alluvial valleys can strongly modulate the downstream migration of sediment and associated contaminants through landscapes. Traditional methods for routing contaminated sediment through valleys focus on in-channel sediment transport but ignore the influence of sediment exchanges with temporary sediment storage reservoirs outside the channel, such as floodplains. In theory, probabilistic analysis of particle trajectories through valleys offers a useful strategy for quantifying the influence of sediment storage on the downstream movement of contaminated sediment. This paper describes a field application and test of this theory, using 137Cs as a sediment tracer over 45 years (1952-1997), downstream of a historical effluent outfall at the Los Alamos National Laboratory (LANL), New Mexico. The theory is parameterized using a sediment budget based on field data and an estimate of the 137Cs release history at the upstream boundary. The uncalibrated model reasonably replicates the approximate magnitude and spatial distribution of channel- and floodplain-stored 137Cs measured in an independent field study. Model runs quantify the role of sediment storage in the long-term migration of a pulse of contaminated sediment, quantify the downstream impact of upstream mitigation, and mathematically decompose the future 137Cs flux near the LANL property boundary to evaluate the relative contributions of various upstream contaminant sources. The fate of many sediment-bound contaminants is determined by the relative timescales of contaminant degradation and particle residence time in different types of sedimentary environments. The theory provides a viable approach for quantifying the long-term movement of contaminated sediment through valleys. Copyright 2005 by the American Geophysical Union.

  18. 15. Detail, lower chord connection point on downstream side, showing ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    15. Detail, lower chord connection point on downstream side, showing pinned connection of lower chord eye bars, laced vertical compression member, diagonal eye bar tension members, turnbuckled diagonal counters, and floor beam. Note also timber floor stringers supported by floor beam, and exposed ends of timber deck members visible at left above lower chord eye bar. View to northwest. - Dry Creek Bridge, Spanning Dry Creek at Cook Road, Ione, Amador County, CA

  19. Downstream influence of swept slot injection in hypersonic turbulent flow

    NASA Technical Reports Server (NTRS)

    Hefner, J. N.; Cary, A. M., Jr.; Bushnell, D. B.

    1977-01-01

    Results of an experimental and numerical investigation of tangential swept slot injection into a thick turbulent boundary layer at Mach 6 are presented. Film cooling effectiveness, skin friction, and flow structure downstream of the swept slot injection were investigated. The data were compared with that for unswept slots, and it was found that cooling effectiveness and skin friction reductions are not significantly affected by sweeping the slot.

  20. TVA`s auto-venting turbines increase downstream aeration

    SciTech Connect

    March, P.

    1996-10-01

    Two auto-venting turbines installed at Norris Hydro Plant to increase dissolved-oxygen levels are briefly described. The turbines introduce aeration through the thrust relief openings, the deflector, the trailing edge of each blade, and the periphery of the draft tube. Downstream dissolved-oxygen levels have been increased by up to 5.5 milligrams per liter. Efficiency losses range from 0 to 4 percent, depending on operating conditions and aeration method.

  1. Reactive extraction for downstream separation of 1,3-propanediol.

    PubMed

    Malinowski, J J

    2000-01-01

    The downstream separation of 1,3-propanediol from dilute aqueous solution was studied. A process combining reversible reaction of 1, 3-propanediol with acetaldehyde to 2-methyl-1,3-dioxane and a simultaneous extraction of the product by organic solvent appears to be technically feasible and attractive. The dioxane yield was 91-92%, the overall conversion of 1,3-propanediol was ca. 98%, and recovery of dioxane into the organic extractant was 75%. PMID:10662493

  2. Regional Characterization of the Downstream Effects of Dams

    NASA Astrophysics Data System (ADS)

    Schmidt, J. C.; Wilcock, P. R.

    2006-05-01

    Metrics with which to assess the causes of channel change downstream from dams permit regional and watershed-scale comparison of the challenge of environmental river management and rehabilitation. Metrics based on Henderson's approximation of the Lane balance, downstream hydraulic geometry, and the Shield's relation allow distinction of general categories of channel response downstream from dams: deficit with bed incision, deficit without incision, and surplus conditions. Each of these categories can occur with or without significant changes in channel width, and channel narrowing occurs in proportion to the degree to which the post-dam flood regime is reduced from that of pre-dam conditions. It is also possible to estimate the degree of perturbation of the watershed sediment delivery rate that causes sediment deficit or surplus, based on a relation between the watershed reservoir storage ratio and the degree of flood control. Estimates of channel change based on these metrics agree well with case studies for the Rio Grande, Colorado River, Missouri River, Trinity River, and Deschutes River. Regional distinction between sediment deficit and surplus conditions is useful, because the management strategies necessary to reverse undesirable conditions differ. Case studies indicate that rehabilitation of sediment deficit river segments is more costly than for sediment surplus segments.

  3. Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos.

    PubMed

    Gürke, Jacqueline; Schindler, Maria; Pendzialek, S Mareike; Thieme, René; Grybel, Katarzyna J; Heller, Regine; Spengler, Katrin; Fleming, Tom P; Fischer, Bernd; Navarrete Santos, Anne

    2016-05-01

    The mammalian target of rapamycin complex 1 (mTORC1) is known to be a central cellular nutrient sensor and master regulator of protein metabolism; therefore, it is indispensable for normal embryonic development. We showed previously in a diabetic pregnancy that embryonic mTORC1 phosphorylation is increased in case of maternal hyperglycaemia and hypoinsulinaemia. Further, the preimplantation embryo is exposed to increased L-leucine levels during a diabetic pregnancy. To understand how mTOR signalling is regulated in preimplantation embryos, we examined consequences of L-leucine and glucose stimulation on mTORC1 signalling and downstream targets in in vitro cultured preimplantation rabbit blastocysts and in vivo. High levels of L-leucine and glucose lead to higher phosphorylation of mTORC1 and its downstream target ribosomal S6 kinase 1 (S6K1) in these embryos. Further, L-leucine supplementation resulted in higher embryonic expression of genes involved in cell cycle (cyclin D1; CCND1), translation initiation (eukaryotic translation initiation factor 4E; EIF4E), amino acid transport (large neutral amino acid transporter 2; Lat2: gene SLC7A8) and proliferation (proliferating cell nuclear antigen; PCNA) in a mTORC1-dependent manner. Phosphorylation of S6K1 and expression patterns of CCND1 and EIF4E were increased in embryos from diabetic rabbits, while the expression of proliferation marker PCNA was decreased. In these embryos, protein synthesis was increased and autophagic activity was decreased. We conclude that mammalian preimplantation embryos sense changes in nutrient supply via mTORC1 signalling. Therefore, mTORC1 may be a decisive mediator of metabolic programming in a diabetic pregnancy. PMID:26836250

  4. Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase

    PubMed Central

    Ohya, Ken-ichi; Kajigaya, Sachiko; Kitanaka, Akira; Yoshida, Koji; Miyazato, Akira; Yamashita, Yoshihiro; Yamanaka, Takeo; Ikeda, Uichi; Shimada, Kazuyuki; Ozawa, Keiya; Mano, Hiroyuki

    1999-01-01

    Tec, Btk, Itk, Bmx, and Txk constitute the Tec family of protein tyrosine kinases (PTKs), a family with the distinct feature of containing a pleckstrin homology (PH) domain. Tec acts in signaling pathways triggered by the B cell antigen receptor (BCR), cytokine receptors, integrins, and receptor-type PTKs. Although upstream regulators of Tec family kinases are relatively well characterized, little is known of the downstream effectors of these enzymes. The yeast two-hybrid system has identified several proteins that interact with the kinase domain of Tec, one of which is now revealed to be a previously unknown docking protein termed BRDG1 (BCR downstream signaling 1). BRDG1 contains a proline-rich motif, a PH domain, and multiple tyrosine residues that are potential target sites for Src homology 2 domains. In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. PMID:10518561

  5. Changing Neuroestrogens Within the Auditory Forebrain Rapidly Transform Stimulus Selectivity in a Downstream Sensorimotor Nucleus

    PubMed Central

    Remage-Healey, Luke; Joshi, Narendra R.

    2012-01-01

    The activity of sensory circuits is shaped by neuromodulators, which can have downstream consequences for both sensorimotor integration and behavioral output. Recent evidence indicates that brain-derived estrogens (‘neuroestrogens’) can act as local circuit modulators in the songbird auditory forebrain. Specifically, neuroestrogens fluctuate in the auditory caudomedial nidopallium (NCM) during social interactions and in response to song stimuli. Within minutes of elevation, neuroestrogens also enhance auditory response properties of NCM neurons, and acute blockade of estrogen production in NCM disrupts behavioral song discrimination. Here, we test the hypothesis that fluctuating neuroestrogens within NCM influence stimulus selectivity in a downstream sensorimotor nucleus (HVC) that receives indirect auditory input from NCM. Dual extracellular recordings coupled with retrodialysis delivery show that song-selectivity in HVC is rapidly enhanced by increasing neuroestrogens in NCM in adult males. Conversely, inhibiting neuroestrogen production in NCM causes a rapid decline in song-selectivity in HVC, demonstrating the endogenous nature of this modulatory network. By contrast, HVC selectivity is unaffected by neuroestrogen delivery to either nearby caudomedial mesopallium (CMM) or into HVC itself, indicating that neuroestrogen actions are restricted to NCM. In juvenile males, identical E2 treatment in NCM also does not alter HVC selectivity, consistent with a developmental maturation of the auditory network. Lastly, the rapid actions of estrogens leading to enhanced HVC selectivity appear to be mediated by membrane-bound receptors in NCM. These findings indicate that steroid-dependent modulation of sensory processing is not locally restricted and can be transmitted transynaptically to influence downstream sensorimotor and premotor targets. PMID:22699904

  6. Pharmacists Can Manage Some Chronic Conditions Effectively, Study Suggests

    MedlinePlus

    ... determine how well pharmacists might perform if they led the management of a person's chronic disease, Wilt ... people. The findings suggest that patients receiving pharmacist-led care were more likely to achieve target goals ...

  7. Nonspecific transcription factor binding can reduce noise in the expression of downstream proteins

    NASA Astrophysics Data System (ADS)

    Soltani, M.; Bokes, P.; Fox, Z.; Singh, A.

    2015-10-01

    Transcription factors (TFs) interact with a multitude of binding sites on DNA and partner proteins inside cells. We investigate how nonspecific binding/unbinding to such decoy binding sites affects the magnitude and time-scale of random fluctuations in TF copy numbers arising from stochastic gene expression. A stochastic model of TF gene expression, together with decoy site interactions is formulated. Distributions for the total (bound and unbound) and free (unbound) TF levels are derived by analytically solving the chemical master equation under physiologically relevant assumptions. Our results show that increasing the number of decoy binding sides considerably reduces stochasticity in free TF copy numbers. The TF autocorrelation function reveals that decoy sites can either enhance or shorten the time-scale of TF fluctuations depending on model parameters. To understand how noise in TF abundances propagates downstream, a TF target gene is included in the model. Intriguingly, we find that noise in the expression of the target gene decreases with increasing decoy sites for linear TF-target protein dose-responses, even in regimes where decoy sites enhance TF autocorrelation times. Moreover, counterintuitive noise transmissions arise for nonlinear dose-responses. In summary, our study highlights the critical role of molecular sequestration by decoy binding sites in regulating the stochastic dynamics of TFs and target proteins at the single-cell level.

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

    PubMed

    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. PMID:24637706

  9. Ecological linkages between headwaters and downstream ecosystems: Transport of organic matter, invertebrates, and wood down headwater channels

    USGS Publications Warehouse

    Wipfli, M.S.; Richardson, J.S.; Naiman, R.J.

    2007-01-01

    Headwater streams make up a large proportion of the total length and watershed area of fluvial networks, and are partially characterized by the large volume of organic matter (large wood, detritus, and dissolved organic matter) and invertebrate inputs from the riparian forest, relative to stream size. Much of those inputs are exported to downstream reaches through time where they potentially subsidize river communities. The relative rates, timing, and conversion processes that carry inputs from small streams to downstream reaches are reasonably well quantified. For example, larger particles are converted to smaller particles, which are more easily exported. Also, dissolved organic matter and surface biofilms are converted to larger particles which can be more easily intercepted by consumers. However, the quality of these materials as it affects biological activity downstream is not well known, nor is the extent to which timing permits biological use of those particles. These ecological unknowns need to be resolved. Further, land uses may disrupt and diminish material transport to downstream reaches by removing sources (e.g., forest harvest), by affecting transport and decomposition processes (e.g., flow regulation, irrigation, changes in biotic communities), and by altering mechanisms of storage within headwaters (e.g., channelization). We present conceptual models of energy and nutrient fluxes that outline small stream processes and pathways important to downstream communities, and we identify informational gaps that, if filled, could significantly advance the understanding of linkages between headwater streams and larger rivers. The models, based on empirical evidence and best professional judgment, suggest that navigable waters are significantly influenced by headwater streams through hydrological and ecological connectivities, and land use can dramatically influence these natural connectivities, impacting downstream riverine ecosystems. ?? 2007 American Water

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

    PubMed Central

    dos Reis, Sávio Pinho; Lima, Aline Medeiros; de Souza, Cláudia Regina Batista

    2012-01-01

    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. PMID:22942725

  11. Growth Characteristics Downstream of a Shallow Bump: Computation and Experiment

    NASA Technical Reports Server (NTRS)

    Joslin, Ronald D.; Grosch, Chester E.

    1996-01-01

    Measurements of the velocity field created by a shallow bump on a wall revealed that an energy peak in the spanwise spectrum associated with the driver decays and an initially small-amplitude secondary mode rapidly grows with distance downstream of the bump. Linear theories could not provide an explanation for this growing mode. The present Navier-Stokes simulation replicates and confirms the experimental results. Insight into the structure of the flow was obtained from a study of the results of the calculations and is presented.

  12. Flow diagnostics downstream of a tribladed rotor model

    NASA Astrophysics Data System (ADS)

    Naumov, I. V.; Rahmanov, V. V.; Okulov, V. L.; Velte, C. M.; Meyer, K. E.; Mikkelsen, R. F.

    2012-06-01

    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 subsequently quantitative data were recorded through velocity field restoration from particle tracks using a stereo PIV system. The study supplied flow diagnostics and recovered the instantaneous 3D velocity fields in the longitudinal cross section behind a tribladed rotor at different values of tip speed ratio. This set of data provided a basis for testing and validating assumptions and hypothesis regarding classical theories of rotors.

  13. Plasma properties downstream of a low-power Hall thruster

    SciTech Connect

    Beal, Brian E.; Gallimore, Alec D.; Hargus, William A. Jr.

    2005-12-15

    Triple Langmuir probes and emissive probes were used to measure the electron number density, electron temperature, and plasma potential downstream of a low-power Hall thruster. The results show a polytropic relation between electron temperature and electron number density throughout the sampled region. Over a large fraction of the plume, the plasma potential obeys the predictions of ambipolar expansion. Near the thruster centerline, however, observations show larger gradients of plasma potential than can be accounted for by this means. Radial profiles of plasma potential in the very-near-field plume are shown to contain large gradients that correspond in location to the boundaries of a visually intense plasma region.

  14. Downstream Impacts of Tank 48H In-tank and Out-of-tank Processing Alternatives

    SciTech Connect

    Lambert, D.P.

    2003-12-22

    Processing Facility, Defense Waste Processing Facility, Actinide Removal Process, Tank Farms, Saltstone Facility, or the HLW evaporators. This list was compiled so that researchers and modelers could target their future work to determine whether these postulated interactions will truly impact the downstream facilities. summarizes the possible downstream impacts noted in this document, and attempts to compare the processing alternatives.

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

    PubMed

    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. PMID:27189362

  16. Plant GSK3 proteins regulate xylem cell differentiation downstream of TDIF-TDR signalling

    NASA Astrophysics Data System (ADS)

    Kondo, Yuki; Ito, Tasuku; Nakagami, Hirofumi; Hirakawa, Yuki; Saito, Masato; Tamaki, Takayuki; Shirasu, Ken; Fukuda, Hiroo

    2014-03-01

    During plant radial growth typically seen in trees, procambial and cambial cells act as meristematic cells in the vascular system to self-proliferate and differentiate into xylem cells. These two processes are regulated by a signalling pathway composed of a peptide ligand and its receptor; tracheary element differentiation inhibitory factor (TDIF) and TDIF RECEPTOR (TDR). Here we show that glycogen synthase kinase 3 proteins (GSK3s) are crucial downstream components of the TDIF signalling pathway suppressing xylem differentiation from procambial cells. TDR interacts with GSK3s at the plasma membrane and activates GSK3s in a TDIF-dependent fashion. Consistently, a specific inhibitor of plant GSK3s strongly induces xylem cell differentiation through BRI1-EMS SUPPRESSOR 1 (BES1), a well-known target transcription factor of GSK3s. Our findings provide insight into the regulation of cell fate determination in meristem maintenance.

  17. Estimating the waiting time of multi-priority emergency patients with downstream blocking.

    PubMed

    Lin, Di; Patrick, Jonathan; Labeau, Fabrice

    2014-03-01

    To characterize the coupling effect between patient flow to access the emergency department (ED) and that to access the inpatient unit (IU), we develop a model with two connected queues: one upstream queue for the patient flow to access the ED and one downstream queue for the patient flow to access the IU. Building on this patient flow model, we employ queueing theory to estimate the average waiting time across patients. Using priority specific wait time targets, we further estimate the necessary number of ED and IU resources. Finally, we investigate how an alternative way of accessing ED (Fast Track) impacts the average waiting time of patients as well as the necessary number of ED/IU resources. This model as well as the analysis on patient flow can help the designer or manager of a hospital make decisions on the allocation of ED/IU resources in a hospital. PMID:23690253

  18. The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action

    PubMed Central

    Abbondanza, Ciro; Medici, Nicola; Nigro, Vincenzo; Rossi, Valentina; Gallo, Luigi; Piluso, Giulio; Belsito, Angela; Roscigno, Annarita; Bontempo, Paola; Puca, Annibale A.; Molinari, Anna Maria; Moncharmont, Bruno; Puca, Giovanni A.

    2000-01-01

    Co-immunoprecipitation experiments in cell extract from cultured cells or target tissues indicated that estrogen receptor was complexed with the retinoblastoma binding protein RIZ in a ligand-dependent manner. Mapping of interaction sites indicated that in both proteins the same regions and motifs responsible for the interaction of transcriptional co-activator and nuclear receptors were involved. In cultured cells, estradiol induced a redistribution of RIZ protein within the nucleus and in the cytoplasm. A similar effect was produced in vivo, in prepuberal rat endometrium, by administration of a physiological dose of estradiol. Therefore, RIZ protein could be a specific effector of estrogen action downstream of the hormone-receptor interaction, presumably involved in proliferation control. PMID:10706618

  19. The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action.

    PubMed

    Abbondanza, C; Medici, N; Nigro, V; Rossi, V; Gallo, L; Piluso, G; Belsito, A; Roscigno, A; Bontempo, P; Puca, A A; Molinari, A M; Moncharmont, B; Puca, G A

    2000-03-28

    Co-immunoprecipitation experiments in cell extract from cultured cells or target tissues indicated that estrogen receptor was complexed with the retinoblastoma binding protein RIZ in a ligand-dependent manner. Mapping of interaction sites indicated that in both proteins the same regions and motifs responsible for the interaction of transcriptional co-activator and nuclear receptors were involved. In cultured cells, estradiol induced a redistribution of RIZ protein within the nucleus and in the cytoplasm. A similar effect was produced in vivo, in prepuberal rat endometrium, by administration of a physiological dose of estradiol. Therefore, RIZ protein could be a specific effector of estrogen action downstream of the hormone-receptor interaction, presumably involved in proliferation control. PMID:10706618

  20. Targeted therapy for gastric cancer.

    PubMed

    Smyth, Elizabeth C; Cunningham, David

    2012-09-01

    For patients with advanced gastric cancer, traditional double or triplet cytotoxic chemotherapy regimens result in a median survival of 9-11 months. As combination therapy is associated with increased survival, but also increased toxicity in a patient population whose performance status often compromised by their malignancy, development of more effective and less toxic treatment choices is mandated. Emerging data from gene expression profiling suggests that differences in pathological appearance and clinical behavior may be due the presence of unique molecular phenotypes. Characterization of the gastric cancer genomic landscape reveals the presence of multiple alterations in expression of receptor tyrosine kinases, which in conjunction with their ligands and downstream effector molecules represent potentially druggable pathways for future drug development. Treatment of HER2 positive gastric cancer with trastuzumab has led to significant gains in overall survival, and further manipulation of this pathway using the novel anti-HER2 directed agents pertuzumab and T-DM1 in addition to dual EGFR/HER2 blockade with lapatinib may yield positive results. In contrast, targeting of the EGFR pathway in combination with chemotherapy in unselected patients has not been fruitful to date, with no significant gains over standard chemotherapy yet demonstrated. Similarly, use of the anti-angiogenic monoclonal antibody bevacizumab was not successful in a large global randomized trial; however intriguing regional variations were seen with respect to efficacy of this drug, leading to calls for a second, regionally stratified study. Careful selection of patient subsets will become a key factor in future clinical trials, as novel targeted agents such as those targeting the MET/HGF and FGFR axes move forward into clinical development. It is hoped that treatment of patients in such molecularly defined groups is will lead to significant gains in survival compared to current treatment

  1. Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease

    PubMed Central

    Werner, Petra; Paluru, Prasuna; Simpson, Anisha M.; Latney, Brande; Iyer, Radhika; Brodeur, Garrett M.; Goldmuntz, Elizabeth

    2014-01-01

    Congenital heart defects (CHDs) are the most common major birth defects and the leading cause of death from congenital malformations. The etiology remains largely unknown, though genetic variants clearly contribute. In a previous study, we identified a large copy number variant (CNV) that deleted 46 genes in a patient with a malalignment type ventricular septal defect (VSD). The CNV included the gene NTRK3 encoding neurotrophic tyrosine kinase receptor C (TrkC), which is essential for normal cardiogenesis in animal models. To evaluate the role of NTRK3 in human CHDs, we studied 467 patients with related heart defects for NTRK3 mutations. We identified four missense mutations in four patients with VSDs that were not found in ethnically matched controls and were predicted to be functionally deleterious. Functional analysis using neuroblastoma cell lines expressing mutant TrkC demonstrated that one of the mutations (c.278C>T, p.T93M) significantly reduced autophosphorylation of TrkC in response to ligand binding, subsequently decreasing phosphorylation of downstream target proteins. In addition compared to WT, three of the four cell lines expressing mutant TrkC showed altered cell growth in low-serum conditions without supplemental NT-3. These findings suggest a novel pathophysiological mechanism involving NTRK3 in the development of VSDs. PMID:25196463

  2. Initial PVO evidence of electron depletion signatures downstream of Venus

    NASA Technical Reports Server (NTRS)

    Intriligator, D. S.; Hartle, R. E.; Perez-De-tejada, H.; Siscoe, G. L.

    1993-01-01

    This first analysis of Pioneer Venus Orbiter (PVO) plasma analyzer electron measurements obtained in early 1992 during teh PVO entry phase of the mission indicates the presence downstream from the terminator of a depletion or 'bite out' of energetic ionosheath electrons similar to that observed on Mariner 10. There is more than one possible explanation for this energetic electron depletion. If it is due to atmospheric scattering, the electrons traveling along draped magnetic flux tubes that thread through the Venus neutral atmosphere would lose energy from impact ionization with oxygen. The cross-section for such electron impact ionization of oxygen has a peak near 100 eV, and it remains high above this energy, so atmospheric loss could provde a natural process for electrons at these energies to be selectively removed. In this case, our results are consistent with the Kar et al. (1994) study of PVO atmospheric entry ion mass spectrometer data, which indicates that electron impact plays a significant role in maintaining the nightside ionosphere. Although it is appealing to interpret the energetic electron depletion in terms of direct atmospheric scattering, alternatively it could result from strong draping which connects the depletion region magnetically to the weak downstream bow shock and thereby reduces the electron source strength.

  3. Initial PVO Evidence of Electron Depletion Signatures Downstream of Venus

    NASA Technical Reports Server (NTRS)

    Intriligator, D. S.; Hartle, R. E.; Perez-de-Tejada, H.; Siscoe, G. L.

    1993-01-01

    This first analysis of Pioneer Venus Orbiter (PVO) plasma analyzer electron measurements obtained in early 1992 during the PVO entry phase of the mission indicates the presence downstream from the terminator of a depletion or "bite out" of energetic ionosheath electrons similar to that observed on Mariner 10. There is more than one possible explanation for this energetic electron depletion. If it is due to atmospheric scattering, the electrons traveling along draped magnetic flux tubes that thread through the Venus neutral atmosphere would lose energy from impact ionization with oxygen. The cross-section for such electron impact ionization of oxygen has a peak near 100 eV, and it remains high above this energy, so atmospheric loss could provide a natural process for electrons at these energies to be selectively removed. In this case, our results are consistent with the Kar et al. (1994) study of PVO atmospheric entry ion mass spectrometer data which indicates that electron impact plays a significant role in maintaining the nightside ionosphere. Although it is appealing to interpret the energetic electron depletion in terms of direct atmospheric scattering, alternatively it could result from strong draping which connects the depletion region magnetically to the weak downstream bow shock and thereby reduces the electron source strength.

  4. Flow downstream of the heliospheric terminal shock. I - Irrotational flow

    NASA Technical Reports Server (NTRS)

    Suess, Steven T.; Nerney, Steven

    1990-01-01

    Recent reports of remote detection of the heliospheric terminal shock place it near 50 AU. These conflict with standard models which, when combined with current data on the local interstellar medium, place the shock beyod 100 AU. Resolution of this discrepancy has led to hypotheses that invoke cosmic ray pressure, momentum exchange with interstellar neutrals, and magnetic field effects between the shock and the contact discontinuity dividing the solar wind from interstellar plasma. These hypotheses depend not only on properties of the interstellar medium, but also on the downstream three-dimensional flow between the shock and the contact discontinuity, in the region called the 'heliosheath'. The downstream flow field in the absence of magnetic fields is examined here under the assumptions that the flow everywhere outside the shock can be approximated as irrotational and incompressible. It is found, in particular, that the distance between the terminal shock and the contact discontinuity is less than the heliocentric distance to the terminal shock, effectively eliminating magnetic field effects in the heliosheath as being dynamically important.

  5. Thermal mixing layer downstream of half-heated turbulence grid

    NASA Astrophysics Data System (ADS)

    Larue, J. C.; Libby, P. A.

    1981-04-01

    Experimental and theoretical results are presented concerning the temperature in the thermal mixing layer downstream of a partially heated turbulence grid. Temperatures were measured by platinum wire thermometers located upstream and downstream of a turbulence grid consisting of 18 horizontal and 18 vertical heating rods, with the uppermost nine horizontal rods heated to a temperature about 200 C above ambient. Experimental results are presented for the mean temperature distribution, the distribution of relative temperature intensity, the distributions of the skewness and kurtosis of the temperature fluctuations, probability density functions for the temperature, the skewness of the temperature derivative and the thickness of the thermal interface in the thermal mixing layer, and are compared with previous experimental results where available. As in previous investigations, the measured intensity of the temperature fluctuations in the center of the mixing layer is found to disagree with that predicted by the analysis of Libby (1975) by 40%, and it is concluded that experiments simultaneously yielding the velocity and temperature characteristics are required to explain the discrepancy.

  6. Dynamic response of ramjet inlets to downstream perturbations

    NASA Astrophysics Data System (ADS)

    Sajben, M.; Bogar, T. J.; Kroutil, J. C.

    1983-01-01

    An external-compression inlet with high-aspect-ratio, rectangular cross sections was investigated in a semi-freejet arrangement at M(infinity) = 1.84 and zero incidence, over a wide range of super- and subcritical conditions. The response of the inlet flows to periodic perturbations imposed at the downstream end was determined. The perturbations were created by mechanical modulation of the choked exhaust area at frequencies from 20 to 360 Hz. The amplitude of the pressure fluctuations induced at the downstream end of the inlet was varied up to 8% of the time-mean static pressure at the same location. The observed oscillations were categorized according to position ranges associated with the shock motion. In supercritical oscillations, the pressure fluctuation amplitudes within the inlet were found to be linearly proportional to the fluctuation intensity at the exit station, establishing the latter as the appropriate quantity for normalization. In subcritical conditions, the inlet displays a large-amplitude natural oscillation (buzz). Superimposed excitation may couple with the natural oscillations in two distinctly different ways, both strongly nonlinear. Combinations of mean flow condition, excitation amplitude, and frequency that cause the terminal shock to move upstream of the cowl or the ramp were determined.

  7. Natural Origin Lycopene and Its "Green" Downstream Processing.

    PubMed

    Papaioannou, Emmanouil H; Liakopoulou-Kyriakides, Maria; Karabelas, Anastasios J

    2016-01-01

    Lycopene is an abundant natural carotenoid pigment with several biological functions (well-known for its antioxidant properties) which is under intensive investigation in recent years. Lycopene chemistry, its natural distribution, bioavailability, biological significance, and toxicological effects are briefly outlined in the first part of this review. The second, major part, deals with various modern downstream processing techniques, which are assessed in order to identify promising approaches for the recovery of lycopene and of similar lipophilic compounds. Natural lycopene is synthesized in plants and by microorganisms, with main representatives of these two categories (for industrial production) tomato and its by-products and the fungus Blakeslea trispora, respectively. Currently, there is a great deal of effort to develop efficient downstream processing for large scale production of natural-origin lycopene, with trends strongly indicating the necessity for "green" and mild extraction conditions. In this review, emphasis is placed on final product safety and ecofriendly processing, which are expected to totally dominate in the field of natural-origin lycopene extraction and purification. PMID:25671774

  8. Reverse micellar extraction for downstream processing of proteins/enzymes.

    PubMed

    Krishna, S Hari; Srinivas, N D; Raghavarao, K S M S; Karanth, N G

    2002-01-01

    New developments in the area of downstream processing are, hopefully, to fulfill the promises of modern biotechnology. The traditional separation processes such as chromatography or electrophoresis can become prohibitively expensive unless the product is of high value. Hence, there is a need to develop efficient and cost-effective downstream processing methods. Reverse micellar extraction is one such potential and a promising liquid-liquid extraction technique, which has received immense attention for isolation and purification of proteins/enzymes in the recent times. This technique is easy to scale-up and offers continuous operation. This review, besides briefly considering important physico-chemical and biological aspects, highlights the engineering aspects including mass transfer, mathematical modeling, and technology development. It also discusses recent developments in reverse micellar extraction such as affinity based separations, enzymatic reactions in reverse micelles coupled with membrane processes, reverse micellar extraction in hollow fibers, etc. Special emphasis has been given to some recent applications of this technique. PMID:11787493

  9. Benzene and total hydrocarbons exposures in the downstream petroleum industries.

    PubMed

    Verma, D K; Johnson, D M; Shaw, M L; des Tombe, K

    2001-01-01

    A review of studies, including both articles published in peer-reviewed journals and reports that were not peer reviewed, regarding occupational exposure to benzene and total hydrocarbons in the downstream petroleum industry operations was performed. The objective was to provide a broad estimate of exposures by compiling exposure data according to the following categories: refinery, pipeline, marine, rail, bulk terminals and trucks, service stations, underground storage tanks, tank cleaning, and site remediations. The data in each category was divided into personal occupational long-term and short-term samples. The summarized data offers valuable assistance to hygienists by providing them with an estimate and range of exposures. The traditional 8-hour time-weighted average (TWA) exposure and the 40-hour workweek do not generally coincide with exposure periods applicable to workers in marine, pipeline, railcar, and trucking operations. They are more comparable with short-term exposure or task-based exposure assessments. The marine sector has a large number of high exposures. Although relatively few workers are exposed, their exposures to benzene and total hydrocarbons are sometimes an order of magnitude higher than the respective exposure limits. It is recommended that in the future, it would be preferable to do more task-based exposure assessments and fewer traditional TWA long-term exposure assessments within the various sectors of the downstream petroleum industry. PMID:11331990

  10. Turbulence downstream of subcoronary stentless and stented aortic valves.

    PubMed

    Funder, Jonas Amstrup; Frost, Markus Winther; Wierup, Per; Klaaborg, Kaj-Erik; Hjortdal, Vibeke; Nygaard, Hans; Hasenkam, J Michael

    2011-08-11

    Regions of turbulence downstream of bioprosthetic heart valves may cause damage to blood components, vessel wall as well as to aortic valve leaflets. Stentless aortic heart valves are known to posses several hemodynamic benefits such as larger effective orifice areas, lower aortic transvalvular pressure difference and faster left ventricular mass regression compared with their stented counterpart. Whether this is reflected by diminished turbulence formation, remains to be shown. We implanted either stented pericardial valve prostheses (Mitroflow), stentless valve prostheses (Solo or Toronto SPV) in pigs or they preserved their native valves. Following surgery, blood velocity was measured in the cross sectional area downstream of the valves using 10MHz ultrasonic probes connected to a dedicated pulsed Doppler equipment. As a measure of turbulence, Reynolds normal stress (RNS) was calculated at two different blood pressures (baseline and 50% increase). We found no difference in maximum RNS measurements between any of the investigated valve groups. The native valve had significantly lower mean RNS values than the Mitroflow (p=0.004), Toronto SPV (p=0.008) and Solo valve (p=0.02). There were no statistically significant differences between the artificial valve groups (p=0.3). The mean RNS was significantly larger when increasing blood pressure (p=0.0006). We, thus, found no advantages for the stentless aortic valves compared with stented prosthesis in terms of lower maximum or mean RNS values. Native valves have a significantly lower mean RNS value than all investigated bioprostheses. PMID:21696741

  11. Laminar-flow heat transfer downstream from U-bends

    SciTech Connect

    Abdelmessih, A.N

    1987-01-01

    The laminar-flow heat transfer downstream from the unheated, vertical bends in horizontal U-tubes with electrically heated straight tube sections was investigated. Four U-tubes with curvature ratios of 4.84, 7.66, 12.35, and 25.36 were studied. Distilled water and almost-pure ethylene glycol solutions (water content 1 to 5%) were the test fluids. For each test section, local axial and peripheral wall temperatures were measured, and the local peripheral heat-transfer coefficients at the various locations were calculated. The experiments covered the local bulk Reynolds number range of 120 to 2500. The local bulk Prandtl number varied between 4 and 110, while the Grashof number ranged from 2500 to 1,130,000. The uniform wall heat flux ranged from 900 to 4230 Btu/hr.sq.ft (3.12 to 13.33 KW/sq.m.). This investigation permitted a better understanding of the interaction of the primary, secondary, and tertiary flow patterns. Also, a correlation was developed that predicts the heat-transfer coefficient downstream from an unheated U-bend and that can be extended to straight tubes.

  12. Ferric chloride based downstream process for microalgae based biodiesel production.

    PubMed

    Seo, Yeong Hwan; Sung, Mina; Kim, Bohwa; Oh, You-Kwan; Kim, Dong Yeon; Han, Jong-In

    2015-04-01

    In this study, ferric chloride (FeCl3) was used to integrate downstream processes (harvesting, lipid extraction, and esterification). At concentration of 200 mg/L and at pH 3, FeCl3 exhibited an expected degree of coagulation and an increase in cell density of ten times (170 mg/10 mL). An iron-mediated oxidation reaction, Fenton-like reaction, was used to extract lipid from the harvested biomass, and efficiency of 80% was obtained with 0.5% H2O2 at 90 °C. The iron compound was also employed in the esterification step, and converted free fatty acids to fatty acid methyl esters under acidic conditions; thus, the fatal problem of saponification during esterification with alkaline catalysts was avoided, and esterification efficiency over 90% was obtained. This study clearly showed that FeCl3 in the harvesting process is beneficial in all downstream steps and have a potential to greatly reduce the production cost of microalgae-originated biodiesel. PMID:25647024

  13. Liver X receptor and STAT1 cooperate downstream of Gas6/Mer to induce anti-inflammatory arginase 2 expression in macrophages

    PubMed Central

    Kim, Si-Yoon; Lim, Eun-Jin; Yoon, Young-So; Ahn, Young-Ho; Park, Eun-Mi; Kim, Hee-Sun; Kang, Jihee Lee

    2016-01-01

    Mer signaling increases the transcriptional activity of liver X receptor (LXR) to promote the resolution of acute sterile inflammation. Here, we aimed to understand the pathway downstream of Mer signaling after growth arrest-specific protein 6 (Gas6) treatment that leads to LXR expression and transcriptional activity in mouse bone-marrow derived macrophages (BMDM). Gas6-induced increases in LXRα and LXRβ and expression of their target genes were inhibited in BMDM from STAT1−/− mice or by the STAT1-specific inhibitor fludarabine. Gas6-induced STAT1 phosphorylation, LXR activation, and LXR target gene expression were inhibited in BMDM from Mer−/− mice or by inhibition of PI3K or Akt. Gas6-induced Akt phosphorylation was inhibited in BMDM from STAT1−/− mice or in the presence of fludarabine. Gas6-induced LXR activity was enhanced through an interaction between LXRα and STAT1 on the DNA promoter of Arg2. Additionally, we found that Gas6 inhibited lipopolysaccharide (LPS)-induced nitrite production in a STAT1 and LXR pathway-dependent manner in BMDM. Additionally, Mer-neutralizing antibody reduced LXR and Arg2 expression in lung tissue and enhanced NO production in bronchoalveolar lavage fluid in LPS-induced acute lung injury. Our data suggest the possibility that the Gas6-Mer-PI3K/Akt-STAT1-LXR-Arg2 pathway plays an essential role for resolving inflammatory response in acute lung injury. PMID:27406916

  14. The Mediator Complex MED15 Subunit Mediates Activation of Downstream Lipid-Related Genes by the WRINKLED1 Transcription Factor1[OPEN

    PubMed Central

    Kim, Mi Jung

    2016-01-01

    The Mediator complex is known to be a master coordinator of transcription by RNA polymerase II, and this complex is recruited by transcription factors (TFs) to target promoters for gene activation or repression. The plant-specific TF WRINKLED1 (WRI1) activates glycolysis-related and fatty acid biosynthetic genes during embryogenesis. However, no Mediator subunit has yet been identified that mediates WRI1 transcriptional activity. Promoter-β-glucuronidase fusion experiments showed that MEDIATOR15 (MED15) is expressed in the same cells in the embryo as WRI1. We found that the Arabidopsis (Arabidopsis thaliana) MED15 subunit of the Mediator complex interacts directly with WRI1 in the nucleus. Overexpression of MED15 or WRI1 increased transcript levels of WRI1 target genes involved in glycolysis and fatty acid biosynthesis; these genes were down-regulated in wild-type or WRI1-overexpressing plants by silencing of MED15. However, overexpression of MED15 in the wri1 mutant also increased transcript levels of WRI1 target genes, suggesting that MED15 also may act with other TFs to activate downstream lipid-related genes. Chromatin immunoprecipitation assays confirmed the association of MED15 with six WRI1 target gene promoters. Additionally, silencing of MED15 resulted in reduced fatty acid content in seedlings and mature seeds, whereas MED15 overexpression increased fatty acid content in both developmental stages. Similar results were found in wri1 mutant and WRI1 overexpression lines. Together, our results indicate that the WRI1/MED15 complex transcriptionally regulates glycolysis-related and fatty acid biosynthetic genes during embryogenesis. PMID:27246098

  15. Isotopic composition of inorganic mercury and methylmercury downstream of a historical gold mining region

    USGS Publications Warehouse

    Donovan, Patrick M.; Blum, Joel D.; Singer, Michael B.; Marvin-DiPasquale, Mark C.; Tsui, Martin T.K.

    2016-01-01

    We measured total mercury (THg) and monomethyl mercury (MMHg) concentrations and mercury (Hg) isotopic compositions in sediment and aquatic organisms from the Yuba River (California, USA) to identify Hg sources and biogeochemical transformations downstream of a historical gold mining region. Sediment THg concentrations and δ202Hg decreased from the upper Yuba Fan to the lower Yuba Fan and the Feather River. These results are consistent with the release of Hg during gold mining followed by downstream mixing and dilution. The Hg isotopic composition of Yuba Fan sediment (δ202Hg = −0.38 ± 0.17‰ and Δ199Hg = 0.04 ± 0.03‰; mean ± 1 SD, n = 7) provides a fingerprint of inorganic Hg (IHg) that could be methylated locally or after transport downstream. The isotopic composition of MMHg in the Yuba River food web was estimated using biota with a range of %MMHg (the percent of THg present as MMHg) and compared to IHg in sediment, algae, and the food web. The estimated δ202Hg of MMHg prior to photodegradation (−1.29 to −1.07‰) was lower than that of IHg and we suggest this is due to mass-dependent fractionation (MDF) of up to −0.9‰ between IHg and MMHg. This result is in contrast to net positive MDF (+0.4 to +0.8‰) previously observed in lakes, estuaries, coastal oceans, and forests. We hypothesize that this unique relationship could be due to differences in the extent or pathway of biotic MMHg degradation in stream environments.

  16. Isotopic Composition of Inorganic Mercury and Methylmercury Downstream of a Historical Gold Mining Region.

    PubMed

    Donovan, Patrick M; Blum, Joel D; Singer, Michael Bliss; Marvin-DiPasquale, Mark; Tsui, Martin T K

    2016-02-16

    We measured total mercury (THg) and monomethyl mercury (MMHg) concentrations and mercury (Hg) isotopic compositions in sediment and aquatic organisms from the Yuba River (California, USA) to identify Hg sources and biogeochemical transformations downstream of a historical gold mining region. Sediment THg concentrations and δ(202)Hg decreased from the upper Yuba Fan to the lower Yuba Fan and the Feather River. These results are consistent with the release of Hg during gold mining followed by downstream mixing and dilution. The Hg isotopic composition of Yuba Fan sediment (δ(202)Hg = -0.38 ± 0.17‰ and Δ(199)Hg = 0.04 ± 0.03‰; mean ± 1 SD, n = 7) provides a fingerprint of inorganic Hg (IHg) that could be methylated locally or after transport downstream. The isotopic composition of MMHg in the Yuba River food web was estimated using biota with a range of %MMHg (the percent of THg present as MMHg) and compared to IHg in sediment, algae, and the food web. The estimated δ(202)Hg of MMHg prior to photodegradation (-1.29 to -1.07‰) was lower than that of IHg and we suggest this is due to mass-dependent fractionation (MDF) of up to -0.9‰ between IHg and MMHg. This result is in contrast to net positive MDF (+0.4 to +0.8‰) previously observed in lakes, estuaries, coastal oceans, and forests. We hypothesize that this unique relationship could be due to differences in the extent or pathway of biotic MMHg degradation in stream environments. PMID:26789018

  17. Geomorphic response of rivers to glacial retreat and increasing peak flows downstream from Mount Rainier, Washington

    NASA Astrophysics Data System (ADS)

    Czuba, J. A.; Barnas, C. R.; Magirl, C. S.; Voss, F. D.

    2010-12-01

    On Mount Rainier, Washington, the National Park Service has documented widespread aggradation of as much as 10 m since the early 20th century, of rivers draining the glaciated stratovolcano. This rapid sedimentation appears to be related to glacial retreat and also may be a function of the increased magnitude and timing of peak flows that mobilize and transport sediment. We are conducting an assessment of the Puget Lowland rivers that drain Mount Rainier, 25-100 km downstream from the park boundary, to document the geomorphic response of the downstream reaches given the widespread aggradation upstream. These downstream reaches provide critical aquatic habitat for spawning and rearing of several species of salmonids, including endangered Chinook salmon and steelhead. Fluvial sedimentation can have both deleterious and beneficial effects on aquatic habitat depending on sediment particle size, river slope and width, and river management. To date, our work shows sedimentation of as much as 2 m between 1984 and 2009 in these lowland rivers. Aggradation rates that were calculated by comparing channel change at 156 cross sections, ranged between 4.8 and 9.1 cm/yr in reaches where rivers exit the mountain front and enter the lowland. Analysis of streamflow-gaging station data from throughout the watersheds draining Mount Rainier show rapid incision and aggradation, suggesting pulses of coarse-grained bedload may be moving down the mountainous rivers as kinetic waves. Preliminary results, however, seem to indicate that the rivers in the Puget Lowland have not yet experienced significant widespread sedimentation directly related to glacial retreat. Estimating the time of arrival of mobilized alluvium is a critical need for resource managers given the potential effects of sedimentation on river flood-conveyance capacity, fish habitat, and estuarine wetlands.

  18. Studies with Cluster upstream and downstream of the bow shock: An experimenter's perspective

    NASA Technical Reports Server (NTRS)

    Moebius, E.

    1995-01-01

    Some open questions in the physics of bow shock formation, the evolution of the particle distributions from solar wind into the magnetosheath, and the acceleration of ions at the moment of the shock are summarized. A layout of the current situation is presented in view of recent theoretical developments and the new diagnostic tools provided by the Cluster mission. The transition of ions across the quasi-perpendicular bow shock and their downstream thermalization are discussed. The processes and spatial scales are found to be species dependent and are discussed for H(+), He(2+), and He(+). The theory of particle acceleration at quasi-parallel shocks are reviewed. It is shown how Cluster can study the time variable structures of the shock as predicted by hybrid simulation. It is emphasized that high time resolution measurement with simultaneous species separation is necessary for the study of the ion acceleration. Suggestions for the spacecraft separations at the bow shock are suggested.

  19. Influence of basin characteristics on the effectiveness and downstream reach of interbasin water transfers: displacing a problem

    NASA Astrophysics Data System (ADS)

    Emanuel, Ryan E.; Buckley, John J.; Caldwell, Peter V.; McNulty, Steven G.; Sun, Ge

    2015-12-01

    Interbasin water transfers are globally important water management strategies, yet little is known about their role in the hydrologic cycle at regional and continental scales. Specifically, there is a dearth of centralized information on transfer locations and characteristics, and few analyses place transfers into a relevant hydrological context. We assessed hydrological characteristics of interbasin transfers (IBTs) in the conterminous US using a nationwide inventory of transfers together with historical climate data and hydrological modeling. Supplying and receiving drainage basins share similar hydroclimatological conditions, suggesting that climatological drivers of water shortages in receiving basins likely have similar effects on supplying basins. This result calls into question the effectiveness of transfers as a strategy to mitigate climate-driven water shortages, as the water shortage may be displaced but not resolved. We also identified hydrologically advantageous and disadvantageous IBTs by comparing the water balances of supplying and receiving basins. Transfer magnitudes did not vary between the two categories, confirming that factors driving individual IBTs, such as patterns of human water demand or engineering constraints, also influence the continental-scale distribution of transfers. Some IBTs impact streamflow for hundreds of kilometers downstream. Transfer magnitude, hydroclimate and organization of downstream river networks mediate downstream impacts, and these impacts have the potential to expand downstream nonlinearly during years of drought. This work sheds new light on IBTs and emphasizes the need for updated inventories and analyses that place IBTs in an appropriate hydrological context.

  20. Large Wood Storage Does Not Decrease Downstream Through a Watershed

    NASA Astrophysics Data System (ADS)

    Vaughan, M.; Pasternack, G. B.; Senter, A. E.; Dahlke, H. E.

    2013-12-01

    The storage of large wood in streams at the watershed scale has long been characterized as decreasing downstream due to a transport limitation in headwater streams, and a supply limitation in larger rivers. The objective of this study was to test this hypothesis through a field study in the Upper Yuba River watershed in Northern California, USA. While most studies surveyed within the wetted channel at selected reaches of different sizes, this study measured overbank deposits of large wood in addition to those in-channel to reflect the total storage within the active river corridor, and used a stratified random sampling scheme to see if relations held at the watershed scale. The watershed is large (2,874 km2), mountainous, mostly forested, and has been dramatically altered by human activities primarily related to gold mining. One hundred fourteen field sites of varied drainage area sizes were visited, inventoried for large wood (length > 1 m, diameter > 10 cm) storage within the active river corridor, and the volume storage per river length was calculated. Inclusion of floodplains in field surveys illuminates the fact that the distribution of large wood changes within the active river corridor, while the total storage does not decrease downstream. Among many watershed-scale control variables, such as drainage area, stream order, and upslope distance, the local amount of shrub cover and bankfull channel width were the only significant predictors of large wood storage in a multiple linear regression model, both with positive coefficients. A critical literature review was also conducted to investigate the evidence for the common conceptual model. Findings were that (1) the observed downstream trend of large wood storage is largely a function of the methods employed by each study, (2) the use of storage per channel area has confounded the commonly held conceptual model, due to its correlation with channel width, and (3) there is little evidence to support the hypothesis

  1. Methylmercury in biota downstream of Arivaca lake, Arizona, USA.

    PubMed

    Marr, Carrie L H; Robertson, Kathy; Reynolds, Kevin D

    2014-04-01

    Concentrations of total mercury (Hg) and methylmercury (MeHg) were determined in water, sediment, periphyton, spiders, and amphibians from the streams and desert marsh downstream from Arivaca Lake, Arizona, to better understand their distribution and bioaccumulation. Mean concentrations of MeHg in water ranged from 0.09 to 0.93 ng/L, and mean concentrations of total Hg in sediment ranged from 10.4 to 126 μg/kg. Hg and MeHg in water and sediments downstream from Arivaca Lake were low enough that they did not exceed human health or ecological thresholds. Hg and MeHg between sites ranged from 0.11 to 1.90 μg/g Hg and 0.01 to 0.3 μg/g MeHg in periphyton, from 0.09 to 0.25 μg/g Hg and 0.04 to 0.10 μg/g MeHg in spiders, and from 0.15 to 0.38 μg/g Hg and 0.14 to 0.35 μg/g MeHg in adult bullfrogs. No Hg toxicity data exist for periphyton or spiders, but MeHg concentrations in tadpoles (0.04 ± 0.005 μg/g) were lower than those known to cause sublethal effects and subchronic mortality. The mean total Hg concentration in adult bullfrogs in the present study was 0.24 μg/g, which is slightly lower than the mean (0.37 μg/g) from an Hg-contaminated wetland in California. MeHg bioaccumulated at each successive trophic level, and MeHg bioconcentration factors from the Arivaca watershed were similar to those for periphyton but greater than amphibians in other studies. Local resource managers can use these data to determine if water should be released from Arivaca Lake to recharge the aquifer downstream or to decrease Hg methylation in the reservoir. PMID:24468966

  2. 19 CFR 351.223 - Procedures for initiation of downstream product monitoring.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 3 2010-04-01 2010-04-01 false Procedures for initiation of downstream product... initiation of downstream product monitoring. (a) Introduction. Section 780 of the Act establishes a mechanism for monitoring imports of “downstream products.” In general, section 780 is aimed at situations...

  3. 40 CFR 80.210 - What sulfur standards apply to gasoline downstream from refineries and importers?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... gasoline downstream from refineries and importers? 80.210 Section 80.210 Protection of Environment... Gasoline Sulfur Gasoline Sulfur Standards § 80.210 What sulfur standards apply to gasoline downstream from... downstream from refineries and import facilities, including gasoline at facilities of distributors,...

  4. Expression of NF-κB and downstream antioxidant genes in skeletal muscle of hibernating ground squirrels, Spermophilus tridecemlineatus.

    PubMed

    Allan, Marcus E; Storey, Kenneth B

    2012-03-01

    Many small mammals survive the winter by hibernating, entering long periods of cold torpor that are interspersed with brief periods of arousal back to euthermia. This cycling is accompanied by wide changes in oxygen consumption, perfusion of tissues and ATP turnover, and the arousal period in particular is challenging because of oxidative stress associated with the huge increase in oxygen consumption needed to support thermogenesis by brown adipose tissue and skeletal muscle. Well-developed antioxidant defences are needed. The present study analyses responses of the redox-sensitive transcription factor, NF-κB, in skeletal muscle over six points on the torpor-arousal cycle to gain insight into its regulation and role during hibernation. Immunoblotting was used to analyse NF-κB p50 and p65 subunit levels, nuclear versus cytoplasmic localization and DNA-binding activity as well as levels and phosphorylation state of the IκBα inhibitor and the kinase IKK that phosphorylates IκBα to trigger its dissociation from NF-κB. The data were generally consistent with an activation of NF-κB during the entrance into torpor with responses including an auto-up-regulation of p50 subunits seen during early torpor and elevated IκBα protein during arousal. Protein levels of two downstream antioxidant targets showed differential regulation, Mn-superoxide dismutase (MnSOD) rising during early torpor versus heme oxygenase 1 (HO-1) increasing during early arousal. The mRNA transcript levels of p50, p65, HO-1 and MnSOD also showed differential expression over the torpor-arousal cycle. The results suggest that antioxidant defences are up-regulated at specific phases of the torpor-arousal cycle and that NF-κB mediates such protective responses. PMID:22086848

  5. Exposure to a putative alarm cue reduces downstream drift in larval sea lamprey Petromyzon marinus in the laboratory.

    PubMed

    Wagner, C M; Kierczynski, K E; Hume, J B; Luhring, T M

    2016-09-01

    An experimental mesocosm study suggested larval sea lamprey Petromyzon marinus detect and respond to an alarm cue released by dead adult conspecifics. Larvae exhibited a reduced tendency to move downstream when exposed to the cue and were less likely to move under continuous v. pulsed exposure. These findings support the hypothesis that short-term exposure to the alarm cue would probably result in retraction into the burrow, consistent with the blind, cryptic lifestyle of the larval P. marinus. PMID:27456088

  6. Flow downstream of the heliospheric terminal shock - Magnetic field kinematics

    NASA Technical Reports Server (NTRS)

    Nerney, S.; Suess, S. T.; Schmahl, E. J.

    1991-01-01

    A kinematic model of the interplanetary magnetic field in the heliosheath beyond the solar wind terminal shock is presented in order to evaluate the possible importance of MHD effects in that region of space. The need for this evaluation arises because the interplanetary magnetic field is compressed across the terminal shock and further amplified by the decreasing flow speed beyond the shock. Streamlines which approach the stagnation point before turning in the downstream direction lead to the strongest effects due to the extreme slowing of the solar wind and consequent compression of the embedded magnetic field. The magnetic volume force therefore cannot be neglected on streamlines that approach the heliopause in the upstream direction, where the volume containing them is a large fraction of the overall of the heliosheath in the upstream direction. The increase in the magnetic pressure may act to bring the upstream terminal shock significantly closer to the sun, potentially reconciling a conflict between models and observations.

  7. Plasma turbulence in the downstream ionosheath of Venus

    NASA Technical Reports Server (NTRS)

    Intriligator, D. S.; Scarf, F. L.

    1982-01-01

    Observations made by the Pioneer Venus Orbiter plasma analyzer and the plasma wave instrument in the Venus ionosheath are compared. Large increases in plasma wave turbulence levels appear to be connected with changing plasma distributions and interpenetrating plasma beams. Some of these plasma waves are identified as Doppler - shifted ion acoustic waves due to beam/beam interactions, but it is noted that different forms of instabilities are probably also operative. The changes in the temperature, intensity and energy of the peak in the PVO plasma distributions are similar to those observed by Venera 10 closer to the planet and appear to be evidence for rarefaction and compression in the downstream ionosheath. Some of the changes in the PVO plasma distributions may be related to the presence of a second ion population or the acceleration of protons.

  8. Optical radiation from regions downstream of mercury bombardment thrusters

    NASA Technical Reports Server (NTRS)

    Milder, N. L.; Sovey, J. S.

    1972-01-01

    A 0.5 meter focal length, plane grating monochromator was used to measure the radiance of spectral radiation emanating from regions downstream of a mercury bombardment thruster. The wavelength range investigated was 2800 A. This radiation was due primarily to the radiative decay of excited mercury atoms exhausted from the thruster. Radiance values ranged from 10 to the minus 11th power to 10 to the minus 9th power W/sq cm sr, varying with wavelength. For resonant radiation, the spectral radiance may exceed 10 to the minus 8th power W/sq cm sr. From such radiance measurements, it was concluded that the thruster background radiation should not interfere with the control functions of a star tracker viewing through the thruster exhaust, provided that the tracker is designed to operate with a sufficiently small field of view.

  9. Ethiopia's Grand Renaissance Dam: Implications for Downstream Riparian Countries

    NASA Astrophysics Data System (ADS)

    Zhang, Y.; Block, P. J.; Hammond, M.; King, A.

    2013-12-01

    Ethiopia has begun seriously developing their significant hydropower potential by launching construction of the Grand Ethiopian Renaissance Dam (GERD) on the Blue Nile River to facilitate local and regional growth. Although this has required substantial planning on Ethiopia's part, no policy dictating the reservoir filling rate strategy has been publicly issued. This filling stage will have clear implications on downstream flows in Sudan and Egypt, complicated by evaporative losses, climate variability, and climate change. In this study, various filling policies and future climate states are simultaneously explored to infer potential streamflow reductions at Lake Nasser, providing regional decision-makers with a set of plausible, justifiable, and comparable outcomes. Schematic of the model framework Box plots of 2017-2032 percent change in annual average streamflow at Lake Nasser for each filling policy constructed from the 100 time-series and weighted precipitation changes. All values are relative to the no dam policy and no changes to future precipitation.

  10. Downstream ecological effects of dams: A geomorphic perspective

    SciTech Connect

    Ligon, F.K.; Dietrich, W.E.; Trush, W.J.

    1995-03-01

    The damming of a river changes the flow of water, sediment, nutrients, energy, and biota, interrupting and altering most of a river`s ecological processes. This article discusses the importance of geomorphological analysis in river conservation and management. To illustrate how subtle geomorphological adjustments may profoundly influence the ecological relationships downstream from dames, three case studies are presented. Then a geomorphically based approach for assessing and possibly mitigating some of the environmental effects of dams by tailoring dam designed and operation is outlined. The cases are as follows: channel simplification and salmon decline on the McKenzie River in Oregon; Channel incision and reduced floodplain inundation on the Oconee river in Georgia; Increased stability of a braided river in New Zealand`s south island. 41 refs., 10 figs., 1 tab.

  11. Progesterone and its downstream molecules as blastocyst implantation essential factors.

    PubMed

    Yoshinaga, Koji

    2014-08-01

    This review is to update the previous review (Am J Reprod Immunol, 63, 2010 and 413) on the research on blastocyst implantation essential factors (BIEFs). Focus of the current review is on progesterone and its downstream molecules in the process of blastocyst implantation. To understand the process of implantation, we need to know where and when the BIEFs are expressed and what they do. Progress in this research area is rapid, and its update is indeed necessary. The basic concept of BIEFs is that they have dual functions, one physiological and the other immunological (J Reprod Dev, 58, 2012 and 196). As we are still exploring the mechanism of implantation, available data are incomplete and human data are few. Thus, I will use information obtained through research on animal models, in vitro studies, cell lines, and some human studies where available. The ultimate goal of the review is to understand human blastocyst implantation. PMID:24754263

  12. Upstream and downstream strategies to economize biodiesel production.

    PubMed

    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. PMID:20974530

  13. Transcriptional regulatory elements downstream of the JunB gene.

    PubMed Central

    Perez-Albuerne, E D; Schatteman, G; Sanders, L K; Nathans, D

    1993-01-01

    JunB is an immediate early transcription factor that is induced by a variety of extracellular signaling agents, including growth factors, phorbol esters, and agents that elevate cyclic AMP. The mechanism of activation of the gene encoding JunB by these agents is not well understood. By using the JunB gene together with flanking DNA in transfection experiments, we show that a serum response element (SRE) and/or a cAMP response element (CRE) downstream of the gene mediate the response of the gene in mouse NIH 3T3 cells to serum, platelet-derived growth factor, basic fibroblast growth factor, phorbol ester, and forskolin. In addition, a segment of DNA just upstream of the TATA box is required for optimal activation of the gene. Images Fig. 1 Fig. 5 PMID:8265655

  14. 7. OBLIQUE VIEW OF NORTH PORTAL AND DOWNSTREAM SIDE OF ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. OBLIQUE VIEW OF NORTH PORTAL AND DOWNSTREAM SIDE OF BRIDGE, LOOKING WEST. Lights and illuminated sign on portal bracing were elements of an overheight load warning system designed to eliminate accidents of the type which damaged the bridge. However, the system was in place only on the north side of the bridge, controlling trucks approaching from Oregon. In theory, trucks with overheight, overwidth, or overweight loads from California would be controlled by the State's permit system. In fact, it was a 'permit' load originating in California, being hauled without the requisite permit which struck and damaged the bridge. - Smith River Bridge, CA State Highway 199 Spanning Smith River, Crescent City, Del Norte County, CA

  15. Continuous downstream processing for high value biological products: A Review.

    PubMed

    Zydney, Andrew L

    2016-03-01

    There is growing interest in the possibility of developing truly continuous processes for the large-scale production of high value biological products. Continuous processing has the potential to provide significant reductions in cost and facility size while improving product quality and facilitating the design of flexible multi-product manufacturing facilities. This paper reviews the current state-of-the-art in separations technology suitable for continuous downstream bioprocessing, focusing on unit operations that would be most appropriate for the production of secreted proteins like monoclonal antibodies. This includes cell separation/recycle from the perfusion bioreactor, initial product recovery (capture), product purification (polishing), and formulation. Of particular importance are the available options, and alternatives, for continuous chromatographic separations. Although there are still significant challenges in developing integrated continuous bioprocesses, recent technological advances have provided process developers with a number of attractive options for development of truly continuous bioprocessing operations. PMID:26153056

  16. Downstream evolution of unconfined vortices: mechanical and thermal aspects

    NASA Astrophysics Data System (ADS)

    Pérez-Saborid, M.; Herrada, M. A.; Gómez-Barea, A.; Barrero, A.

    2002-11-01

    We present a numerical study of the downstream evolution (mechanical and thermal) of vortex-jet cores whose velocity and temperature fields far from the axis match a family of inviscid and non-conducting vortices. The far-velocity field is rotational, except for a particular case which corresponds to the well-known Long's vortex. The evolution of the vortex core depends on both the conditions at a certain upstream station, characterized by the dimensionless value of the velocity at the axis, and a dimensionless swirling parameter L defined as the ratio of the values of the azimuthal and axial velocities outside the vortex core. This numerical study, based on the quasi-cylindrical approximation (QC) of the Navier Stokes equations, determines the conditions under which the vortex evolution proceeds smoothly, eventually reaching an asymptotic self-similar behaviour as described in the literature (Fernández-Feria, Fernández de la Mora & Barrero 1995; Herrada, Pérez-Saborid & Barrero 1999), or breaks in a non-slender solution (vortex breakdown). In particular, the critical value L = Lb(a) beyond which vortex breakdown occurs downstream is a function of a dimensionless parameter a characterizing the axial momentum of the vortex jet at an initial upstream station. It is found numerically that for very large values of a this vortex breakdown criterion tends to an asymptote which is precisely the value L = L* predicted by the self-similar analysis, and beyond which a self-similar structure of the vortex core does not exist. In addition, the computation of the total temperature field provides useful information on the physical mechanisms responsible for the thermal separation phenomenon observed in Ranque Hilsch tubes and other swirling jet devices. In particular, the mechanical work of viscous forces which gives rise to an intense loss of kinetic energy during the initial stages of the evolution has been identified as the physical mechanism responsible for thermal

  17. An analytical solution to river profile concavity and downstream fining

    NASA Astrophysics Data System (ADS)

    Blom, A.; Chavarrias, V.

    2014-12-01

    We present an analytical solution to the steady state upward-concave bed profile, as well as downstream fining, for a river dominated by gravel and sand. The model is based on (i) the conservation equation of streamwise momentum of the flow, (ii) the conservation equation of the mass of each grain size fraction in the surface layer of the bed (the Hirano equation) yet including sediment abrasion, and (iii) the conservation equation of total sediment mass (the Exner equation). The model includes downstream fining induced by abrasion as well as by grainsize-selective transport of gravel and sand. In order to arrive at an analytical solution, the model is deliberately kept simple through assumptions such as a constant width and no tributaries. The model is then reduced to the case of steady state conditions, which means that all time derivatives in the equations are set to zero. We find a solution to the steady state streamwise profile of both the bed slope and the volume fraction of gravel in the surface layer of the bed. Like existing empirical predictors, the analytical solution is of an exponential type. The main variables that affect the solution are the total load at the upstream boundary, the gravel fraction in this upstream load, the abrasion coefficient, the grain sizes of the sediment, and the water discharge at the upstream boundary. The below image shows an example of how the gravel fraction in the upstream load affects the solution to the longitudinal profiles of, respectively, bed slope (S), the gravel fraction at the bed surface (Fg), and the mean grain size of the sediment at the bed surface (Dgs). We can see how an increase in the gravel fraction in the upstream load results in a larger overall slope and an increase in profile concavity. It also induces an increase of the gravel fraction at the bed surface.

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

    NASA Astrophysics Data System (ADS)

    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.

  19. Operating multireservoir hydropower systems for downstream water quality

    SciTech Connect

    Hayes, D.F.

    1990-01-01

    Hydropower reservoir operations often impact tailwater quality and water quality in the stream or river below the impoundment for many miles. Determining optimal operating strategies for a system of hydropower reservoirs involves solving a highly dimensional nonlinear, nonconvex optimization problem. This research adds the additional complexities of downstream water quality considerations within the optimization formulation to determine operating strategies for a system of hydropower reservoirs operating in series (tandem) or parallel. The formulation was used to determine operating strategies for six reservoirs of the upper Cumberland river basin in Tennessee and Kentucky. Significant dissolved oxygen (DO) violations occur just upstream of Nashville, Tennessee below Old Hickory dam during the months of August and September. Daily reservoir releases were determined for the period of June through September which would produce the maximum hydropower revenue while meeting downstream water quality objectives. Optimal releases for three operational strategies were compared to historical operations for the years 1985, 1986, and 1988. These strategies included: spilling as necessary to meet water quality criteria, near normal operation (minimal spills), and drawdown of reservoirs as necessary to meet criteria without spills. Optimization results showed an 8% to 15% hydropower loss may be necessary to meet water quality criteria through spills and a 2% to 9% improvement in DO below Old Hickory may be possible without significant spills. Results also showed that substantial increases in initial headwater elevations would be necessary to meet daily DO criteria and avoid spills. The optimal control theory algorithm used to solve the problem proved to be an efficient and robust solver of this large optimization problem.

  20. Particle injection and acceleration at earth's bow shock - Comparison of upstream and downstream events

    NASA Technical Reports Server (NTRS)

    Ellison, Donald C.; Moebius, Eberhard; Paschmann, Goetz

    1990-01-01

    The injection and acceleration of thermal solar wind ions at the quasi-parallel earth's bow shock during radial interplanetary magnetic field conditions is investigated. Active Magnetospheric Particle Tracer Explorers/Ion Release Module satellite observations of complete proton spectra, and of heavy ion spectra above 10 keV/Q, made on September 12, 1984 near the nose of the shock, are presented and compared to the predictions of a Monte Carlo shock simulation which includes diffusive shock acceleration. It is found that the spectral observations are in good agreement with the predictions of the simulation when it is assumed that all accelerated ions originate in the solar wind and are injected into the acceleration mechanism by thermal leakage from the downstream plasma. The efficiency, which is determined directly from the downstream observations, is high, with at least 15 percent of the solar wind energy flux going into accelerated particles. The comparisons allow constraints to be placed on the rigidity dependence of the scattering mean free path and suggest that the upstream solar wind must be slowed substantially by backstreaming accelerated ions prior to undergoing a sharp transition in the viscous subshock.

  1. Biogeochemically diverse organic matter in Alpine glaciers and its downstream fate

    NASA Astrophysics Data System (ADS)

    Singer, Gabriel A.; Fasching, Christina; Wilhelm, Linda; Niggemann, Jutta; Steier, Peter; Dittmar, Thorsten; Battin, Tom J.

    2012-10-01

    Besides their role in the hydrological cycle, glaciers could play an important role in the carbon cycle. They store and transform organic carbon, which on release could support downstream microbial life. Yet the origin and composition of glacial organic carbon, and its implications for the carbon cycle, remain unclear. Here, we examine the molecular composition, radiocarbon age and bioavailability of dissolved organic matter (DOM) in 26 glaciers in the European Alps, using ultrahigh-resolution mass spectrometry, fluorescence spectroscopy and incubation experiments. We also measure carbon dioxide partial pressures in glacier-fed streams. We show that the glacier organic matter is highly diverse, and that a significant fraction of this material is bioavailable. Phenolic compounds derived from vascular plants or soil dominate, together with peptides and lipids, potentially derived from in situ microbial communities. Combustion products, in contrast, seem to contribute only marginally to the DOM sampled. We further show that organic matter bioavailability is positively correlated with in-stream carbon dioxide concentrations. We suggest that glacier-derived DOM contributes to downstream carbon cycling in glacier-fed streams. Our findings highlight the relevance of mountain glaciers for carbon cycling--a role that may change as glaciers recede.

  2. Targeting CXCL13 During Neuroinflammation

    PubMed Central

    Huber, Amanda K.; Irani, David N.

    2016-01-01

    The chemokine, C-X-C motif ligand 13 (CXCL13), is constitutively expressed in lymphoid organs and controls the recruitment and compartmentalization of lymphocytes and antigen presenting cells within these specialized structures. Recent data, however, also find induction of this molecule during central nervous system (CNS) inflammation under a variety of circumstances. While its role(s) in the pathogenesis of neoplastic, infectious and autoimmune disorders of the CNS remain incompletely understood, several lines of evidence suggest that CXCL13 could become a relevant therapeutic target in at least some of these diseases. This review focuses on how CXCL13 contributes to the pathogenesis of selected CNS disorders involving both experimental animals and humans, paying particular attention to the issue of whether (and if so, how) blockade of this ligand or its receptor might benefit the host. Current blocking strategies largely involve the use of monoclonal antibodies, but an improved understanding of downstream signaling pathways makes small molecule inhibition a future possibility. PMID:26855687

  3. Pattern Genes Suggest Functional Connectivity of Organs.

    PubMed

    Qin, Yangmei; Pan, Jianbo; Cai, Meichun; Yao, Lixia; Ji, Zhiliang

    2016-01-01

    Human organ, as the basic structural and functional unit in human body, is made of a large community of different cell types that organically bound together. Each organ usually exerts highly specified physiological function; while several related organs work smartly together to perform complicated body functions. In this study, we present a computational effort to understand the roles of genes in building functional connection between organs. More specifically, we mined multiple transcriptome datasets sampled from 36 human organs and tissues, and quantitatively identified 3,149 genes whose expressions showed consensus modularly patterns: specific to one organ/tissue, selectively expressed in several functionally related tissues and ubiquitously expressed. These pattern genes imply intrinsic connections between organs. According to the expression abundance of the 766 selective genes, we consistently cluster the 36 human organs/tissues into seven functional groups: adipose &gland, brain, muscle, immune, metabolism, mucoid and nerve conduction. The organs and tissues in each group either work together to form organ systems or coordinate to perform particular body functions. The particular roles of specific genes and selective genes suggest that they could not only be used to mechanistically explore organ functions, but also be designed for selective biomarkers and therapeutic targets. PMID:27225987

  4. Pattern Genes Suggest Functional Connectivity of Organs

    PubMed Central

    Qin, Yangmei; Pan, Jianbo; Cai, Meichun; Yao, Lixia; Ji, Zhiliang

    2016-01-01

    Human organ, as the basic structural and functional unit in human body, is made of a large community of different cell types that organically bound together. Each organ usually exerts highly specified physiological function; while several related organs work smartly together to perform complicated body functions. In this study, we present a computational effort to understand the roles of genes in building functional connection between organs. More specifically, we mined multiple transcriptome datasets sampled from 36 human organs and tissues, and quantitatively identified 3,149 genes whose expressions showed consensus modularly patterns: specific to one organ/tissue, selectively expressed in several functionally related tissues and ubiquitously expressed. These pattern genes imply intrinsic connections between organs. According to the expression abundance of the 766 selective genes, we consistently cluster the 36 human organs/tissues into seven functional groups: adipose & gland, brain, muscle, immune, metabolism, mucoid and nerve conduction. The organs and tissues in each group either work together to form organ systems or coordinate to perform particular body functions. The particular roles of specific genes and selective genes suggest that they could not only be used to mechanistically explore organ functions, but also be designed for selective biomarkers and therapeutic targets. PMID:27225987

  5. Pattern Genes Suggest Functional Connectivity of Organs

    NASA Astrophysics Data System (ADS)

    Qin, Yangmei; Pan, Jianbo; Cai, Meichun; Yao, Lixia; Ji, Zhiliang

    2016-05-01

    Human organ, as the basic structural and functional unit in human body, is made of a large community of different cell types that organically bound together. Each organ usually exerts highly specified physiological function; while several related organs work smartly together to perform complicated body functions. In this study, we present a computational effort to understand the roles of genes in building functional connection between organs. More specifically, we mined multiple transcriptome datasets sampled from 36 human organs and tissues, and quantitatively identified 3,149 genes whose expressions showed consensus modularly patterns: specific to one organ/tissue, selectively expressed in several functionally related tissues and ubiquitously expressed. These pattern genes imply intrinsic connections between organs. According to the expression abundance of the 766 selective genes, we consistently cluster the 36 human organs/tissues into seven functional groups: adipose & gland, brain, muscle, immune, metabolism, mucoid and nerve conduction. The organs and tissues in each group either work together to form organ systems or coordinate to perform particular body functions. The particular roles of specific genes and selective genes suggest that they could not only be used to mechanistically explore organ functions, but also be designed for selective biomarkers and therapeutic targets.

  6. Cysteine S-Glutathionylation Promotes Stability and Activation of the Hippo Downstream Effector Transcriptional Co-activator with PDZ-binding Motif (TAZ).

    PubMed

    Gandhirajan, Rajesh Kumar; Jain, Manaswita; Walla, Benedikt; Johnsen, Marc; Bartram, Malte P; Huynh Anh, Minh; Rinschen, Markus M; Benzing, Thomas; Schermer, Bernhard

    2016-05-27

    Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are critical transcriptional co-activators downstream of the Hippo pathway involved in the regulation of organ size, tissue regeneration, proliferation, and apoptosis. Recent studies suggested common and distinct functions of TAZ and YAP and their diverse impact under several pathological conditions. Here we report differential regulation of TAZ and YAP in response to oxidative stress. H2O2 exposure leads to increased stability and activation of TAZ but not of YAP. H2O2 induces reversible S-glutathionylation at conserved cysteine residues within TAZ. We further demonstrate that TAZ S-glutathionylation is critical for reactive oxygen species (ROS)-mediated, TAZ-dependent TEA domain transcription factor (TEAD) trans-activation. Lysophosphatidic acid, a physiological activator of YAP and TAZ, induces ROS elevation and, subsequently, TAZ S-glutathionylation, which promotes TAZ-mediated target gene expression. TAZ expression is essential for renal homeostasis in mice, and we identify basal TAZ S-glutathionylation in murine kidney lysates, which is elevated during ischemia/reperfusion injury in vivo This induced nuclear localization of TAZ and increased expression of connective tissue growth factor. These results describe a novel mechanism by which ROS sustains total cellular levels of TAZ. This preferential regulation suggests TAZ to be a redox sensor of the Hippo pathway. PMID:27048650

  7. The case for soluble Aβ oligomers as a drug target in Alzheimer's disease.

    PubMed

    Hefti, Franz; Goure, William F; Jerecic, Jasna; Iverson, Kent S; Walicke, Patricia A; Krafft, Grant A

    2013-05-01

    Soluble Aβ oligomers are now widely recognized as key pathogenic structures in Alzheimer's disease. They inhibit synaptic function, leading to early memory deficits and synaptic degeneration, and they trigger the downstream neuronal signaling responsible for phospho-tau Alzheimer's pathology. The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric Aβ, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in amyloid plaques. Accumulating scientific data suggest that soluble Aβ oligomers represent the optimal intervention target within the amyloid manifold. Active drug discovery approaches include antibodies that selectively capture soluble Aβ oligomers, selective modifiers of oligomer assembly, and receptor antagonists. The onset of symptomatic clinical benefit is expected to be rapid for such agents, because neuronal memory signaling should normalize on blockage of soluble Aβ oligomers. This key feature is not shared by amyloid-lowering therapeutics, and it should translate into streamlined clinical development for oligomer-targeting drugs. Oligomer-targeting drugs should also confer long-term disease modification and slowing of disease progression, because they prevent the downstream signaling responsible for phospho-tau mediated cytoskeletal degeneration. PMID:23582316

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

    PubMed

    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. PMID:26658782

  9. Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells.

    PubMed

    Yang, Jun; Li, Xiaohui; Li, Ying; Southwood, Mark; Ye, Lingying; Long, Lu; Al-Lamki, Rafia S; Morrell, Nicholas W

    2013-08-15

    Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1-4) are major downstream transcriptional targets of BMP signaling. However, the impact of BMPR-II mutation on the expression of the range of Id proteins and the contribution of individual Id proteins to abnormal PASMC function remain unclear. Human PASMCs were used to determine the expression of Id proteins (Id1-4) by real-time PCR and immunoblotting. The BMP responses in control cells were compared with PASMCs harboring BMPR-II mutations and cells in which BMPR-II was knocked down by siRNA transfection. Id3 expression in pulmonary vessels was also investigated in BMPR-II mutant mice and in patients with heritable PAH. BMP4 and BMP6, but not BMP9, induced mRNA expression of Id1, Id2, and Id3. The BMP-stimulated induction of Id1 and Id3 was markedly reduced in BMPR-II mutant PASMCs and in control PASMCs following siRNA silencing of BMPR-II. Pulmonary arteries in BMPR-II mutant mice and patients with heritable PAH demonstrated reduced levels of Id3 compared with control subjects. Lentiviral overexpression of Id3 reduced cell cycle progression and inhibited proliferation of PASMCs. Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli. PMID:23771884

  10. Libby Dam Hydro-electric Project Mitigation: Efforts for Downstream Ecosystem Restoration.

    SciTech Connect

    Holderman, Charles

    2009-02-10

    Construction of Libby Dam, a large hydropower and flood control dam occurred from 1966 to 1975 on the Kootenai River, near Libby, Montana in the Northwestern United States. Live reservoir storage is substantial, with water residence time of about 5 1/2 months (based on mean annual discharge of about 440 m{sup 3}/s). Downstream river discharge and thermal regimes and the dependent habitat conditions have been significantly altered by dam construction and operation relative to pre-dam conditions. Highly valued Kootenai River fish populations, including white sturgeon Acipenser transmontanus, burbot Lota lota and bull trout Salvelinus confluentus and their supporting ecological conditions have been deteriorating during post-dam years. Measurements of the presence of very low (ultraoligotrophic) concentrations of dissolved phosphorus in the river downstream from Libby Dam were identified as a critical limitation on primary production and overall ecosystem health. A decision was made to initiate the largest experimental river fertilization project to date in the Kootenai River at the Montana-Idaho border. Pre-treatment aquatic biomonitoring began in 2001; post-treatment monitoring began in 2005. A solar-powered nutrient addition system was custom designed and built to dose small releases of dissolved nutrients at rates from 10 to 40 L/hour, depending on river discharge, which averaged several hundred m3/s. Closely monitored experimental additions of ammonium polyphosphate solution (10-34-0) into the river occurred during the summers of 2005 through 2008. Targets for mixed in-river P concentrations were 1.5 {micro}g/L in 2005, and 3 {micro}g/L in subsequent years. Primary productivity and algal accrual rates along with invertebrate and fish community metrics and conditions were consistently measured annually, before and after experimental fertilization. Initial results from the program are very encouraging, and are reported.

  11. Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

    PubMed Central

    Yang, Jun; Li, Xiaohui; Li, Ying; Southwood, Mark; Ye, Lingying; Long, Lu; Al-Lamki, Rafia S.

    2013-01-01

    Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1–4) are major downstream transcriptional targets of BMP signaling. However, the impact of BMPR-II mutation on the expression of the range of Id proteins and the contribution of individual Id proteins to abnormal PASMC function remain unclear. Human PASMCs were used to determine the expression of Id proteins (Id1–4) by real-time PCR and immunoblotting. The BMP responses in control cells were compared with PASMCs harboring BMPR-II mutations and cells in which BMPR-II was knocked down by siRNA transfection. Id3 expression in pulmonary vessels was also investigated in BMPR-II mutant mice and in patients with heritable PAH. BMP4 and BMP6, but not BMP9, induced mRNA expression of Id1, Id2, and Id3. The BMP-stimulated induction of Id1 and Id3 was markedly reduced in BMPR-II mutant PASMCs and in control PASMCs following siRNA silencing of BMPR-II. Pulmonary arteries in BMPR-II mutant mice and patients with heritable PAH demonstrated reduced levels of Id3 compared with control subjects. Lentiviral overexpression of Id3 reduced cell cycle progression and inhibited proliferation of PASMCs. Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli. PMID:23771884

  12. Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues

    PubMed Central

    2013-01-01

    Background Fasting induces specific molecular and metabolic adaptions in most organisms. In biomedical research fasting is used in metabolic studies to synchronize nutritional states of study subjects. Because there is a lack of standardization for this procedure, we need a deeper understanding of the dynamics and the molecular mechanisms in fasting. Results We investigated the dynamic changes of liver gene expression and serum parameters of mice at several time points during a 48 hour fasting experiment and then focused on the global gene expression changes in epididymal white adipose tissue (WAT) as well as on pathways common to WAT, liver, and skeletal muscle. This approach produced several intriguing insights: (i) rather than a sequential activation of biochemical pathways in fasted liver, as current knowledge dictates, our data indicates a concerted parallel response; (ii) this first characterization of the transcriptome signature of WAT of fasted mice reveals a remarkable activation of components of the transcription apparatus; (iii) most importantly, our bioinformatic analyses indicate p53 as central node in the regulation of fasting in major metabolic tissues; and (iv) forced expression of Ddit4, a fasting-regulated p53 target gene, is sufficient to augment lipolysis in cultured adipocytes. Conclusions In summary, this combination of focused and global profiling approaches provides a comprehensive molecular characterization of the processes operating during fasting in mice and suggests a role for p53, and its downstream target Ddit4, as novel components in the transcriptional response to food deprivation. PMID:24191950

  13. Relative impact of amyloid-β, lacunes, and downstream imaging markers on cognitive trajectories.

    PubMed

    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

    thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β = 0.19, P = 0.026). Our multimodal imaging analyses suggest that cognitive trajectories related to amyloid-β and lacunes have distinct paths, and that amyloid-β or lacunes have greatest impact on cognitive decline. Our results provide rationale for the targeting of amyloid-β and lacunes in therapeutic strategies aimed at ameliorating cognitive decline. PMID:27329772

  14. Electron acceleration at nearly perpendicular collisionless shocks. 3: Downstream distributions

    NASA Technical Reports Server (NTRS)

    Krauss-Varban, D.

    1994-01-01

    Spacecraft observations at the Earth's bow shock and at interplanetary shocks have established that the largest fluxes of accelerated suprathermal electrons occur in so-called shock spike events immediately downstream of the shock ramp. Previous theoretical efforts have mainly focused on explaining upstream energetic electron beams. Here we investigate the general motion and acceleration of energetic electrons in a curved, nearly perpendicular shock by numerically integrating the orbits of solar wind halo electrons in shock fields generated by a hybrid simulation (core electron fluid and kinetic ions). Close to the angle Theta(sub Bn) = 90 degs between the upstream magnetic field and shock normal, the calculations result in a (perpendicular) temperature increase proportional to the magnetic field ratio and give the highest phase space densities in the overshoot. For a steep distribution, the temperature change can correspond to an enhancement of the distribution by several orders of magnitude. These results are in agreement with predictions from adiabatic mapping. With smaller angles Theta(sub Bn), the overshoot and downstream densities fall off quickly, because the adiabatic energy gain is less and fewer electrons transmit. The shock curvature also leads to an accumulation of electrons close to 90 degs. Without pitch angle scattering, energization is only significant within a few (approximately 5 to 10 degs) degrees of the point of tangency. However, shock spike events appear to be observed more easily and farther away from 90 degs. Given that over a region of several degrees around 90 degs the theory gives enhancements of up to approximately 4 orders of magnitude, such electrons could in principle account for the typically observed enhancements of 1 to 2 orders of magnitude, if they were distributed over Theta(sub Bn). To test the idea that scattering could efficiently redistribute the energetic electrons, we have conducted test particle simulations in which

  15. The impact of proglacial lakes on downstream sediment delivery

    NASA Astrophysics Data System (ADS)

    Bogen, Jim; Xu, Mengzhen; Kennie, Patricia

    2013-04-01

    This paper discusses the impact of proglacial lakes on sediment transport of three different glaciers: Nigardsbre, Engabre and Tunsbergdalsbre. All of these lakes were developed in modern time. The recession of the Nigardsbre uncovered a 1.8 km long and on average 15 m deep proglacial lake during the years 1937 to 1968. From that time the glacier front was situated entirely on land, and the sediment input and output to the lake were measured. Sediment samples were collected 2- 4 times a day and the water discharge was recorded. The sediment transport into and out of the lake was on average 10504 t yr-1 and 2340 t yr-1during the years 1968 - 1981. Thus, 23% remained in suspension at the outlet. In 2011 an excessively high transport of 32356 t yr-1was recorded, due to several large flash floods that year. A 1.9 km long and up to 90 m deep proglacial lake downstream from Engabre glacier was uncovered during the years 1930 - 1945. The average suspended sediment load delivered from the glacier during the years 1970 - 1981 amounted to 12375 t yr-1and the transport out of the lake was 2021 t yr-1, giving an average of 16% remaining in suspension. In 2000 the sediment transport into the lake amounted to 15450 t yr-1. For the Tunsbergdalsbre glacier, measurements in the early 1970s indicated that the suspended sediment transport was on average 44000 t yr-1. From 1987 to 1993 the recession of the glacier uncovered a proglacial lake. Downstream from this 0.3 km long and around 9 m deep lake, the suspended sediment load was measured as 28 000 t yr-1in 2009, indicating that as much as 64% remained in suspension. The various factors affecting the sedimentation rates in the proglacial lakes are discussed. The low sedimentation rate of the lake in front of the Tunsbergdalsbre was due to its limited length and depth. Hence the meltwater from the glacier maintains a high flow velocity. The lake will however increase its size as the glacier recedes. The two other lakes have gone

  16. Role of nitrogen in the downstream etching of silicon nitride

    SciTech Connect

    Blain, M.G.; Meisenheimer, T.L.; Stevens, J.E.

    1996-07-01

    Chemical downstream etching of silicon nitride (Si{sub 3}N{sub 4}) requires the addition of nitrogen to the discharge for obtaining efficient etch rates. A 10{percent} addition of N{sub 2} to a CF{sub 4}/O{sub 2} discharge (CF{sub 4}/O{sub 2} = 1.2, 0.525 Torr) causes a factor of 6 increase in the Si{sub 3}N{sub 4} etch rate and a 8{percent} decrease in the silicon dioxide etch rate. The result is selectivities approaching 9:1. Importantly, the conversion of CF{sub 4} to F and F-containing reactive species by the discharge decreases or remains constant as nitrogen is added to the discharge mix, indicating that the etching reaction is not limited by delivery of these species to the substrate. By measuring the amount of NO and NO{sub 2} in the etch chamber, it is found that the NO concentration increases by a factor of 6 as N{sub 2} is added, while the amount of NO{sub 2} remains small and constant. The NO signal is significantly reduced during nitride etching compared to the signal observed during a discharge with an empty etch chamber, implying that the increase in Si{sub 3}N{sub 4} etch rate is related to the formation of NO in the discharge. This view is consistent with the observation that an NF{sub 3} plasma in a quartz discharge tube results in a nitride etch rate which is a factor of 2 higher than for the same discharge in a sapphire tube. The conclusion is that the oxygen liberated by erosion of the quartz tube allows the formation of NO. That NO is a key Si{sub 3}N{sub 4} etch reactant was confirmed by performing a series of experiments in which N{sub 2}, NO, NO{sub 2}, and N{sub 2}O were injected into the discharge and then downstream in the reaction chamber during a CF{sub 4}/O{sub 2} discharge. Nitride etch rates increased significantly upon injection of NO into both discharge and etch chamber as compared to injection of the other N{sub {ital x}}O{sub {ital y}} species. {copyright} {ital 1996 American Vacuum Society}

  17. A theoretical study of mixing downstream of transverse injection into a supersonic boundary layer

    NASA Technical Reports Server (NTRS)

    Baker, A. J.; Zelazny, S. W.

    1972-01-01

    A theoretical and analytical study was made of mixing downstream of transverse hydrogen injection, from single and multiple orifices, into a Mach 4 air boundary layer over a flat plate. Numerical solutions to the governing three-dimensional, elliptic boundary layer equations were obtained using a general purpose computer program. Founded upon a finite element solution algorithm. A prototype three-dimensional turbulent transport model was developed using mixing length theory in the wall region and the mass defect concept in the outer region. Excellent agreement between the computed flow field and experimental data for a jet/freestream dynamic pressure ratio of unity was obtained in the centerplane region of the single-jet configuration. Poorer agreement off centerplane suggests an inadequacy of the extrapolated two-dimensional turbulence model. Considerable improvement in off-centerplane computational agreement occured for a multi-jet configuration, using the same turbulent transport model.

  18. Effects of bursty protein production on the noisy oscillatory properties of downstream pathways

    NASA Astrophysics Data System (ADS)

    Toner, D. L. K.; Grima, R.

    2013-08-01

    Experiments show that proteins are translated in sharp bursts; similar bursty phenomena have been observed for protein import into compartments. Here we investigate the effect of burstiness in protein expression and import on the stochastic properties of downstream pathways. We consider two identical pathways with equal mean input rates, except in one pathway proteins are input one at a time and in the other proteins are input in bursts. Deterministically the dynamics of these two pathways are indistinguishable. However the stochastic behavior falls in three categories: (i) both pathways display or do not display noise-induced oscillations; (ii) the non-bursty input pathway displays noise-induced oscillations whereas the bursty one does not; (iii) the reverse of (ii). We derive necessary conditions for these three cases to classify systems involving autocatalysis, trimerization and genetic feedback loops. Our results suggest that single cell rhythms can be controlled by regulation of burstiness in protein production.

  19. Effect of initial conditions on turbulent reattachment downstream of a backward-facing step

    NASA Technical Reports Server (NTRS)

    Westphal, R. V.; Johnston, J. P.

    1984-01-01

    The reattachment of a fully turbulent, two-dimentional shear layer downstream of a backward-facing step has been studied experimentally. The work examines the effect of variations in inlet conditions on the process of reattachment. A series of experiments was conducted in a low-speed wind tunnel using specialized instrumentation suited to the highly turbulent reversing flow near reattachment. Accurate characterization of the time-mean features of the reattaching flows was possible. Assuming linear scaling normalized on distance from reattachment, distributions of normalized pressure coefficient and forward flow fraction, and time-averaged skin friction coefficient appear universal for two-dimensional reattachment, independent of initial conditions and step height, for given duct geometry (area ratio) and for high step-height Reyolds numbers with thin separating boundary layers. The results suggest universal flow structure in the reattachment zone.

  20. Observational evidence for aerosol invigoration in shallow cumulus downstream of Mount Kilauea

    NASA Astrophysics Data System (ADS)

    Mace, G. G.; Abernathy, A. C.

    2016-03-01

    Knowledge of how marine boundary layer (MBL) shallow cumulus clouds respond to changes in aerosol is central to understanding how MBL clouds modulate the climate system. Mount Kilauea on the island of Hawaii began erupting in 2008 injecting substantial SO2 into the marine boundary layer creating a unique natural laboratory. Examining data from approximately 600 passes of the A-Train downstream of Mount Kilauea over a 3 year period and separating data into aerosol optical depth quartiles, we find an unambiguous increase in marine boundary cloud top height and an increase in surface wind speed as aerosol increases while the radar reflectivity does not change substantially. We conclude that increased aerosols may have caused invigoration of the MBL clouds. Additionally, we find that increases in sub 1 km cloud fraction combined with increasing aerosol explain the increased visible reflectance suggesting that evidence for the so-called first aerosol indirect effect should be reexamined.

  1. Ion Energy Distribution Measurements Downstream of the High Power Helicon Plasma Thruster with a Flux Conserving Nozzle Configuration

    NASA Astrophysics Data System (ADS)

    Slobodov, Ilia; Winglee, Robert; Prager, James; Ziemba, Tim; Race Roberson, B.

    2010-11-01

    The high power helicon (HPH) deposits up to 40 kW of power into a plasma, generating a plasma beam with a measured source density of 1x10^20 m-3 and energies in the range of 20-40 eV. Recently, the arrangement of magnetic nozzles downstream of the plasma source has been modified in order to produce a flux conserving configuration. Retarded field energy analyzer (RFEA) measurements of the ion energy distribution functions at two locations downstream of the plasma source, 67 cm and 144 cm away, have been carried out. Data on the number density, ion velocity, and energy density of the plasma beam at these locations will be presented. An improvement in performance over the previous nozzle configuration is observed. Additionally, results suggest that the energy density of the beam does not decrease with distance from the source between the two locations.

  2. Downstream Processing, Formulation Development and Antithrombotic Evaluation of Microbial Nattokinase.

    PubMed

    Kapoor, Rohit; Harde, Harshad; Jain, Sanyog; Panda, Amulya Kumar; Panda, Bibhu Prasad

    2015-07-01

    The present research work describes the downstreaming of nattokinase (NK) produced by Bacillus subtilis under solid state fermentation; and the role of efficient oral formulation of purified NK in the management of thrombotic disorders. Molecular weight of purified NK was estimated to be 28 kDa with specific activity of 504.4 FU/mg. Acid stable nattokinase loaded chitosan nanoparticles (sNLCN) were fabricated for oral delivery of this enzyme. Box-Behnken design (BBD) was employed to investigate and validate the effect of process (independent) variables on the quality attributes (dependent variables) of nanoparticles. The integrity, conformational stability and preservation of fibrinolytic activity of NK (in both free and sNLCN forms) were established by SDS-PAGE, CD analysis and in vitro clot lytic examination, respectively. A 'tail thrombosis model' demonstrated significant decrease in frequency of thrombosis in Wistar rats upon peroral administration of sNLCN in comparison with negative control and free NK group. Furthermore, coagulation analysis, namely the measurement of prothrombin and activated partial thromboplastin time illustrated that sNLCN showed significantly (p < 0.001) higher anti-thrombotic potential in comparison to the free NK. Further, sNLCN showed anti-thrombotic profile similar to warfarin. This study signifies the potential of sNLCN in oral delivery of NK for the management of thrombotic disorders. PMID:26307844

  3. Synthetic Routes to Methylerythritol Phosphate Pathway Intermediates and Downstream Isoprenoids

    PubMed Central

    Jarchow-Choy, Sarah K; Koppisch, Andrew T; Fox, David T

    2014-01-01

    Isoprenoids constitute the largest class of natural products with greater than 55,000 identified members. They play essential roles in maintaining proper cellular function leading to maintenance of human health, plant defense mechanisms against predators, and are often exploited for their beneficial properties in the pharmaceutical and nutraceutical industries. Most impressively, all known isoprenoids are derived from one of two C5-precursors, isopentenyl diphosphate (IPP) or dimethylallyl diphosphate (DMAPP). In order to study the enzyme transformations leading to the extensive structural diversity found within this class of compounds there must be access to the substrates. Sometimes, intermediates within a biological pathway can be isolated and used directly to study enzyme/pathway function. However, the primary route to most of the isoprenoid intermediates is through chemical catalysis. As such, this review provides the first exhaustive examination of synthetic routes to isoprenoid and isoprenoid precursors with particular emphasis on the syntheses of intermediates found as part of the 2C-methylerythritol 4-phosphate (MEP) pathway. In addition, representative syntheses are presented for the monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), triterpenes (C30) and tetraterpenes (C40). Finally, in some instances, the synthetic routes to substrate analogs found both within the MEP pathway and downstream isoprenoids are examined. PMID:25009443

  4. Oxidative stress and its downstream signaling in aging eyes

    PubMed Central

    Pinazo-Durán, María Dolores; Gallego-Pinazo, Roberto; García-Medina, Jose Javier; Zanón-Moreno, Vicente; Nucci, Carlo; Dolz-Marco, Rosa; Martínez-Castillo, Sebastián; Galbis-Estrada, Carmen; Marco-Ramírez, Carla; López-Gálvez, Maria Isabel; Galarreta, David J; Díaz-Llópis, Manuel

    2014-01-01

    Background Oxidative stress (OS) and its biomarkers are the biochemical end point of the imbalance between reactive oxygen species (ROS) production and the ability of the antioxidant (AOX) biological systems to fight against oxidative injury. Objective We reviewed the role of OS and its downstream signaling in aging eyes. Methods A search of the literature and current knowledge on the physiological and pathological mechanisms of OS were revisited in relation to the eyes and the aging process. Most prevalent ocular diseases have been analyzed herein in relation to OS and nutraceutic supplements, such as dry-eye disorders, glaucoma, age-related macular degeneration, and diabetic retinopathy. Results Clinical, biochemical, and molecular data from anterior and posterior eye segment diseases point to OS as the common pathogenic mechanism in the majority of these ocular disorders, many of which are pathologies causing visual impairment, blindness, and subsequent loss of life quality. Studies with nutraceutic supplements in aging eye-related pathologies have also been reviewed. Conclusion OS, nutritional status, and nutraceutic supplements have to be considered within the standards of care of older ophthalmologic patients. OS biomarkers and surrogate end points may help in managing the aging population with ocular diseases. PMID:24748782

  5. NRP2 transcriptionally regulates its downstream effector WDFY1

    PubMed Central

    Dutta, Samikshan; Roy, Sohini; Polavaram, Navatha S; Baretton, Gustavo B.; Muders, Michael H.; Batra, Surinder; Datta, Kaustubh

    2016-01-01

    Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)–protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, essential for promotion of oncogenic activation and cancer cell survival. Here, we have delineated the underlying molecular mechanism of WDFY1 synthesis by NRP2. Our results indicated that NRP2 inhibits WDFY1 transcription by preventing the nuclear localization of a transcription factor, Fetal ALZ50-reactive clone 1 (FAC1). Our finding is novel as transcriptional regulation of a gene by NRP2 axis has not been reported previously. Regulation of WDFY1 transcription by NRP2 axis is a critical event in maintaining metastatic phenotype in cancer cells. Thus, inhibiting NRP2 or hyper-activating WDFY1 can be an effective strategy to induce cell death in metastatic cancer. PMID:27026195

  6. NRP2 transcriptionally regulates its downstream effector WDFY1.

    PubMed

    Dutta, Samikshan; Roy, Sohini; Polavaram, Navatha S; Baretton, Gustavo B; Muders, Michael H; Batra, Surinder; Datta, Kaustubh

    2016-01-01

    Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)-protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, essential for promotion of oncogenic activation and cancer cell survival. Here, we have delineated the underlying molecular mechanism of WDFY1 synthesis by NRP2. Our results indicated that NRP2 inhibits WDFY1 transcription by preventing the nuclear localization of a transcription factor, Fetal ALZ50-reactive clone 1 (FAC1). Our finding is novel as transcriptional regulation of a gene by NRP2 axis has not been reported previously. Regulation of WDFY1 transcription by NRP2 axis is a critical event in maintaining metastatic phenotype in cancer cells. Thus, inhibiting NRP2 or hyper-activating WDFY1 can be an effective strategy to induce cell death in metastatic cancer. PMID:27026195

  7. Characterisation of turbulence downstream of a linear compressor cascade

    NASA Astrophysics Data System (ADS)

    di Mare, Luca; Jelly, Thomas; Day, Ivor

    2014-11-01

    Characterisation of turbulence in turbomachinery remains one of the most complex tasks in fluid mechanics. In addition, current closure models required for Reynolds-averaged Navier-Stokes computations do not accurately represent the action of turbulent forces against the mean flow. Therefore, the statistical properties of turbulence in turbomachinery are of significant interest. In the current work, single- and two-point hot-wire measurements have been acquired downstream of a linear compressor cascade in order to examine the properties of large-scale turbulent structures and to assess how they affect turbulent momentum and energy transfer in compressor passages. The cascade has seven controlled diffusion which are representative of high-pressure stator blades found in turbofan engines. Blade chord, thickness and camber are 0.1515 m, 9.3% and 42 degrees, respectively. Measurements were acquired at a chord Reynolds number of 6 . 92 ×105 . Single-point statistics highlight differences in turbulence structure when comparing mid-span and end-wall regions. Evaluation of two-point correlations and their corresponding spectra reveal the length-scales of the energy-bearing eddies in the cascade. Ultimately, these measurements can be used to calibrate future computational models. The authors gratefully acknowledge Rolls-Royce plc for funding this work and granting permission for its publication.

  8. Deformability-based cell selection with downstream immunofluorescence analysis.

    PubMed

    Shaw Bagnall, Josephine; Byun, Sangwon; Miyamoto, David T; Kang, Joon Ho; Maheswaran, Shyamala; Stott, Shannon L; Toner, Mehmet; Manalis, Scott R

    2016-05-16

    Mechanical properties of single cells have been shown to relate to cell phenotype and malignancy. However, until recently, it has been difficult to directly correlate each cell's biophysical characteristics to its molecular traits. Here, we present a cell sorting technique for use with a suspended microchannel resonator (SMR), which can measure biophysical characteristics of a single cell based on the sensor's record of its buoyant mass as well as its precise position while it traverses through a constricted microfluidic channel. The measurement provides information regarding the amount of time a cell takes to pass through a constriction (passage time), as related to the cell's deformability and surface friction, as well as the particular manner in which it passes through. In the method presented here, cells of interest are determined based on passage time, and are collected off-chip for downstream immunofluorescence imaging. The biophysical single-cell SMR measurement can then be correlated to the molecular expression of the collected cell. This proof-of-principle is demonstrated by sorting and collecting tumor cells from cell line-spiked blood samples as well as a metastatic prostate cancer patient blood sample, identifying them by their surface protein expression and relating them to distinct SMR signal trajectories. PMID:26999591

  9. Upstream versus downstream control of meltwater plumes under ice shelves

    NASA Astrophysics Data System (ADS)

    Wells, Andrew

    2013-11-01

    In many locations the Greenland and Antarctic ice sheets discharge into the ocean through ice shelves floating on top of a warm salty ocean. The turbulent buoyancy-driven flow of meltwater beneath the sloping ice-shelf base enhances heat transfer and provides a feedback on ice melting rates, with consequences for ice sheet dynamics and predictions of sea-level rise. Previous steady-state models of meltwater plumes under ice shelves have solved for the development of flow along the slope from an initial source, corresponding to solely upstream control of the plume dynamics. I re-interpret the plume dynamics embedded within the framework of a time-dependent model, and show that the flow exhibits distinct regimes depending on the source conditions. Solutions with upstream control are physically consistent for certain source conditions, but the plume is influenced by a combination of upstream and downstream conditions in other regions of parameter space. The dynamics are illustrated for flow underneath a two-dimensional ice shelf of initially constant basal slope, and stable attracting states are determined. The implications for modelling meltwater flow under ice shelves are discussed.

  10. Alternative downstream processes for production of antibodies and antibody fragments.

    PubMed

    Arakawa, Tsutomu; Tsumoto, Kouhei; Ejima, Daisuke

    2014-11-01

    Protein-A or Protein-L affinity chromatography and virus inactivation are key processes for the manufacturing of therapeutic antibodies and antibody fragments. These two processes often involve exposure of therapeutic proteins to denaturing low pH conditions. Antibodies have been shown to undergo conformational changes at low pH, which can lead to irreversible damages on the final product. Here, we review alternative downstream approaches that can reduce the degree of low pH exposure and consequently damaged product. We and others have been developing technologies that minimize or eliminate such low pH processes. We here cover facilitated elution of antibodies using arginine in Protein-A and Protein-G affinity chromatography, a more positively charged amidated Protein-A, two Protein-A mimetics (MEP and Mabsorbent), mixed-mode and steric exclusion chromatography, and finally enhanced virus inactivation by solvents containing arginine. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody. PMID:24859179

  11. Quenching downstream of an external vapor catalyst separator

    SciTech Connect

    Forgac, J.M.; Hauschildt, F.W.; Quinn, G.P.; Rundell, D.N.; Schwartz, J.G.; Camp, M.S.

    1991-08-20

    This patent describes a catalytic cracking process. It comprises catalytically cracking feed oil in a catalytic cracking unit comprising a regenerator and at least one catalytic cracking reactor selected from the group consisting of a riser reactor and a fluidized bed reactor, in the presence of a cracking catalyst to produce a catalyst-laden stream comprising upgraded oil and coked catalyst; separating substantially all of the cracking catalyst from the catalyst laden stream in an external gross-cut separator downstream of the reactor into a catalyst rich stream comprising the coked catalyst and a product stream comprising the upgraded oil, and substantially immediately thereafter; quenching the product stream of upgraded oil discharged from the external gross-cut separator to substantially decrease thermal cracking of the upgraded oil to less valuable hydrocarbon products and light hydrocarbon gases and concurrently enhance the yield of naphtha to substantially increase the production of gasoline; regenerating the coked catalyst in a regenerator; and recycling the regenerated catalyst to the catalytic cracking reactor.

  12. Targeting autophagy in neurodegenerative diseases.

    PubMed

    Vidal, René L; Matus, Soledad; Bargsted, Leslie; Hetz, Claudio

    2014-11-01

    The most prevalent neurodegenerative disorders involve protein misfolding and the aggregation of specific proteins. Autophagy is becoming an attractive target to treat neurodegenerative disorders through the selective degradation of abnormally folded proteins by the lysosomal pathway. However, accumulating evidence indicates that autophagy impairment at different regulatory steps may contribute to the neurodegenerative process. Thus, a complex scenario is emerging where autophagy may play a dual role in neurodegenerative diseases by causing the downstream effect of promoting the degradation of misfolded proteins and an upstream effect where its deregulation perturbs global proteostasis, contributing to disease progression. Challenges in the future development of therapeutic strategies to target the autophagy pathway are discussed. PMID:25270767

  13. 29 CFR 785.45 - Suggestion systems.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Suggestion systems. 785.45 Section 785.45 Labor Regulations..., Medical Attention, Civic and Charitable Work, and Suggestion Systems § 785.45 Suggestion systems... general suggestion system is not working time, but if employees are permitted to work on...

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

    NASA Astrophysics Data System (ADS)

    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

  15. Downstream Propagation of Thermal Pollution in Urban Streams

    NASA Astrophysics Data System (ADS)

    Somers, K. A.; Urban, D. L.; Bernhardt, E. S.; Losordo, M.

    2011-12-01

    Cities create "heat islands" with air temperatures up to 12 degrees C greater than surrounding areas and impervious surface temperatures reaching 50 degrees C greater than the air. Streams that drain urban areas tend to be hotter at baseflow due to warmer air temperatures and decreased riparian canopy cover. Further, urban stormflow routes precipitation over hot impervious surfaces and through storm drains directly into streams, creating rapid changes in stream temperatures. The resulting alterations in stream thermal regimes directly stress aquatic organisms and indirectly lead to changes in stream microbial activity and dissolved oxygen concentrations. To date, there has been little work done to understand how urban heating of streams propagates downstream from thermal pollution sources. In response to this lack, we used a fiber optic distributed temperature sensor as well as multiple individual temperature loggers to measure high spatiotemporal resolution patterns of stream temperature along 1.5 km of Mud Creek in Durham, NC. Mud Creek originates in the storm drains of a suburban neighborhood, where high-density residential complexes with large amounts of impervious surface are connected directly to the stream. The stream flows in a confined channel alongside apartment complexes for 0.5 km before entering a protected forest area. At baseflow, we found temperature was heterogeneous and explained primarily by canopy openness, rather than the amount of development upstream of the location. During summer stormflows, stream temperatures became more homogeneous and increased by up to 4 degrees C due to runoff at the top of the reach. These peak temperatures were dampened to only 2 degrees C increases after 1 km of travel through mature forest. In contrast, a fully forested tributary to Mud Creek decreased in temperature for the same storm events. This spatial propagation of stormflow heat pulses will substantially limit our ability to protect urban stream ecosystems.

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

    PubMed Central

    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

  17. Downstream composition changes of acidic volcanic waters discharged into the Banyupahit stream, Ijen caldera, Indonesia

    NASA Astrophysics Data System (ADS)

    Delmelle, P.; Bernard, A.

    2000-04-01

    certain stream sections, consistent with the thermochemical model results. Downstream concentration trends and mineral saturation levels suggest that precipitation of Sr-, Pb-rich barite and celestite consume Ba, Sr and Pb, whereas dissolved Cu, Pb and Zn may adsorb onto solid particles, especially after the junctions of the acidic stream with non-acidic rivers. We calculated that significant fluxes of SO 4, F, Cl, Al, SiO 2, Ti, Mn and Cu may reach the irrigation system, possibly causing serious environmental impacts such as soil acidification and induration.

  18. Curcumin exerts anti-inflammatory and antioxidative properties in 1-methyl-4-phenylpyridinium ion (MPP(+))-stimulated mesencephalic astrocytes by interference with TLR4 and downstream signaling pathway.

    PubMed

    Yu, Song; Wang, Xu; He, Xingliang; Wang, Yue; Gao, Sujie; Ren, Lu; Shi, Yan

    2016-07-01

    Neuroinflammation is closely associated with the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent evidence indicates that astrocytes also play pro-inflammatory roles in the central nervous system (CNS) by activation with toll-like receptor (TLR) ligands. Therefore, targeting anti-inflammation may provide a promising therapeutic strategy for PD. Curcumin, a polyphenolic compound isolated from Curcuma longa root, has been commonly used for the treatment of neurodegenerative diseases. However, the details of how curcumin exerts neuroprotection remain uncertain. Here, we investigated the protective effect of curcumin on 1-methyl-4-phenylpyridinium ion-(MPP(+)-) stimulated primary astrocytes. Our results showed that MPP(+) stimulation resulted in significant production of tumor necrosis factor (TNF)-α, interleukin (IL-6), and reactive oxygen species (ROS) in primary mesencephalic astrocytes. Curcumin pretreatment decreased the levels of these pro-inflammatory cytokines while increased IL-10 expression in MPP(+)-stimulated astrocytes. In addition, curcumin increased the levels of antioxidant glutathione (GSH) and reduced ROS production. Our results further showed that curcumin decreased the levels of TLR4 and its downstream effectors including NF-κB, IRF3, MyD88, and TIRF that are induced by MPP(+) as well as inhibited the immunoreactivity of TLR4 and morphological activation in MPP(+)-stimulated astrocytes. Together, data suggest that curcumin might exert a beneficial effect on neuroinflammation in the pathophysiology of PD. PMID:27164829

  19. Wake Vortices and Tropical Cyclogenesis Downstream of Sumatra over the Indian Ocean

    NASA Astrophysics Data System (ADS)

    Fine, Caitlin Marie

    with regard to easterly flow between October and December favored flow blocking and splitting, more so for Sumatra's northern tip due to the higher terrain there. Correlations between zonal wind and relative vorticity are more significant near Sumatra's northern tip than near and downstream of the island's southern tip. Cyclonic vorticity was maximized at the level of Sumatra's topography for most easterly wind days west of both the north and south ends of the island, suggesting that topography was contributing to vorticity generation. Thirteen tropical cyclones in the Indian Ocean during the YOTC and DYNAMO campaigns were determined to develop from cyclonic wake vortices downstream of Sumatra, including three tropical cyclone pairs. Over 75% of these tropical cyclones formed between October and December. In four cases, wake vortices were generated by anomalously easterly low-level flow that preceded the active phase of the Madden Julian Oscillation. These vortices proceeded to encounter the MJO convective envelope, which is frequently accompanied by convectively coupled waves and may have altered the environment to be more moist and favorable for tropical cyclogenesis. In many cases, equatorial westerly winds, which may have been related to westerly wind bursts from the MJO or to convectively coupled equatorial Rossby waves, intensified low-level cyclonic circulations. It is suggested that diabatic heating in the vicinity of twin tropical cyclones may disturb the atmosphere enough to invigorate extant convectively coupled Kelvin waves, or contribute to the formation of a Kelvin wave. The research presented herein describes the interaction of the flow with steep topography on Sumatra and its role in tropical cyclogenesis over the Indian Ocean, a mechanism for TC genesis that has heretofore received little attention. iv.

  20. Assessment of equine fecal contamination: the search for alternative bacterial source-tracking targets.

    PubMed

    Simpson, Joyce M; Santo Domingo, Jorge W; Reasoner, Donald J

    2004-01-01

    16S rDNA clone libraries were evaluated for detection of fecal source-identifying bacteria from a collapsed equine manure pile. Libraries were constructed using universal eubacterial primers and Bacteroides-Prevotella group-specific primers. Eubacterial sequences indicated that upstream and downstream water samples were predominantly beta- and gamma-Proteobacteria (35 and 19%, respectively), while the manure library consisted predominantly of Firmicutes (31%) and previously unidentified sequences (60%). Manure-specific eubacterial sequences were not detectable beyond 5 m downstream of the pile, suggesting either poor survival or high dilution rates. In contrast, Bacteroides and Prevotella sp. sequences were detected both in manure and downstream using group-specific primers. Novel sequences from Bacteroides and Prevotella analysis produced an equine-specific phylogenetic cluster as compared to previous data sets obtained for human and bovine samples. While these results suggest that some anaerobic fecal bacteria might be potential identifiers for use in source-tracking applications, a comprehensive examination of environmental sequences within these species should be performed before methods targeting these bacterial groups are applied to watersheds for development of microbial source-tracking protocols. PMID:19712347

  1. Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors.

    PubMed

    Udgata, Atul; Qureshi, Rahila; Mukhopadhyay, Sangita

    2016-09-01

    As pathogen-associated molecular pattern sensors, the TLRs can detect diverse ligands to elicit either proinflammatory or anti-inflammatory responses, but the mechanism that dictates such contrasting immune responses is not well understood. In this work, we demonstrate that proline-proline-glutamic acid (PPE)17 protein of Mycobacterium tuberculosis induces TLR1/2 heterodimerization to elicit proinflammatory-type response, whereas PPE18-induced homodimerization of TLR2 triggers anti-inflammatory type responses. Ligation of TLR1/2 caused an increased recruitment of IL-1R-associated kinase (IRAK)1, MyD88, and protein kinase C (PKC)ε to the downstream TLR-signaling complex that translocated PKCε into the nucleus in an IRAK1-dependent manner. PKCε-mediated phosphorylation allowed the nuclear IRAK3 to be exported to the cytoplasm, leading to increased activation of ERK1/2, stabilization of MAPK phosphatase 1 (MKP-1), and induction of TNF-α with concomitant downregulation of p38MAPK. Silencing of TLR1 inhibited PPE17-triggered cytoplasmic export of IRAK3 as well as TNF-α induction, suggesting an important role of TLR1/2 heterodimer in regulating proinflammatory responses via the IRAK3-signaling pathway. In contrast, PPE18-mediated homodimerization of TLR2 caused poorer cytoplasmic export of nuclear IRAK3 and MKP-1 stabilization, resulting in increased p38MAPK activation. Our study hints to a novel mechanism that implicates PKCε-IRAK3-MKP-1 signaling in the regulation of MAPK activity and inflammatory cascades downstream of TLR2 in tuberculosis. PMID:27481848

  2. Long-range downstream enhancers are essential for Pax6 expression

    PubMed Central

    Kleinjan, Dirk A.; Seawright, Anne; Mella, Sebastien; Carr, Catherine B.; Tyas, David A.; Simpson, T. Ian; Mason, John O.; Price, David J.; van Heyningen, Veronica

    2006-01-01

    Pax6 is a developmental control gene with an essential role in development of the eye, brain and pancreas. Pax6, as many other developmental regulators, depends on a substantial number of cis-regulatory elements in addition to its promoters for correct spatiotemporal and quantitative expression. Here we report on our analysis of a set of mice transgenic for a modified yeast artificial chromosome carrying the human PAX6 locus. In this 420 kb YAC a tauGFP-IRES-Neomycin reporter cassette has been inserted into the PAX6 translational start site in exon 4. The YAC has been further engineered to insert LoxP sites flanking a 35 kb long, distant downstream regulatory region (DRR) containing previously described DNaseI hypersensitive sites, to allow direct comparison between the presence or absence of this region in the same genomic context. Five independent transgenic lines were obtained that vary in the extent of downstream PAX6 locus that has integrated. Analysis of transgenic embryos carrying full-length and truncated versions of the YAC indicates the location and putative function of several novel tissue-specific enhancers. Absence of these distal regulatory elements abolishes expression in specific tissues despite the presence of more proximal enhancers with overlapping specificity, strongly suggesting interaction between these control elements. Using plasmid-based reporter transgenic analysis we provide detailed characterization of one of these enhancers in isolation. Furthermore, we show that overexpression of a short PAX6 isoform derived from an internal promoter in a multicopy YAC transgenic line results in a microphthalmia phenotype. Finally, direct comparison of a single-copy line with the floxed DRR before and after Cre-mediated deletion demonstrates unequivocally the essential role of these long-range control elements for PAX6 expression. PMID:17014839

  3. Long-range downstream enhancers are essential for Pax6 expression.

    PubMed

    Kleinjan, Dirk A; Seawright, Anne; Mella, Sebastien; Carr, Catherine B; Tyas, David A; Simpson, T Ian; Mason, John O; Price, David J; van Heyningen, Veronica

    2006-11-15

    Pax6 is a developmental control gene with an essential role in development of the eye, brain and pancreas. Pax6, as many other developmental regulators, depends on a substantial number of cis-regulatory elements in addition to its promoters for correct spatiotemporal and quantitative expression. Here we report on our analysis of a set of mice transgenic for a modified yeast artificial chromosome carrying the human PAX6 locus. In this 420 kb YAC a tauGFP-IRES-Neomycin reporter cassette has been inserted into the PAX6 translational start site in exon 4. The YAC has been further engineered to insert LoxP sites flanking a 35 kb long, distant downstream regulatory region (DRR) containing previously described DNaseI hypersensitive sites, to allow direct comparison between the presence or absence of this region in the same genomic context. Five independent transgenic lines were obtained that vary in the extent of downstream PAX6 locus that has integrated. Analysis of transgenic embryos carrying full-length and truncated versions of the YAC indicates the location and putative function of several novel tissue-specific enhancers. Absence of these distal regulatory elements abolishes expression in specific tissues despite the presence of more proximal enhancers with overlapping specificity, strongly suggesting interaction between these control elements. Using plasmid-based reporter transgenic analysis we provide detailed characterization of one of these enhancers in isolation. Furthermore, we show that overexpression of a short PAX6 isoform derived from an internal promoter in a multicopy YAC transgenic line results in a microphthalmia phenotype. Finally, direct comparison of a single-copy line with the floxed DRR before and after Cre-mediated deletion demonstrates unequivocally the essential role of these long-range control elements for PAX6 expression. PMID:17014839

  4. Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

    PubMed Central

    Nonami, Atsushi; Sattler, Martin; Weisberg, Ellen; Liu, Qingsong; Zhang, Jianming; Patricelli, Matthew P.; Christie, Amanda L.; Saur, Amy M.; Kohl, Nancy E.; Kung, Andrew L.; Yoon, Hojong; Sim, Taebo; Griffin, James D.

    2015-01-01

    Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes. PMID:25833960

  5. Biliverdin reductase: a target for cancer therapy?

    PubMed Central

    Gibbs, Peter E. M.; Miralem, Tihomir; Maines, Mahin D.

    2015-01-01

    Biliverdin reductase (BVR) is a multifunctional protein that is the primary source of the potent antioxidant, bilirubin. BVR regulates activities/functions in the insulin/IGF-1/IRK/PI3K/MAPK pathways. Activation of certain kinases in these pathways is/are hallmark(s) of cancerous cells. The protein is a scaffold/bridge and intracellular transporter of kinases that regulate growth and proliferation of cells, including PKCs, ERK and Akt, and their targets including NF-κB, Elk1, HO-1, and iNOS. The scaffold and transport functions enable activated BVR to relocate from the cytosol to the nucleus or to the plasma membrane, depending on the activating stimulus. This enables the reductase to function in diverse signaling pathways. And, its expression at the transcript and protein levels are increased in human tumors and the infiltrating T-cells, monocytes and circulating lymphocytes, as well as the circulating and infiltrating macrophages. These functions suggest that the cytoprotective role of BVR may be permissive for cancer/tumor growth. In this review, we summarize the recent developments that define the pro-growth activities of BVR, particularly with respect to its input into the MAPK signaling pathway and present evidence that BVR-based peptides inhibit activation of protein kinases, including MEK, PKCδ, and ERK as well as downstream targets including Elk1 and iNOS, and thus offers a credible novel approach to reduce cancer cell proliferation. PMID:26089799

  6. Definition of essential sequences and functional equivalence of elements downstream of the adenovirus E2A and the early simian virus 40 polyadenylation sites.

    PubMed Central

    Hart, R P; McDevitt, M A; Ali, H; Nevins, J R

    1985-01-01

    In addition to the highly conserved AATAAA sequence, there is a requirement for specific sequences downstream of polyadenylic acid [poly(A)] cleavage sites to generate correct mRNA 3' termini. Previous experiments demonstrated that 35 nucleotides downstream of the E2A poly(A) site were sufficient but 20 nucleotides were not. The construction and assay of bidirectional deletion mutants in the adenovirus E2A poly(A) site indicates that there may be redundant multiple sequence elements that affect poly(A) site usage. Sequences between the poly(A) site and 31 nucleotides downstream were not essential for efficient cleavage. Further deletion downstream (3' to +31) abolished efficient cleavage in certain constructions but not all. Between +20 and +38 the sequence T(A/G)TTTTT was duplicated. Function was retained when one copy of the sequence was present, suggesting that this sequence represents an essential element. There may also be additional sequences distal to +43 that can function. To establish common features of poly(A) sites, we also analyzed the early simian virus 40 (SV40) poly(A) site for essential sequences. An SV40 poly(A) site deletion that retained 18 nucleotides downstream of the cleavage site was fully functional while one that retained 5 nucleotides downstream was not, thus defining sequences required for cleavage. Comparison of the SV40 sequences with those from E2A did not reveal significant homologies. Nevertheless, normal cleavage and polyadenylation could be restored at the early SV40 poly(A) site by the addition of downstream sequences from the adenovirus E2A poly(A) site to the SV40 +5 mutant. The same sequences that were required in the E2A site for efficient cleavage also restored activity to the SV40 poly(A) site. Images PMID:3018490

  7. Influences of body size and environmental factors on autumn downstream migration of bull trout in the Boise River, Idaho

    USGS Publications Warehouse

    Monnot, L.; Dunham, J.B.; Hoem, T.; Koetsier, P.

    2008-01-01

    Many fishes migrate extensively through stream networks, yet patterns are commonly described only in terms of the origin and destination of migration (e.g., between natal and feeding habitats). To better understand patterns of migration in bull trout,Salvelinus confluentus we studied the influences of body size (total length [TL]) and environmental factors (stream temperature and discharge) on migrations in the Boise River basin, Idaho. During the autumns of 2001-2003, we tracked the downstream migrations of 174 radio-tagged bull trout ranging in size from 21 to 73 cm TL. The results indicated that large bull trout (>30 cm) were more likely than small fish to migrate rapidly downstream after spawning in headwater streams in early autumn. Large bull trout also had a higher probability of arriving at the current terminus of migration in the system, Arrowrock Reservoir. The rate of migration by small bull trout was more variable and individuals were less likely to move into Arrowrock Reservoir. The rate of downstream migration by all fish was slower when stream discharge was greater. Temperature was not associated with the rate of migration. These findings indicate that fish size and environmentally related changes in behavior have important influences on patterns of migration. In a broader context, these results and other recent work suggest, at least in some cases, that commonly used classifications of migratory behavior may not accurately reflect the full range of behaviors and variability among individuals (or life stages) and environmental conditions. ?? Copyright by the American Fisheries Society 2008.

  8. Smoking Harms Black Americans' Kidneys, Study Suggests

    MedlinePlus

    ... medlineplus/news/fullstory_159032.html Smoking Harms Black Americans' Kidneys, Study Suggests Researchers say inflammation or cigarette ... a significant risk to kidney health for black Americans, new research suggests. The study included more than ...

  9. Bitter, sweet and umami taste receptors and downstream signaling effectors: Expression in embryonic and growing chicken gastrointestinal tract.

    PubMed

    Cheled-Shoval, Shira L; Druyan, Shelly; Uni, Zehava

    2015-08-01

    Taste perception is a crucial biological mechanism affecting food and water choices and consumption in the animal kingdom. Bitter taste perception is mediated by a G-protein-coupled receptor (GPCR) family-the taste 2 receptors (T2R)-and their downstream proteins, whereas sweet and umami tastes are mediated by the GPCR family -taste 1 receptors (T1R) and their downstream proteins. Taste receptors and their downstream proteins have been identified in extra-gustatory tissues in mammals, such as the lungs and gastrointestinal tract (GIT), and their GIT activation has been linked with different metabolic and endocrinic pathways in the GIT. The chicken genome contains three bitter taste receptors termed ggTas2r1, ggTas2r2, and ggTas2r7, and the sweet/umami receptors ggTas1r1 and ggTas1r3, but it lacks the sweet receptor ggTas1r2. The aim of this study was to identify and determine the expression of genes related to taste perception in the chicken GIT, both at the embryonic stage and in growing chickens. The results of this study demonstrate for the first time, using real-time PCR, expression of the chicken taste receptor genes ggTas2r1, ggTas2r2, ggTas2r7, ggTas1r1, and ggTas1r3 and of their downstream protein-encoding genes TRPM5, α-gustducin, and PLCβ2 in both gustatory tissues-the palate and tongue, and extra-gustatory tissues-the proventriculus, duodenum, jejunum, ileum, cecum, and colon of embryonic day 19 (E19) and growing (21 d old) chickens. Expression of these genes suggests the involvement of taste pathways for sensing carbohydrates, amino acids and bitter compounds in the chicken GIT. PMID:26049797

  10. Historical and Contemporary Patterns of Mercury in a Hydroelectric Reservoir and Downstream Fishery: Concentration Decline in Water and Fishes.

    PubMed

    Green, Derek J; Duffy, Mark; Janz, David M; McCullum, Kevin; Carrière, Gary; Jardine, Timothy D

    2016-08-01

    Mercury (Hg) contamination can pose risks to human and animal health as well as commercial fisheries. Reservoir construction in riverine systems produces flooded conditions amenable to Hg(II)-methylating bacteria, which can transform this relatively benign environmental contaminant into the bioaccumulative, environmentally relevant, and neurotoxic methyl-Hg (MeHg). Hg concentrations ([Hg]) in fishes from reservoirs can take decades to decrease to pre-dam levels, but less is known about Hg exported downstream and its dynamics within downstream fish populations. We examined and compared the multidecadal rates of biotic [Hg] decrease and contemporary factors affecting [Hg] in fish collected from a hydroelectric reservoir (Tobin Lake) and a related downstream fishery (Cumberland Lake) along the Saskatchewan River, Canada. Rates of [Hg] decrease were considered in four species-northern pike (Esox lucius), sauger (Sander canadensis), goldeye (Hiodon alosoides), and walleye (S. vitreus)-all of which showed a significant decrease over time (p < 0.001) and are now lower than Health Canada consumption guidelines (0.5 μg/g). Rates of decrease ranged from 0.5 to 3.9 %/year and were similar between sites in the cases of northern pike and sauger. Contemporary factors affecting [Hg] in walleye collected downstream include fish length (p < 0.001), fish age (p < 0.001), and trophic magnification through the food web (p < 0.001), and relationships between [Hg] and trophic level in predatory and prey fish are now similar to those found in non-Hg-inundated systems at a similar latitude. Together, these results suggest connected contamination between the two sites and delineate the timeline during which [Hg] in a variety of fish species decreased to nontoxic levels in both locations. PMID:27272416

  11. Discovery of (S)-4-isobutyloxazolidin-2-one as a novel leucyl-tRNA synthetase (LRS)-targeted mTORC1 inhibitor.

    PubMed

    Yoon, Suyoung; Kim, Jong Hyun; Yoon, Ina; Kim, Changhoon; Kim, Sung-Eun; Koh, Yura; Jeong, Seung Jae; Lee, Jiyoun; Kim, Sunghoon; Lee, Jeewoo

    2016-07-01

    A series of leucinol analogs were investigated as leucyl-tRNA synthetase-targeted mTORC1 inhibitors. Among them, compound 5, (S)-4-isobutyloxazolidin-2-one, showed the most potent inhibition on the mTORC1 pathway in a concentration-dependent manner. Compound 5 inhibited downstream phosphorylation of mTORC1 by blocking leucine-sensing ability of LRS, without affecting the catalytic activity of LRS. In addition, compound 5 exhibited cytotoxicity against rapamycin-resistant colon cancer cells, suggesting that LRS has the potential to serve as a novel therapeutic target. PMID:27209231

  12. PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase

    PubMed Central

    Leenders, Frauke; Möpert, Kristin; Schmiedeknecht, Anett; Santel, Ansgar; Czauderna, Frank; Aleku, Manuela; Penschuck, Silke; Dames, Sibylle; Sternberger, Maria; Röhl, Thomas; Wellmann, Axel; Arnold, Wolfgang; Giese, Klaus; Kaufmann, Jörg; Klippel, Anke

    2004-01-01

    Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three-dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C-related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K. PMID:15282551

  13. Characterization of the direct targets of FOXO transcription factors throughout evolution.

    PubMed

    Webb, Ashley E; Kundaje, Anshul; Brunet, Anne

    2016-08-01

    FOXO transcription factors (FOXOs) are central regulators of lifespan across species, yet they also have cell-specific functions, including adult stem cell homeostasis and immune function. Direct targets of FOXOs have been identified genome-wide in several species and cell types. However, whether FOXO targets are specific to cell types and species or conserved across cell types and throughout evolution remains uncharacterized. Here, we perform a meta-analysis of direct FOXO targets across tissues and organisms, using data from mammals as well as Caenorhabditis elegans and Drosophila. We show that FOXOs bind cell type-specific targets, which have functions related to that particular cell. Interestingly, FOXOs also share targets across different tissues in mammals, and the function and even the identity of these shared mammalian targets are conserved in invertebrates. Evolutionarily conserved targets show enrichment for growth factor signaling, metabolism, stress resistance, and proteostasis, suggesting an ancestral, conserved role in the regulation of these processes. We also identify candidate cofactors at conserved FOXO targets that change in expression with age, including CREB and ETS family factors. This meta-analysis provides insight into the evolution of the FOXO network and highlights downstream genes and cofactors that may be particularly important for FOXO's conserved function in adult homeostasis and longevity. PMID:27061590

  14. A Study of the Ion Hose Instability in the DARHT-II Downstream Transport Region

    SciTech Connect

    McCarrick, J F

    2004-11-11

    The second axis of the DARHT flash X-ray facility at Los Alamos National Laboratory (''DARHT-II'') is a multiple-pulse, 18.4 MeV, 2 kA induction electron linear accelerator [1]. A train of short ({approx}50 ns) pulses are converted via bremsstrahlung to X-rays, which are then used to make radiographic images at various times (nominally four) during a ''hydrotest'' experiment. The train of pulses is created by carving them out of a two microsecond long macropulse, using a fast switching element called a kicker [2]. The unused portion of the macropulse is absorbed in a beam dump. Thus, upstream of the kicker, two microseconds of beam are transported through a vacuum system roughly sixty meters long. These conditions involve length and, specifically, time scales which are new to the transport of high-current beams. A concern under such conditions are the macroscopic interactions between the electron beam and positive ions created by impact ionization of the residual gas in the vacuum system. Over two microseconds, the ion density can develop to a hundredth or even a tenth of a percent of the beam density--small, to be sure, but large enough to have cumulative effects over such a long transport distance. Two such effects will be considered here: the ion hose instability, where transverse forces conspire to pull the electron beam farther and farther off axis, and background gas focusing, where radial forces (with respect to the beam) change the beam envelope during the course of the macropulse. The former effect can cause beam emittance growth (affecting the ability to focus the beam on the target) and eventually catastrophic beam loss; the latter can cause either serious degradation of the statically tuned final focus on the converter target, or a pinching of the beam on the surface of the main dump to the point where the heat flux causes damage. The beam transport upstream of the kicker has two distinct phases. First, the beam is created and accelerated up to 18.4 Me

  15. 4-Aminoethylamino-emodin – a novel potent inhibitor of GSK-3β– acts as an insulin-sensitizer avoiding downstream effects of activated β-catenin

    PubMed Central

    Gebhardt, Rolf; Lerche, Katja S; Götschel, Frank; Günther, Robert; Kolander, Jens; Teich, Lars; Zellmer, Sebastian; Hofmann, Hans-Jörg; Eger, Kurt; Hecht, Andreas; Gaunitz, Frank

    2010-01-01

    Abstract Glycogen synthase kinase-3β (GSK-3β) is a key target and effector of downstream insulin signalling. Using comparative protein kinase assays and molecular docking studies we characterize the emodin-derivative 4-[N-2-(aminoethyl)-amino]-emodin (L4) as a sensitive and potent inhibitor of GSK-3β with peculiar features. Compound L4 shows a low cytotoxic potential compared to other GSK-3β inhibitors determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and cellular ATP levels. Physiologically, L4 acts as an insulin-sensitizing agent that is able to enhance hepatocellular glycogen and fatty acid biosynthesis. These functions are particularly stimulated in the presence of elevated concentrations of glucose and in synergy with the hormone action at moderate but not high insulin levels. In contrast to other low molecular weight GSK-3β inhibitors (SB216763 and LiCl) or Wnt-3α-conditioned medium, however, L4 does not induce reporter and target genes of activated β-catenin such as TOPflash, Axin2 and glutamine synthetase. Moreover, when present together with SB216763 or LiCl, L4 counteracts expression of TOPflash or induction of glutamine synthetase by these inhibitors. Because L4 slightly activates β-catenin on its own, these results suggest that a downstream molecular step essential for activation of gene transcription by β-catenin is also inhibited by L4. It is concluded that L4 represents a potent insulin-sensitizing agent favouring physiological effects of insulin mediated by GSK-3β inhibition but avoiding hazardous effects such as activation of β-catenin-dependent gene expression which may lead to aberrant induction of cell proliferation and cancer. PMID:19228266

  16. Integrating ChIP-sequencing and digital gene expression profiling to identify BRD7 downstream genes and construct their regulating network.

    PubMed

    Xu, Ke; Xiong, Wei; Zhou, Ming; Wang, Heran; Yang, Jing; Li, Xiayu; Chen, Pan; Liao, Qianjin; Deng, Hao; Li, Xiaoling; Li, Guiyuan; Zeng, Zhaoyang

    2016-01-01

    BRD7 is a single bromodomain-containing protein that functions as a subunit of the SWI/SNF chromatin-remodeling complex to regulate transcription. It also interacts with the well-known tumor suppressor protein p53 to trans-activate genes involved in cell cycle arrest. In this paper, we report an integrative analysis of genome-wide chromatin occupancy of BRD7 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and digital gene expression (DGE) profiling by RNA-sequencing upon the overexpression of BRD7 in human cells. We localized 156 BRD7-binding peaks representing 184 genes by ChIP-sequencing, and most of these peaks were co-localized with histone modification sites. Four novel motifs were significantly represented in these BRD7-enriched regions. Ingenuity pathway analysis revealed that 22 of these BRD7 target genes were involved in a network regulating cell death and survival. DGE profiling identified 560 up-regulated genes and 1088 down-regulated genes regulated by BRD7. Using Gene Ontology and pathway analysis, we found significant enrichment of the cell cycle and apoptosis pathway genes. For the integrative analysis of the ChIP-seq and DEG data, we constructed a regulating network of BRD7 downstream genes, and this network suggests multiple feedback regulations of the pathways. Furthermore, we validated BIRC2, BIRC3, TXN2, and NOTCH1 genes as direct, functional BRD7 targets, which were involved in the cell cycle and apoptosis pathways. These results provide a genome-wide view of chromatin occupancy and the gene regulation network of the BRD7 signaling pathway. PMID:26407966

  17. 17 CFR 270.57b-1 - Exemption for downstream affiliates of business development companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Exemption for downstream affiliates of business development companies. 270.57b-1 Section 270.57b-1 Commodity and Securities Exchanges....57b-1 Exemption for downstream affiliates of business development companies....

  18. 40 CFR 80.210 - What sulfur standards apply to gasoline downstream from refineries and importers?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... gasoline downstream from refineries and importers? 80.210 Section 80.210 Protection of Environment... Gasoline Sulfur Gasoline Sulfur Standards § 80.210 What sulfur standards apply to gasoline downstream from refineries and importers? The sulfur standard for gasoline at any point in the gasoline distribution...

  19. DOWNSTREAM-WATER-LEVEL CONTROL TEST RESULTS ON THE WM LATERAL CANAL

    Technology Transfer Automated Retrieval System (TEKTRAN)

    On steep canals, distant downstream water-level control can be challenging. SacMan (Software for Automated Canal Management) was developed, in part, to test various distant downstream water level controllers. It was implemented on the WM canal of the Maricopa Stanfield Irrigation and Drainage Distri...

  20. 19 CFR 351.223 - Procedures for initiation of downstream product monitoring.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 3 2012-04-01 2012-04-01 false Procedures for initiation of downstream product monitoring. 351.223 Section 351.223 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Antidumping and Countervailing Duty Procedures § 351.223 Procedures for initiation of downstream...

  1. Concentrated standing tailwater: a mechanism for nutrient delivery to downstream aquatic ecosystems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Contribution of first flush runoff events from intense rainfall to downstream aquatic ecosystems are often reported in terms of sediment and nutrient delivery, with hardly any consideration to the contribution that standing, concentrated tailwater in primary aquatic systems makes to downstream nutri...

  2. Downstream approaches to phosphorus management in agricultural landscapes: Regional applicability and use

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review provides a synthesis of conservation practices that are aimed at improving water quality by retaining phosphorus (P) downstream of runoff genesis. The review is structured around specific downstream practices that are prevalent in various parts of the United States, but also focuses on t...

  3. Downstream fish assemblage response to river impoundment varies with degree of hydrologic alteration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    River impoundments alter downstream hydrology and habitat, often resulting in significant changes in stream communities. The degree of impact of a river impoundment on downstream hydrology and biological communities can be dependent on many factors, including underlying natural hydrologic regimes an...

  4. Induction of interferon-gamma and downstream pathways during establishment of fetal persistent infection with bovine viral diarrhea virus.

    PubMed

    Smirnova, Natalia P; Webb, Brett T; McGill, Jodi L; Schaut, Robert G; Bielefeldt-Ohmann, Helle; Van Campen, Hana; Sacco, Randy E; Hansen, Thomas R

    2014-04-01

    Development of transplacental infection depends on the ability of the virus to cross the placenta and replicate within the fetus while counteracting maternal and fetal immune responses. Unfortunately, little is known about this complex process. Non-cytopathic (ncp) strains of bovine viral diarrhea virus (BVDV), a pestivirus in the Flaviviridae family, cause persistent infection in early gestational fetuses (<150 days; persistently infected, PI), but are cleared by immunocompetent animals and late gestational fetuses (>150 days; transiently infected, TI). Evasion of innate immune response and development of immunotolerance to ncp BVDV have been suggested as possible mechanisms for the establishment of the persistent infection. Previously we have observed a robust temporal induction of interferon (IFN) type I (innate immune response) and upregulation of IFN stimulated genes (ISGs) in BVDV TI fetuses. Modest chronic upregulation of ISGs in PI fetuses and calves reflects a stimulated innate immune response during persistent BVDV infection. We hypothesized that establishing persistent fetal BVDV infection is also accompanied by the induction of IFN-gamma (IFN-γ). The aims of the present study were to determine IFN-γ concentration in blood and amniotic fluid from control, TI and PI fetuses during BVDV infection and analyze induction of the IFN-γ downstream pathways in fetal lymphoid tissues. Two experiments with in vivo BVDV infections were completed. In Experiment 1, pregnant heifers were infected with ncp BVDV type 2 on day 75 or 175 of gestation or kept naïve to generate PI, TI and control fetuses, respectively. Fetuses were collected by Cesarean section on day 190. In Experiment 2, fetuses were collected on days 82, 89, 97, 192 and 245 following infection of pregnant heifers on day 75 of gestation. The results were consistent with the hypothesis that ncp BVDV infection induces IFN-γ secretion during acute infection in both TI and PI fetuses and that lymphoid

  5. The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways.

    PubMed

    Kovacevic, Zaklina; Menezes, Sharleen V; Sahni, Sumit; Kalinowski, Danuta S; Bae, Dong-Hun; Lane, Darius J R; Richardson, Des R

    2016-01-15

    N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors. PMID:26534963

  6. Effects of stereotypes and suggestion on memory.

    PubMed

    Shechory, Mally; Nachson, Israel; Glicksohn, Joseph

    2010-02-01

    In this study, the interactive effect of stereotype and suggestion on accuracy of memory was examined by presenting 645 participants (native Israelis and immigrants from the former Soviet Union and Ethiopia) with three versions of a story about a worker who is waiting in a manager's office for a meeting. All versions were identical except for the worker's name, which implied a Russian or an Ethiopian immigrant or a person of no ethnic origin. Each participant was presented with one version of the story. After an hour delay, the participants' memories were tested via two questionnaires that differed in terms of level of suggestion. Data analyses show that (a) when a suggestion matched the participant's stereotypical perception, the suggestion was incorporated into memory but (b) when the suggestion contradicted the stereotype, it did not influence memory. The conclusion was that recall is influenced by stereotypes but can be enhanced by compatible suggestions. PMID:18662974

  7. Hypnotizability, not suggestion, influences false memory development.

    PubMed

    Dasse, Michelle N; Elkins, Gary R; Weaver, Charles A

    2015-01-01

    Hypnotizability influences the development of false memories. In Experiment 1, participants heard a positive or negative suggestion regarding hypnosis and then listened to 8 Deese-Roediger-McDermott (DRM) false memory paradigm lists in a hypnotic state. Neither hypnosis nor prehypnotic suggestion affected memory. Highly hypnotizable participants were more accurate in recall and recognition. In Experiment 2, suggestions were delivered in the form of feedback. Participants heard a positive or negative suggestion about their performance prior to either the encoding or retrieval of 8 DRM lists. Neither accurate nor false memories were affected by the suggestion. Highly hypnotizable individuals recognized fewer critical lures if they received a negative suggestion about their performance. These results highlight the unusual role of hypnotizability in the creation of false memories. PMID:25365130

  8. Individual personality characteristics related to suggestibility.

    PubMed

    Van Hook, Cheryl W; Steele, Connie

    2002-12-01

    The current study investigated the relationship between suggestibility of memory, personality characteristics identified by the Millon Index of Personality Traits, and tolerance for ambiguity measured by MacDonald's Ambiguity Tolerance-20. 85 female and 16 male college students were assigned to either an experimental group receiving the suggestive information or a control group. Suggestibility was assessed using Lindberg's suggestibility measure consisting of a short video, followed by a questionnaire used to assess memory, and a second administration one week later. Logistical regression analyses were used to construct a model of the personality characteristics predictive of suggestibility and indicated that susceptibility to suggestive information may differ across personalities for variables such as sensing, innovating, agreeing, and low tolerance of ambiguity. PMID:12530759

  9. Experimental and analytical investigation of fan flow interaction with downstream struts

    NASA Technical Reports Server (NTRS)

    Olsen, T. L.; Ng, W. F.; Obrien, W. F., Jr.

    1985-01-01

    An investigation which was designed to provide insight into the fundamental aspects of fan rotor-downstream strut interaction was undertaken. High response, miniature pressure transducers were embedded in the rotor blades of an experimental fan rig. Five downstream struts were placed at several downstream locations in the discharge flow annulus of the single-stage machine. Significant interaction of the rotor blade surface pressures with the flow disturbance produced by the downstream struts was measured. Several numerical procedures for calculating the quasi-steady rotor response due to downstream flow obstructions were developed. A preliminary comparison of experimental and calculated fluctuating blade pressures on the rotor blades shows general agreement between the experimental and calculated values.

  10. Downstream gradients in bioindicator responses: Point source contaminant effects on fish health

    SciTech Connect

    Marshall Adams, S.; Ham, K.D.; Greeley, M.S.; Hinton, D.E.

    1995-12-31

    To investigate potential causal relationships between contaminant exposure and biological responses in fish, a suite of bioindicators ranging from the biochemical to the community-level were measured in fish populations and communities downstream from a bleached kraft mill effluent (BKME) discharge. Downstream gradients in responses were evident in elevated hepatic mixed-function oxygenase activity, several measures of condition and bioenergetic status, growth, the health assessment index, and several fish community-level parameters. A multivariate discriminant analysis procedure, which included many of the individual bioindicators, also demonstrated a gradient in integrated health status of a sentinel fish species in the contaminated river. These downstream response gradients were probably influenced to a greater degree by contaminant discharges than by natural or anthropogenic nutrient sources downstream. Establishing causal relationships between a specific contaminant source and responses in sentinel aquatic organisms becomes relatively more straightforward when downstream gradients in biological responses are observed at multiple levels of biological organization.

  11. Genomic targets of the human c-Myc protein

    PubMed Central

    Fernandez, Paula C.; Frank, Scott R.; Wang, Luquan; Schroeder, Marianne; Liu, Suxing; Greene, Jonathan; Cocito, Andrea; Amati, Bruno

    2003-01-01

    The transcription factor Myc is induced by mitogenic signals and regulates downstream cellular responses. If overexpressed, Myc promotes malignant transformation. Myc modulates expression of diverse genes in experimental systems, but few are proven direct targets. Here, we present a large-scale screen for genomic Myc-binding sites in live human cells. We used bioinformatics to select consensus DNA elements (CACGTG or E-boxes) situated in the 5′ regulatory region of genes and measured Myc binding to those sequences in vivo by quantitative chromatin immunoprecipitation. Strikingly, most promoter-associated E-boxes showed selective recovery with Myc, unlike non-E-box promoters or E-boxes in bulk genomic DNA. Promoter E-boxes were distributed in two groups bound by Myc at distinct frequencies. The high-affinity group included an estimated 11% of all cellular loci, was highly conserved among different cells, and was bound independently of Myc expression levels. Overexpressed Myc associated at increased frequency with low-affinity targets and, at extreme levels, also with other sequences, suggesting that some binding was not sequence-specific. The strongest DNA-sequence parameter defining high-affinity targets was the location of E-boxes within CpG islands, correlating with an open, preacetylated state of chromatin. Myc further enhanced histone acetylation, with or without accompanying induction of mRNA expression. Our findings point to a high regulatory and biological diversity among Myc-target genes. PMID:12695333

  12. Melanocortin receptors as drug targets for disorders of energy balance.

    PubMed

    Adan, Roger A H; van Dijk, Gertjan

    2006-06-01

    There is overwhelming evidence that the brain melanocortin system is a key regulator of energy balance, and dysregulations in the brain melanocortin system can lead to obesity. The melanocortin system is one of the major downstream leptin signaling pathways in the brain. In contrast to leptin, preclinical studies indicate that diet-induced obese animals are still responsive to the anorectic effects of melanocortin receptor agonists, suggesting the melanocortin system is an interesting therapeutic opportunity. Besides regulating energy balance, melanocortins are involved in a variety of other neuroendocrine processes, including inflammation, blood pressure regulation, addictive and sexual behavior, and sensation of pain. This review evaluates the melanocortin system function from the perspective to use specific melanocortin (MC) receptors as drug targets, with a focus on the treatment of obesity and eating disorders in humans, and the implications this may have on mechanisms beyond the control of energy balance. PMID:16787227

  13. Downstream mixing of sediment and tracers in agricultural catchments: Evidence of changing sediment sources and fluvial processes?

    NASA Astrophysics Data System (ADS)

    Ralph, Timothy; Wethered, Adam; Smith, Hugh; Heijnis, Henk

    2014-05-01

    Land clearance, soil tillage and grazing in agricultural catchments have liberated sediment and altered hydrological connectivity between hillslopes and channels, leading to increased sediment availability, mobilisation and delivery to rivers. The type and amount of sediment supplied to rivers is critical for fluvial geomorphology and aquatic ecosystem health. Contemporary sediment dynamics are routinely investigated using environmental radionuclides such as caesium-137 (Cs-137) and excess lead-210 (Pb-210ex), which can provide information regarding sediment source types and fluvial processes if sediment sources can be distinguished from one another and mixing models applied to representative samples. However, downstream transport, mixing and dilution of radionuclide-labelled sediment (especially from sources with low initial concentrations) can obliterate the tracer signal; sometimes before anything of geomorphological importance happens in the catchment. Can these findings be used as evidence of sediment source variations and fluvial processes when the limits of detection (of Cs-137 in particular) are being exceeded so rapidly downstream? Sediment sources and downstream sediment dynamics were investigated in Coolbaggie Creek, a major supplier of sediment to the Macquarie River in an agricultural catchment with temperate to semi-arid climate in Australia. Radionuclides were used to discriminate between the <63 micron fraction of sediment sources including forested topsoils (Cs-137 11.28 +/- 0.75 Bq/kg; Pb-210ex 181.87 +/- 20.00 Bq/kg), agricultural topsoils (Cs-137 3.21 +/- 0.26 Bq/kg; Pb-210ex 29.59 +/- 10.94 Bq/kg) and sub-soils from channel banks and gullies (Cs-137 1.45 +/- 0.47 Bq/kg; Pb-210ex 4.67 +/- 1.93 Bq/kg). Within the trunk stream, suspended sediment, organic matter and Cs-137 and Pb-210ex concentrations declined downstream. Results from a mixing model suggest that agricultural topsoils account for 95% of fine sediment entering the channel in the

  14. Maltreated Children's Memory: Accuracy, Suggestibility, and Psychopathology

    ERIC Educational Resources Information Center

    Eisen, Mitchell L.; Goodman, Gail S.; Qin, Jianjian; Davis, Suzanne; Crayton, John

    2007-01-01

    Memory, suggestibility, stress arousal, and trauma-related psychopathology were examined in 328 3- to 16-year-olds involved in forensic investigations of abuse and neglect. Children's memory and suggestibility were assessed for a medical examination and venipuncture. Being older and scoring higher in cognitive functioning were related to fewer…

  15. Suggested Learnings: Consumer and Homemaking Education.

    ERIC Educational Resources Information Center

    Edmondson, Dorothy Jean; Swanson, Bettye B.

    The guide presents suggested learning concepts, experiences, and references for home economics educators in the planning and organization of secondary level consumer and homemaking programs. The suggestions are based on questionnaires and interviews with teachers and administrators involved in this program. The guide's main focus is on the process…

  16. Lateral versus downstream transport of gravel in gravel-bed meandering rivers

    NASA Astrophysics Data System (ADS)

    Braudrick, C. A.; Dietrich, W. E.

    2014-12-01

    The degree to which gravel is exchanged laterally from eroding banks to point bars rather than transported downstream is largely unknown in gravel-bed meanders. This is crucial for understanding the potential effects bank stabilization on channel form. We use a compilation of field data to calculate the number of bends required for the supply of gravel from bank erosion to equal transport rate of gravel through a reach (Nb). A low value of Nb suggests that most of the gravel transport by the river is derived from local bank erosion and that, in essence, gravel is being shifted from outer bank to downstream bars with little net downslope flux. We compared the migration rate in 18 gravel-bed meanders rivers with calculations of the gravel transport capacity. Using the average bend length measured for the reach, and assuming the fraction of gravel in the banks ranged from 0.1 to 0.8 of the bank height, Nb was < 1 bend for 12 of the 18 rivers and generally < 10 bends for the remainder of the rivers. The meanders with Nb<1 had Shields stresses less than 0.044, which is the median Shields stress of 115 gravel-bed meanders in the literature. We compared these results to 9 gravel-bed meanders where gravel transport rates were available but the migration rates were unknown. For these rivers, we assumed migration rates ranged from 0.005-0.1 widths/yr (the range observed for gravel-bed meanders) and the gravel fraction in the banks ranged from 0.1-0.8. Nb was ranged from <1 to 20 bends, but was generally higher than for the gravel-bed meanders where we calculated the gravel transport capacity. This is not surprising because 7 of the 9 rivers had Shields stresses > 0.045, and higher gravel transport rates would be expected for this dataset. Our calculations suggest that for many gravel-bed meanders, gravel is being exchanged between the bed and banks within one bend, and even gravel-bed meanders with higher Shields stresses are likely exchanging gravel within a given reach

  17. The River Orontes in Syria and Turkey: Downstream variation of fluvial archives in different crustal blocks

    NASA Astrophysics Data System (ADS)

    Bridgland, David R.; Westaway, Rob; Romieh, Mohammad Abou; Candy, Ian; Daoud, Mohamad; Demir, Tuncer; Galiatsatos, Nikolaos; Schreve, Danielle C.; Seyrek, Ali; Shaw, Andrew D.; White, Tom S.; Whittaker, John

    2012-09-01

    The geomorphology and Quaternary history of the River Orontes in western Syria and south-central Turkey have been studied using a combination of methods: field survey, differential GPS, satellite imagery, analysis of sediments to determine provenance, flow direction and fluvial environment, incorporation of evidence from fossils for both palaeoenvironments and biostratigraphy, uranium-series dating of calcrete cement, reconciliation of Palaeolithic archaeological contents, and uplift modelling based on terrace height distribution. The results underline the contrasting nature of different reaches of the Orontes, in part reflecting different crustal blocks, with different histories of landscape evolution. Upstream from Homs the Orontes has a system of calcreted terraces that form a staircase extending to ~200 m above the river. New U-series dating provides an age constraint within the lower part of the sequence that suggests underestimation of terrace ages in previous reviews. This upper valley is separated from another terraced reach, in the Middle Orontes, by a gorge cut through the Late Miocene-Early Pliocene Homs Basalt. The Middle Orontes terraces have long been recognized as a source of mammalian fossils and Palaeolithic artefacts, particularly from Latamneh, near the downstream end of the reach. This terraced section of the valley ends at a fault scarp, marking the edge of the subsiding Ghab Basin (a segment of the Dead Sea Fault Zone), which has been filled to a depth of ~ 1 km by dominantly lacustrine sediments of Pliocene-Quaternary age. Review of the fauna from Latamneh suggests that its age is 1.2-0.9 Ma, significantly older than previously supposed, and commensurate with less uplift in this reach than both the Upper and Lower Orontes. Two localities near the downstream end of the Ghab have provided molluscan and ostracod assemblages that record somewhat saline environments, perhaps caused by desiccation within the former lacustrine basin, although they

  18. Sputter target

    DOEpatents

    Gates, Willard G.; Hale, Gerald J.

    1980-01-01

    The disclosure relates to an improved sputter target for use in the deposition of hard coatings. An exemplary target is given wherein titanium diboride is brazed to a tantalum backing plate using a gold-palladium-nickel braze alloy.

  19. Emittance growth in the DARHT Axis-II Downstream Transport

    SciTech Connect

    Ekdahl, Jr., Carl August; Schulze, Martin E.

    2015-04-14

    Using a particle-in-cell (PIC) code, we investigated the possibilities for emittance growth through the quadrupole magnets of the system used to transport the high-current electron beam from an induction accelerator to the bremsstrahlung converter target used for flash radiography. We found that even highly mismatched beams exhibited little emittance growth (< 6%), which we attribute to softening of their initial hard edge current distributions. We also used this PIC code to evaluate the accuracy of emittance measurements using a solenoid focal scan following the quadrupole magnets. If the beam is round after the solenoids, the simulations indicate that the measurement is highly accurate, but it is substantially inaccurate for elliptical beams

  20. SWATH2stats: An R/Bioconductor Package to Process and Convert Quantitative SWATH-MS Proteomics Data for Downstream Analysis Tools

    PubMed Central

    Blattmann, Peter; Heusel, Moritz; Aebersold, Ruedi

    2016-01-01

    SWATH-MS is an acquisition and analysis technique of targeted proteomics that enables measuring several thousand proteins with high reproducibility and accuracy across many samples. OpenSWATH is popular open-source software for peptide identification and quantification from SWATH-MS data. For downstream statistical and quantitative analysis there exist different tools such as MSstats, mapDIA and aLFQ. However, the transfer of data from OpenSWATH to the downstream statistical tools is currently technically challenging. Here we introduce the R/Bioconductor package SWATH2stats, which allows convenient processing of the data into a format directly readable by the downstream analysis tools. In addition, SWATH2stats allows annotation, analyzing the variation and the reproducibility of the measurements, FDR estimation, and advanced filtering before submitting the processed data to downstream tools. These functionalities are important to quickly analyze the quality of the SWATH-MS data. Hence, SWATH2stats is a new open-source tool that summarizes several practical functionalities for analyzing, processing, and converting SWATH-MS data and thus facilitates the efficient analysis of large-scale SWATH/DIA datasets. PMID:27054327