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

PubMed

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

2016-12-01

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

Lateral and vertical distribution of downstream migrating juvenile sea lamprey

USGS Publications Warehouse

Sotola, V. Alex; Miehls, Scott M.; Simard, Lee G.; Marsden, J. Ellen

2018-01-01

Sea lamprey is considered an invasive and nuisance species in the Laurentian Great Lakes, Lake Champlain, and the Finger Lakes of New York and is a major focus of control efforts. Currently, management practices focus on limiting the area of infestation using barriers to block migratory adults, and lampricides to kill ammocoetes in infested tributaries. No control efforts currently target the downstream-migrating post-metamorphic life stage which could provide another management opportunity. In order to apply control methods to this life stage, a better understanding of their downstream movement patterns is needed. To quantify spatial distribution of downstream migrants, we deployed fyke and drift nets laterally and vertically across the stream channel in two tributaries of Lake Champlain. Sea lamprey was not randomly distributed across the stream width and lateral distribution showed a significant association with discharge. Results indicated that juvenile sea lamprey is most likely to be present in the thalweg and at midwater depths of the stream channel. Further, a majority of the catch occurred during high flow events, suggesting an increase in downstream movement activity when water levels are higher than base flow. Discharge and flow are strong predictors of the distribution of out-migrating sea lamprey, thus managers will need to either target capture efforts in high discharge areas of streams or develop means to guide sea lamprey away from these areas.

Integrative Analysis of DNA Methylation and Gene Expression Data Identifies EPAS1 as a Key Regulator of COPD

PubMed Central

Yoo, Seungyeul; Takikawa, Sachiko; Geraghty, Patrick; Argmann, Carmen; Campbell, Joshua; Lin, Luan; Huang, Tao; Tu, Zhidong; Feronjy, Robert; Spira, Avrum; Schadt, Eric E.; Powell, Charles A.; Zhu, Jun

2015-01-01

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profile and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system development. We confirmed that EPAS1 protein levels are lower in human COPD lung tissue compared to non-disease controls and that Epas1 gene expression is reduced in mice chronically exposed to cigarette smoke. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human endothelial cells. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes, and genes associated with emphysema severity. Our first integrative analysis of genome-wide DNA methylation and gene expression profiles illustrates that not only does DNA methylation play a ‘causal’ role in the molecular pathophysiology of COPD, but it can be leveraged to directly identify novel key mediators of this pathophysiology. PMID:25569234

Integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD.

PubMed

Yoo, Seungyeul; Takikawa, Sachiko; Geraghty, Patrick; Argmann, Carmen; Campbell, Joshua; Lin, Luan; Huang, Tao; Tu, Zhidong; Foronjy, Robert F; Feronjy, Robert; Spira, Avrum; Schadt, Eric E; Powell, Charles A; Zhu, Jun

2015-01-01

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profile and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system development. We confirmed that EPAS1 protein levels are lower in human COPD lung tissue compared to non-disease controls and that Epas1 gene expression is reduced in mice chronically exposed to cigarette smoke. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human endothelial cells. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes, and genes associated with emphysema severity. Our first integrative analysis of genome-wide DNA methylation and gene expression profiles illustrates that not only does DNA methylation play a 'causal' role in the molecular pathophysiology of COPD, but it can be leveraged to directly identify novel key mediators of this pathophysiology.

Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59.

PubMed

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

2013-02-01

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 SCF(COI1), 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 SCF(COI1)-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59.

P38 pathway as a key downstream signal of connective tissue growth factor to regulate metastatic potential in non-small-cell lung cancer.

PubMed

Kato, Shinichiro; Yokoyama, Satoru; Hayakawa, Yoshihiro; Li, Luhui; Iwakami, Yusuke; Sakurai, Hiroaki; Saiki, Ikuo

2016-10-01

Although the secretory matricellular protein connective tissue growth factor (CTGF) has been reported to be related to lung cancer metastasis, the precise mechanism by which CTGF regulates lung cancer metastasis has not been elucidated. In the present study, we show the molecular link between CTGF secretion and the p38 pathway in the invasive and metastatic potential of non-small-cell lung cancer (NSCLC). Among three different human NSCLC cell lines (PC-14, A549, and PC-9), their in vitro invasiveness was inversely correlated with the level of CTGF secretion. By supplementing or reducing CTGF secretion in NSCLC culture, dysregulation of the invasive and metastatic potential of NSCLC cell lines was largely compensated. By focusing on the protein kinases that are known to be regulated by CTGF, we found that the p38 pathway is a key downstream signal of CTGF to regulate the metastatic potential of NSCLC. Importantly, a negative correlation between CTGF and phosphorylation status of p38 was identified in The Cancer Genome Atlas lung adenocarcinoma dataset. In the context of the clinical importance of our findings, we showed that p38 inhibitor, SB203580, reduced the metastatic potential of NSCLC secreting low levels of CTGF. Collectively, our present findings indicate that the CTGF/p38 axis is a novel therapeutic target of NSCLC metastasis, particularly NSCLC secreting low levels of CTGF. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Current and Future Trials of Targeted Therapies in Cutaneous Melanoma

PubMed Central

Madhunapantula, SubbaRao V.; Robertson, Gavin P.; Drabick, Joseph J.

2013-01-01

In order to effectively treat melanoma, targeted inhibition of key mechanistic events regulating melanoma development such as cell proliferation, survival, angiogenesis and invasion or metastasis needs to be accomplished. The Mitogen Activated Protein Kinase (MAPK) pathway has been identified as a key player in melanoma development making this cascade an important therapeutic target. However, identification of the ideal pathway member to therapeutically target for maximal clinical benefit remains a challenge. In normal cells, the MAPK pathway relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events, which promote cancer development. Dysregulation of the MAPK pathway occurs frequently in many human cancers including melanoma. Mutations in the B-RAF and RAS genes, genetic or epigenetic modifications are the key aberrations observed in this signaling cascade. Constitutive activation of this pathway causes oncogenic transformation of cells by promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. This review provides an overview of (a) key members of MAPK signaling regulating melanoma development; (b) key proteins which can serve as biomarkers to assess disease progression; (c) the clinical efficacy of various pharmacological agents targeting MAPK pathway; (d) current clinical trials evaluating downstream targets of the MAPK pathway; (e) issues associated with pharmacological agents such as drug resistance, induction of cancers; and finally (e) various strategies overcoming drug resistance. PMID:23288642

The developing oligodendrocyte: key cellular target in brain injury in the premature infant

PubMed Central

Volpe, Joseph J.; Kinney, Hannah C.; Jensen, Frances, E.; Rosenberg, Paul A.

2011-01-01

Brain injury in the premature infant, a problem of enormous importance, is associated with a high risk of neurodevelopmental disability. The major type of injury involves cerebral white matter and the principal cellular target is the developing oligodendrocyte. The specific phase of the oligodendroglial lineage affected has been defined from study of both human brain and experimental models. This premyelinating cell (pre-OL) is vulnerable because of a series of maturation-dependent events. The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischemia and systemic infection/inflammation, both of which are common occurrences in premature infants. The focus of this review and of our research over the past 15-20 years has been the cellular and molecular bases for the maturation-dependent vulnerability of the pre-OL to the action of the two upstream mechanisms. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack. The work in both experimental models and human brain has identified a remarkable confluence of maturation-dependent factors that render the pre-OL so exquisitely vulnerable to these downstream mechanisms. Most importantly, elucidation of these factors has led to delineation of a series of potential therapeutic interventions, which in experimental models show marked protective properties. The critical next step, i.e., clinical trials in the living infant, is now on the horizon. PMID:21382469

Akt Regulates TNFα Synthesis Downstream of RIP1 Kinase Activation during Necroptosis

PubMed Central

McNamara, Colleen R.; Ahuja, Ruchita; Osafo-Addo, Awo D.; Barrows, Douglas; Kettenbach, Arminja; Skidan, Igor; Teng, Xin; Cuny, Gregory D.; Gerber, Scott; Degterev, Alexei

2013-01-01

Necroptosis is a regulated form of necrotic cell death that has been implicated in the pathogenesis of various diseases including intestinal inflammation and systemic inflammatory response syndrome (SIRS). In this work, we investigated the signaling mechanisms controlled by the necroptosis mediator receptor interacting protein-1 (RIP1) kinase. We show that Akt kinase activity is critical for necroptosis in L929 cells and plays a key role in TNFα production. During necroptosis, Akt is activated in a RIP1 dependent fashion through its phosphorylation on Thr308. In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1. Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1). Akt activity, mediated in part through mTORC1, links RIP1 to JNK activation and autocrine production of TNFα. In other cell types, such as mouse lung fibroblasts and macrophages, Akt exhibited control over necroptosis-associated TNFα production without contributing to cell death. Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation. PMID:23469174

La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1).

PubMed

Fonseca, Bruno D; Zakaria, Chadi; Jia, Jian-Jun; Graber, Tyson E; Svitkin, Yuri; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, Jacob M; Diao, Ilo T; Lussier, Alexandre; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta-Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, Jose L; Hernández, Greco; Alain, Tommy; Damgaard, Christian K

2015-06-26

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5'TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)*

PubMed Central

Fonseca, Bruno D.; Zakaria, Chadi; Jia, Jian-Jun; Graber, Tyson E.; Svitkin, Yuri; Tahmasebi, Soroush; Healy, Danielle; Hoang, Huy-Dung; Jensen, Jacob M.; Diao, Ilo T.; Lussier, Alexandre; Dajadian, Christopher; Padmanabhan, Niranjan; Wang, Walter; Matta-Camacho, Edna; Hearnden, Jaclyn; Smith, Ewan M.; Tsukumo, Yoshinori; Yanagiya, Akiko; Morita, Masahiro; Petroulakis, Emmanuel; González, Jose L.; Hernández, Greco; Alain, Tommy; Damgaard, Christian K.

2015-01-01

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5′TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1. PMID:25940091

Key parameters design of an aerial target detection system on a space-based platform

NASA Astrophysics Data System (ADS)

Zhu, Hanlu; Li, Yejin; Hu, Tingliang; Rao, Peng

2018-02-01

To ensure flight safety of an aerial aircraft and avoid recurrence of aircraft collisions, a method of multi-information fusion is proposed to design the key parameter to realize aircraft target detection on a space-based platform. The key parameters of a detection wave band and spatial resolution using the target-background absolute contrast, target-background relative contrast, and signal-to-clutter ratio were determined. This study also presented the signal-to-interference ratio for analyzing system performance. Key parameters are obtained through the simulation of a specific aircraft. And the simulation results show that the boundary ground sampling distance is 30 and 35 m in the mid- wavelength infrared (MWIR) and long-wavelength infrared (LWIR) bands for most aircraft detection, and the most reasonable detection wavebands is 3.4 to 4.2 μm and 4.35 to 4.5 μm in the MWIR bands, and 9.2 to 9.8 μm in the LWIR bands. We also found that the direction of detection has a great impact on the detection efficiency, especially in MWIR bands.

Downstream change of velocity in rivers

USGS Publications Warehouse

Leopold, Luna Bergere

1953-01-01

Because river slope generally decreases in a downstream direction, it is generally supposed that velocity of flow also decreases downstream. Analysis of some of the large number of velocity measurements made at stream-gaging stations demonstrates that mean velocity generally tends to increase downstream. Although there are many reaches in nearly all rivers where mean velocity decreases downstream, the general tendency for conservation or for downstream increase was found in all data studied.Computations of bed velocity indicate that this parameter also tends to increase downstream.Near the streambed, shear in the vertical profile of velocity (rate of decrease of velocity with depth) tends to decrease downstream. This down-valley decrease of shear implies decreasing competence downstream.

Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

PubMed

Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

2013-05-01

Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

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

Texas Quality Workforce Planning: 1993 Key Industries and Targeted Occupations for Texas' 24 Quality Work Force Planning Regions.

ERIC Educational Resources Information Center

Texas State Dept. of Commerce, Austin.

In 1993, Texas' 24 quality work force planning committees used a state-developed targeted occupations planning methodology to identify key industries and targeted occupations with the greatest potential for job openings in their respective regions. Between 11 and 20 key industries (13.5 on average) were identified for each region. The following 10…

Downstream variation in bankfull width of wadeable streams across the conterminous United States

EPA Science Inventory

Bankfull channel width is a fundamental measure of stream size and a key parameter of interest for many applications in hydrology, fluvial geomorphology, and stream ecology. We developed downstream hydraulic geometry relationships for bankfull channel width w as a function of dra...

Extraction and purification methods in downstream processing of plant-based recombinant proteins.

PubMed

Łojewska, Ewelina; Kowalczyk, Tomasz; Olejniczak, Szymon; Sakowicz, Tomasz

2016-04-01

During the last two decades, the production of recombinant proteins in plant systems has been receiving increased attention. Currently, proteins are considered as the most important biopharmaceuticals. However, high costs and problems with scaling up the purification and isolation processes make the production of plant-based recombinant proteins a challenging task. This paper presents a summary of the information regarding the downstream processing in plant systems and provides a comprehensible overview of its key steps, such as extraction and purification. To highlight the recent progress, mainly new developments in the downstream technology have been chosen. Furthermore, besides most popular techniques, alternative methods have been described. Copyright © 2015 Elsevier Inc. All rights reserved.

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

Downstream targets of HOXB4 in a cell line model of primitive hematopoietic progenitor cells.

PubMed

Lee, Han M; Zhang, Hui; Schulz, Vincent; Tuck, David P; Forget, Bernard G

2010-08-05

Enforced expression of the homeobox transcription factor HOXB4 has been shown to enhance hematopoietic stem cell self-renewal and expansion ex vivo and in vivo. To investigate the downstream targets of HOXB4 in hematopoietic progenitor cells, HOXB4 was constitutively overexpressed in the primitive hematopoietic progenitor cell line EML. Two genome-wide analytical techniques were used: RNA expression profiling using microarrays and chromatin immunoprecipitation (ChIP)-chip. RNA expression profiling revealed that 465 gene transcripts were differentially expressed in KLS (c-Kit(+), Lin(-), Sca-1(+))-EML cells that overexpressed HOXB4 (KLS-EML-HOXB4) compared with control KLS-EML cells that were transduced with vector alone. In particular, erythroid-specific gene transcripts were observed to be highly down-regulated in KLS-EML-HOXB4 cells. ChIP-chip analysis revealed that the promoter region for 1910 genes, such as CD34, Sox4, and B220, were occupied by HOXB4 in KLS-EML-HOXB4 cells. Side-by-side comparison of the ChIP-chip and RNA expression profiling datasets provided correlative information and identified Gp49a and Laptm4b as candidate "stemness-related" genes. Both genes were highly ranked in both dataset lists and have been previously shown to be preferentially expressed in hematopoietic stem cells and down-regulated in mature hematopoietic cells, thus making them attractive candidates for future functional studies in hematopoietic cells.

Differential 14-3-3 affinity capture reveals new downstream targets of phosphatidylinositol 3-kinase signaling.

PubMed

Dubois, Fanny; Vandermoere, Franck; Gernez, Aurélie; Murphy, Jane; Toth, Rachel; Chen, Shuai; Geraghty, Kathryn M; Morrice, Nick A; MacKintosh, Carol

2009-11-01

We devised a strategy of 14-3-3 affinity capture and release, isotope differential (d(0)/d(4)) dimethyl labeling of tryptic digests, and phosphopeptide characterization to identify novel targets of insulin/IGF1/phosphatidylinositol 3-kinase signaling. Notably four known insulin-regulated proteins (PFK-2, PRAS40, AS160, and MYO1C) had high d(0)/d(4) values meaning that they were more highly represented among 14-3-3-binding proteins from insulin-stimulated than unstimulated cells. Among novel candidates, insulin receptor substrate 2, the proapoptotic CCDC6, E3 ubiquitin ligase ZNRF2, and signaling adapter SASH1 were confirmed to bind to 14-3-3s in response to IGF1/phosphatidylinositol 3-kinase signaling. Insulin receptor substrate 2, ZNRF2, and SASH1 were also regulated by phorbol ester via p90RSK, whereas CCDC6 and PRAS40 were not. In contrast, the actin-associated protein vasodilator-stimulated phosphoprotein and lipolysis-stimulated lipoprotein receptor, which had low d(0)/d(4) scores, bound 14-3-3s irrespective of IGF1 and phorbol ester. Phosphorylated Ser(19) of ZNRF2 (RTRAYpS(19)GS), phospho-Ser(90) of SASH1 (RKRRVpS(90)QD), and phospho- Ser(493) of lipolysis-stimulated lipoprotein receptor (RPRARpS(493)LD) provide one of the 14-3-3-binding sites on each of these proteins. Differential 14-3-3 capture provides a powerful approach to defining downstream regulatory mechanisms for specific signaling pathways.

Digging a hole under Hedgehog: downstream inhibition as an emerging anticancer strategy.

PubMed

Di Magno, Laura; Coni, Sonia; Di Marcotullio, Lucia; Canettieri, Gianluca

2015-08-01

Hedgehog signaling is a key regulator of development and stem cell fate and its aberrant activation is a leading cause of a number of tumors. Activating germline or somatic mutations of genes encoding Hh pathway components are found in Basal Cell Carcinoma (BCC) and Medulloblastoma (MB). Ligand-dependent Hedgehog hyperactivation, due to autocrine or paracrine mechanisms, is also observed in a large number of malignancies of the breast, colon, skin, bladder, pancreas and other tissues. The key tumorigenic role of Hedgehog has prompted effort aimed at identifying inhibitors of this signaling. To date, only the antagonists of the membrane transducer Smo have been approved for therapy or are under clinical trials in patients with BCC and MB linked to Ptch or Smo mutations. Despite the good initial response, patients treated with Smo antagonists have eventually developed resistance due to the occurrence of compensating mechanisms. Furthermore, Smo antagonists are not effective in tumors where the Hedgehog hyperactivation is due to mutations of pathway components downstream of Smo, or in case of non-canonical, Smo-independent activation of the Gli transcription factors. For all these reasons, the research of Hh inhibitors acting downstream of Smo is becoming an area of intensive investigation. In this review we illustrate the progresses made in the identification of effective Hedgehog inhibitors and their application in cancer, with a special emphasis on the newly identified downstream inhibitors. We describe in detail the Gli inhibitors and illustrate their mode of action and applications in experimental and/or clinical settings. Copyright © 2015 Elsevier B.V. All rights reserved.

Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling

PubMed Central

Norris, Megan L; Pauli, Andrea; Gagnon, James A; Lord, Nathan D; Rogers, Katherine W; Mosimann, Christian; Zon, Leonard I

2017-01-01

Toddler/Apela/Elabela is a conserved secreted peptide that regulates mesendoderm development during zebrafish gastrulation. Two non-exclusive models have been proposed to explain Toddler function. The ‘specification model’ postulates that Toddler signaling enhances Nodal signaling to properly specify endoderm, whereas the ‘migration model’ posits that Toddler signaling regulates mesendodermal cell migration downstream of Nodal signaling. Here, we test key predictions of both models. We find that in toddler mutants Nodal signaling is initially normal and increasing endoderm specification does not rescue mesendodermal cell migration. Mesodermal cell migration defects in toddler mutants result from a decrease in animal pole-directed migration and are independent of endoderm. Conversely, endodermal cell migration defects are dependent on a Cxcr4a-regulated tether of the endoderm to mesoderm. These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling. PMID:29117894

Differential 14-3-3 Affinity Capture Reveals New Downstream Targets of Phosphatidylinositol 3-Kinase Signaling*

PubMed Central

Dubois, Fanny; Vandermoere, Franck; Gernez, Aurélie; Murphy, Jane; Toth, Rachel; Chen, Shuai; Geraghty, Kathryn M.; Morrice, Nick A.; MacKintosh, Carol

2009-01-01

We devised a strategy of 14-3-3 affinity capture and release, isotope differential (d0/d4) dimethyl labeling of tryptic digests, and phosphopeptide characterization to identify novel targets of insulin/IGF1/phosphatidylinositol 3-kinase signaling. Notably four known insulin-regulated proteins (PFK-2, PRAS40, AS160, and MYO1C) had high d0/d4 values meaning that they were more highly represented among 14-3-3-binding proteins from insulin-stimulated than unstimulated cells. Among novel candidates, insulin receptor substrate 2, the proapoptotic CCDC6, E3 ubiquitin ligase ZNRF2, and signaling adapter SASH1 were confirmed to bind to 14-3-3s in response to IGF1/phosphatidylinositol 3-kinase signaling. Insulin receptor substrate 2, ZNRF2, and SASH1 were also regulated by phorbol ester via p90RSK, whereas CCDC6 and PRAS40 were not. In contrast, the actin-associated protein vasodilator-stimulated phosphoprotein and lipolysis-stimulated lipoprotein receptor, which had low d0/d4 scores, bound 14-3-3s irrespective of IGF1 and phorbol ester. Phosphorylated Ser19 of ZNRF2 (RTRAYpS19GS), phospho-Ser90 of SASH1 (RKRRVpS90QD), and phospho- Ser493 of lipolysis-stimulated lipoprotein receptor (RPRARpS493LD) provide one of the 14-3-3-binding sites on each of these proteins. Differential 14-3-3 capture provides a powerful approach to defining downstream regulatory mechanisms for specific signaling pathways. PMID:19648646

Effects of small impoundments on downstream crayfish assemblages

Treesearch

Susan B. Adams

2013-01-01

Dams and impoundments, both large and small, affect downstream physicochemical characteristics and up- and downstream biotic communities. I tested whether small dams and their impoundments altered downstream crayfish assemblages in northern Mississippi. I sampled crayfish and measured physicochemical variables at 4 sites downstream of impoundments (outlet sites) and 4...

Adolescent women as a key target population for community nutrition education programs in Indonesia.

PubMed

Savage, Amy; Februhartanty, Judhiastuty; Worsley, Anthony

2017-05-01

Adolescence is a critical life-stage that sets the foundation for health in adulthood. Adolescent women are a unique population and should be targeted as such for nutrition promotion activities. Using Indonesia as a case study, this qualitative study aimed to identify existing nutrition promotion programs aimed at adolescent girls, how best to target this population and effective recommendations to inform nutrition education program design for this important group. Semi-structured interviews and questionnaires were conducted with ten key informants working in public health in Indonesia. Interview transcripts were analysed and coded to identify key themes. No existing nutrition education programs targeting adolescent women in Indonesia were identified. Several strategies apply to nutrition programs for adolescent girls: 1) nutrition promotion messages that are relevant to the lifestyles and interests of adolescent women; 2) technology-based interventions show promise, however, they need to be appropriately targeted to sub-groups; 3) school remains an important setting; and 4) early marriage is an important issue affecting nutritional status and engagement of adolescent girls. The informants recommended that: 1) more research is needed about the underlying motivations for behaviour change among adolescent women and ways to effectively implement the identified engagement strategies; 2) adolescent girls should be included in program design to improve its suitability and uptake; and 3) government budget and policy support is crucial to success. Adolescent women are an important population group and more research is required to identify the optimal forms of engagement to improve nutrition programs for them.

Brachyury downstream notochord differentiation in the ascidian embryo

PubMed Central

Takahashi, Hiroki; Hotta, Kohji; Erives, Albert; Di Gregorio, Anna; Zeller, Robert W.; Levine, Michael; Satoh, Nori

1999-01-01

The ascidian tadpole represents the most simplified chordate body plan. It contains a notochord composed of just 40 cells, but as in vertebrates Brachyury is essential for notochord differentiation. Here, we show that the misexpression of the Brachyury gene (Ci-Bra) of Ciona intestinalis is sufficient to transform endoderm into notochord. Subtractive hybridization screens were conducted to identify potential Brachyury target genes that are induced upon Ci-Bra misexpression. Of 501 independent cDNA clones that were surveyed, 38 were specifically expressed in notochord cells. These potential Ci-Bra downstream genes appear to encode a broad spectrum of divergent proteins associated with notochord formation. PMID:10385620

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

PubMed

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

2014-04-01

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

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

Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling

PubMed Central

Guiu, Jordi; Shimizu, Ritsuko; D’Altri, Teresa; Fraser, Stuart T.; Hatakeyama, Jun; Bresnick, Emery H.; Kageyama, Ryoichiro; Dzierzak, Elaine; Yamamoto, Masayuki; Espinosa, Lluis

2013-01-01

Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs. PMID:23267012

An electrophysiological investigation of reinforcement effects in attention deficit/hyperactivity disorder: Dissociating cue sensitivity from down-stream effects on target engagement and performance.

PubMed

Chronaki, Georgia; Soltesz, Fruzsina; Benikos, Nicholas; Sonuga-Barke, Edmund J S

2017-12-01

Neural hypo-sensitivity to cues predicting positive reinforcement has been observed in ADHD using the Monetary Incentive Delay (MID) task. Here we report the first study using an electrophysiological analogue of this task to distinguish between (i) cue related anticipation of reinforcement and downstream effects on (ii) target engagement and (iii) performance in a clinical sample of adolescents with ADHD and controls. Thirty-one controls and 32 adolescents with ADHD aged 10-16 years performed the electrophysiological (e)-MID task - in which preparatory cues signal whether a response to an upcoming target will be reinforced or not - under three conditions; positive reinforcement, negative reinforcement (response cost) and no consequence (neutral). We extracted values for both cue-related potentials known to be, both, associated with response preparation and modulated by reinforcement (Cue P3 and Cue CNV) and target-related potentials (target P3) and compared these between ADHD and controls. ADHD and controls did not differ on cue-related components on neutral trials. Against expectation, adolescents with ADHD displayed Cue P3 and Cue CNV reinforcement-related enhancement (versus neutral trials) compared to controls. ADHD individuals displayed smaller target P3 amplitudes and slower and more variable performance - but effects were not modulated by reinforcement contingencies. When age, IQ and conduct problems were controlled effects were marginally significant but the pattern of results did not change. ADHD was associated with hypersensitivity to positive (and marginally negative) reinforcement reflected on components often thought to be associated with response preparation - however these did not translate into improved attention to targets. In the case of ADHD, upregulated CNV may be a specific marker of hyper-arousal rather than an enhancement of anticipatory attention to upcoming targets. Future studies should examine the effects of age, IQ and conduct problems

Distinct downstream targets manifest p53-dependent pathologies in mice.

PubMed

Pant, V; Xiong, S; Chau, G; Tsai, K; Shetty, G; Lozano, G

2016-11-03

Mdm2, the principal negative regulator of p53, is critical for survival, a fact clearly demonstrated by the p53-dependent death of germline or conditional mice following deletion of Mdm2. On the other hand, Mdm2 hypomorphic (Mdm2 Puro/Δ7-12 ) or heterozygous (Mdm2 +/- ) mice that express either 30 or 50% of normal Mdm2 levels, respectively, are viable but present distinct phenotypes because of increased p53 activity. Mdm2 levels are also transcriptionally regulated by p53. We evaluated the significance of this reciprocal relationship in a new hypomorphic mouse model inheriting an aberrant Mdm2 allele with insertion of the neomycin cassette and deletion of 184-bp sequence in intron 3. These mice also carry mutations in the Mdm2 P2-promoter and thus express suboptimal levels of Mdm2 entirely encoded from the P1-promoter. Resulting mice exhibit abnormalities in skin pigmentation and reproductive tissue architecture, and are subfertile. Notably, all these phenotypes are rescued on a p53-null background. Furthermore, these phenotypes depend on distinct p53 downstream activities as genetic ablation of the pro-apoptotic gene Puma reverts the reproductive abnormalities but not skin hyperpigmentation, whereas deletion of cell cycle arrest gene p21 does not rescue either phenotype. Moreover, p53-mediated upregulation of Kitl influences skin pigmentation. Altogether, these data emphasize tissue-specific p53 activities that regulate cell fate.

Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models.

PubMed

Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

2012-11-01

Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.

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

NASA Astrophysics Data System (ADS)

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

2014-12-01

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

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

PubMed

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

2015-08-18

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

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

PubMed

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

2018-05-01

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

The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF-ERK signaling.

PubMed

Maity, Gargi; Haque, Inamul; Ghosh, Arnab; Dhar, Gopal; Gupta, Vijayalaxmi; Sarkar, Sandipto; Azeem, Imaan; McGregor, Douglas; Choudhary, Abhishek; Campbell, Donald R; Kambhampati, Suman; Banerjee, Sushanta K; Banerjee, Snigdha

2018-03-23

Myc-associated zinc-finger protein (MAZ) is a transcription factor with dual roles in transcription initiation and termination. Deregulation of MAZ expression is associated with the progression of pancreatic ductal adenocarcinoma (PDAC). However, the mechanism of action of MAZ in PDAC progression is largely unknown. Here, we present evidence that MAZ mRNA expression and protein levels are increased in human PDAC cell lines, tissue samples, a subcutaneous tumor xenograft in a nude mouse model, and spontaneous cancer in the genetically engineered PDAC mouse model. We also found that MAZ is predominantly expressed in pancreatic cancer stem cells. Functional analysis indicated that MAZ depletion in PDAC cells inhibits invasive phenotypes such as the epithelial-to-mesenchymal transition, migration, invasion, and the sphere-forming ability of PDAC cells. Mechanistically, we detected no direct effects of MAZ on the expression of K-Ras mutants, but MAZ increased the activity of CRAF-ERK signaling, a downstream signaling target of K-Ras. The MAZ-induced activation of CRAF-ERK signaling was mediated via p21-activated protein kinase (PAK) and protein kinase B (AKT/PKB) signaling cascades and promoted PDAC cell invasiveness. Moreover, we found that the matricellular oncoprotein cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) regulates MAZ expression via Notch-1-sonic hedgehog signaling in PDAC cells. We propose that Cyr61/CCN1-induced expression of MAZ promotes invasive phenotypes of PDAC cells not through direct K-Ras activation but instead through the activation of CRAF-ERK signaling. Collectively, these results highlight key molecular players in PDAC invasiveness and may help inform therapeutic strategies to improve clinical management and outcomes of PDAC.

Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models1

PubMed Central

Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

2012-01-01

Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC. PMID:23226094

Target of rapamycin complex 2 signals to downstream effector yeast protein kinase 2 (Ypk2) through adheres-voraciously-to-target-of-rapamycin-2 protein 1 (Avo1) in Saccharomyces cerevisiae.

PubMed

Liao, Hsien-Ching; Chen, Mei-Yu

2012-02-24

The conserved Ser/Thr kinase target of rapamycin (TOR) serves as a central regulator in controlling cell growth-related functions. There exist two distinct TOR complexes, TORC1 and TORC2, each coupling to specific downstream effectors and signaling pathways. In Saccharomyces cerevisiae, TORC2 is involved in regulating actin organization and maintaining cell wall integrity. Ypk2 (yeast protein kinase 2), a member of the cAMP-dependent, cGMP-dependent, and PKC (AGC) kinase family, is a TORC2 substrate known to participate in actin and cell wall regulation. Employing avo3(ts) mutants with defects in TORC2 functions that are suppressible by active Ypk2, we investigated the molecular interactions involved in mediating TORC2 signaling to Ypk2. GST pulldown assays in yeast lysates demonstrated physical interactions between Ypk2 and components of TORC2. In vitro binding assays revealed that Avo1 directly binds to Ypk2. In avo3(ts) mutants, the TORC2-Ypk2 interaction was reduced and could be restored by AVO1 overexpression, highlighting the important role of Avo1 in coupling TORC2 to Ypk2. The interaction was mapped to an internal region (amino acids 600-840) of Avo1 and a C-terminal region of Ypk2. Ypk2(334-677), a truncated form of Ypk2 containing the Avo1-interacting region, was able to interfere with Avo1-Ypk2 interaction in vitro. Overexpressing Ypk2(334-677) in yeast cells resulted in a perturbation of TORC2 functions, causing defective cell wall integrity, aberrant actin organization, and diminished TORC2-dependent Ypk2 phosphorylation evidenced by the loss of an electrophoretic mobility shift. Together, our data support the conclusion that the direct Avo1-Ypk2 interaction is crucial for TORC2 signaling to the downstream Ypk2 pathway.

mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy.

PubMed

Weiler, Markus; Blaes, Jonas; Pusch, Stefan; Sahm, Felix; Czabanka, Marcus; Luger, Sebastian; Bunse, Lukas; Solecki, Gergely; Eichwald, Viktoria; Jugold, Manfred; Hodecker, Sibylle; Osswald, Matthias; Meisner, Christoph; Hielscher, Thomas; Rübmann, Petra; Pfenning, Philipp-Niklas; Ronellenfitsch, Michael; Kempf, Tore; Schnölzer, Martina; Abdollahi, Amir; Lang, Florian; Bendszus, Martin; von Deimling, Andreas; Winkler, Frank; Weller, Michael; Vajkoczy, Peter; Platten, Michael; Wick, Wolfgang

2014-01-07

A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.

mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

PubMed Central

Weiler, Markus; Blaes, Jonas; Pusch, Stefan; Sahm, Felix; Czabanka, Marcus; Luger, Sebastian; Bunse, Lukas; Solecki, Gergely; Eichwald, Viktoria; Jugold, Manfred; Hodecker, Sibylle; Osswald, Matthias; Meisner, Christoph; Hielscher, Thomas; Rübmann, Petra; Pfenning, Philipp-Niklas; Ronellenfitsch, Michael; Kempf, Tore; Schnölzer, Martina; Abdollahi, Amir; Lang, Florian; Bendszus, Martin; von Deimling, Andreas; Winkler, Frank; Weller, Michael; Vajkoczy, Peter; Platten, Michael; Wick, Wolfgang

2014-01-01

A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O6-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids. PMID:24367102

WRKY transcription factors: key components in abscisic acid signalling.

PubMed

Rushton, Deena L; Tripathi, Prateek; Rabara, Roel C; Lin, Jun; Ringler, Patricia; Boken, Ashley K; Langum, Tanner J; Smidt, Lucas; Boomsma, Darius D; Emme, Nicholas J; Chen, Xianfeng; Finer, John J; Shen, Qingxi J; Rushton, Paul J

2012-01-01

WRKY transcription factors (TFs) are key regulators of many plant processes, including the responses to biotic and abiotic stresses, senescence, seed dormancy and seed germination. For over 15 years, limited evidence has been available suggesting that WRKY TFs may play roles in regulating plant responses to the phytohormone abscisic acid (ABA), notably some WRKY TFs are ABA-inducible repressors of seed germination. However, the roles of WRKY TFs in other aspects of ABA signalling, and the mechanisms involved, have remained unclear. Recent significant progress in ABA research has now placed specific WRKY TFs firmly in ABA-responsive signalling pathways, where they act at multiple levels. In Arabidopsis, WRKY TFs appear to act downstream of at least two ABA receptors: the cytoplasmic PYR/PYL/RCAR-protein phosphatase 2C-ABA complex and the chloroplast envelope-located ABAR-ABA complex. In vivo and in vitro promoter-binding studies show that the target genes for WRKY TFs that are involved in ABA signalling include well-known ABA-responsive genes such as ABF2, ABF4, ABI4, ABI5, MYB2, DREB1a, DREB2a and RAB18. Additional well-characterized stress-inducible genes such as RD29A and COR47 are also found in signalling pathways downstream of WRKY TFs. These new insights also reveal that some WRKY TFs are positive regulators of ABA-mediated stomatal closure and hence drought responses. Conversely, many WRKY TFs are negative regulators of seed germination, and controlling seed germination appears a common function of a subset of WRKY TFs in flowering plants. Taken together, these new data demonstrate that WRKY TFs are key nodes in ABA-responsive signalling networks. © 2011 The Authors. Plant Biotechnology Journal © 2011 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

Power Budget Analysis of Colorless Hybrid WDM/TDM-PON Scheme Using Downstream DPSK and Re-modulated Upstream OOK Data Signals

NASA Astrophysics Data System (ADS)

Khan, Yousaf; Afridi, Muhammad Idrees; Khan, Ahmed Mudassir; Rehman, Waheed Ur; Khan, Jahanzeb

2014-09-01

Hybrid wavelength-division multiplexed/time-division multiplexed passive optical access networks (WDM/TDM-PONs) combine the advance features of both WDM and TDM PONs to provide a cost-effective access network solution. We demonstrate and analyze the transmission performances and power budget issues of a colorless hybrid WDM/TDM-PON scheme. A 10-Gb/s downstream differential phase shift keying (DPSK) and remodulated upstream on/off keying (OOK) data signals are transmitted over 25 km standard single mode fiber. Simulation results show error free transmission having adequate power margins in both downstream and upstream transmission, which prove the applicability of the proposed scheme to future passive optical access networks. The power budget confines both the PON splitting ratio and the distance between the Optical Line Terminal (OLT) and Optical Network Unit (ONU).

EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation.

PubMed

Hamaoka, Yuho; Negishi, Manabu; Katoh, Hironori

2016-08-01

EphA2, a member of the Eph receptor tyrosine kinases, is frequently overexpressed in a variety of malignancies, including glioblastoma, and its expression is correlated with poor prognosis. EphA2 acts as a tumor promoter through a ligand ephrin-independent mechanism, which requires phosphorylation of EphA2 on serine 897 (S897), leading to increased cell migration and invasion. In this study, we show that ligand-independent EphA2 signaling occurs downstream of the MEK/ERK/RSK pathway and mediates epidermal growth factor (EGF)-induced cell proliferation in glioblastoma cells. Suppression of EphA2 expression by long-term exposure to ligand ephrinA1 or EphA2-targeted shRNA inhibited EGF-induced cell proliferation. Stimulation of the cells with EGF induced EphA2 S897 phosphorylation, which was suppressed by MEK and RSK inhibitors, but not by phosphatidylinositol 3-kinase (PI3K) and Akt inhibitors. The RSK inhibitor or RSK2-targeted shRNA also suppressed EGF-induced cell proliferation. Furthermore, overexpression of wild-type EphA2 promoted cell proliferation without EGF stimulation, whereas overexpression of EphA2-S897A mutant suppressed EGF- or RSK2-induced proliferation. Taken together, these results suggest that EphA2 is a key downstream target of the MEK/ERK/RSK signaling pathway in the regulation of glioblastoma cell proliferation. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Targeting the Dopamine 1 Receptor or its Downstream Signalling by Inhibiting Phosphodiesterase-1 Improves Cognitive Performance.

PubMed

Pekcec, Anton; Schülert, Niklas; Stierstorfer, Birgit; Deiana, Serena; Dorner-Ciossek, Cornelia; Rosenbrock, Holger

2018-05-03

Insufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the phosphodiesterase-1 (PDE1) isoform B (PDE1B) is postulated to regulate D1 receptor-dependent signal transduction, this study intended to elucidate the role of PDE1 for cognitive processes reliant on D1 receptor function. Cognitive performance of the D1 receptor agonist, SKF38393, was studied in the T-maze continuous alternation task and the 5-Choice Serial Reaction Time Task. D1 receptor/ PDE1B double-immunohistochemistry was performed using human and rat prefrontal brain sections. Pharmacological activity of the PDE1 inhibitor, ITI-214, was assessed by measuring the increase of cAMP/ cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on modulation of prefrontal neuronal transmission by SKF38393 and ITI-214 were performed using extracellular recordings in brain slices. SKF38393 improved working memory and attentional performance in rodents. D1 receptor/ PDE1B co-expression was verified in both, human and rat prefrontal brain sections. The pharmacological activity of ITI-214 on its target was demonstrated by increased prefrontal cAMP/ cGMP upon administration. In addition, ITI-214 improved working memory performance. SKF38393 and ITI-214 facilitated neuronal transmission in prefrontal brain slices. We hypothesise that PDE1 inhibition may improve working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data may therefore support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction. This article is protected by copyright. All rights reserved.

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.

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

Proliferation of murine c-kit(pos) cardiac stem cells stimulated with IGF-1 is associated with Akt-1 mediated phosphorylation and nuclear export of FoxO3a and its effect on downstream cell cycle regulators.

PubMed

Johnson, Ann Mary; Kartha, C C

2014-04-01

Insulin-like growth factor-1 (IGF-1) is known to promote proliferation in many cell types including c-kit(pos) cardiac stem cells (CSCs). Downstream signaling pathways of IGF-1 induced CSC proliferation have not been investigated. An important downstream target of IGF-1/Akt-1 signaling is FoxO3a, a key negative regulator of cell-cycle progression. We studied the effect of IGF-1 on proliferation of c-kit(pos) murine CSCs and found that IGF-1-mediated cell proliferation is associated with FoxO3a phosphorylation and inactivation of its transcriptional activity. PI3 inhibitors LY294002 and Wortmannin abolished the effect of IGF-1 on FoxO3a phosphorylation indicating that FoxO3a phosphorylation is mediated by PI3/Akt-1 pathway. In cells with FoxO3a translocation to the cytoplasm, there is decreased expression of cell-cycle inhibitors such as p27(kip1) and p57(kip2) and increased expression of CyclinD1. Our study provides evidence that IGF-1 induced CSC proliferation could be the result of FoxO3a inactivation and its downstream effect on cell-cycle regulators.

Recent developments in anti-cancer agents targeting PI3K, Akt and mTORC1/2.

PubMed

Dienstmann, Rodrigo; Rodon, Jordi; Markman, Ben; Tabernero, Josep

2011-05-01

Inappropriate PI3K signaling is one of the most frequent occurrences in human cancer and is critical for tumor progression. A variety of genetic mutations and amplifications have been described affecting key components of this pathway, with implications not only for tumorigenesis but also for resistance to targeted agents. Emerging preclinical research has significantly advanced our understanding of the PI3K pathway and its complex downstream signalling, interactions and crosstalk. This knowledge, combined with the limited clinical antitumor activity of mTOR complex 1 inhibitors, has led to the development of rationally designed drugs targeting key elements of this pathway, such as pure PI3K inhibitors (both pan-PI3K and isoform-specific), dual PI3K/ mTOR inhibitors, Akt inhibitors, and mTOR complexes 1 and 2 catalytic site inhibitors. This review will focus primarily on an analysis of newly developed inhibitors of this pathway that have entered clinical trials, and recently registered patents in this field.

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.

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

PubMed

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

2017-07-01

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

Spatiotemporal patterns of the fish assemblages downstream of the Gezhouba Dam on the Yangtze River.

PubMed

Tao, Jiangping; Gong, Yutian; Tan, Xichang; Yang, Zhi; Chang, Jianbo

2012-07-01

An explicit demonstration of the changes in fish assemblages is required to reveal the influence of damming on fish species. However, information from which to draw general conclusions regarding changes in fish assemblages is insufficient because of the limitations of available approaches. We used a combination of acoustic surveys, gillnet sampling, and geostatistical simulations to document the spatiotemporal variations in the fish assemblages downstream of the Gezhouba Dam, before and after the third impoundment of Three Gorges Reservoir (TGR). To conduct a hydroacoustic identification of individual species, we matched the size distributions of the fishes captured by gillnet with those of the acoustic surveys. An optimum threshold of target strength of -50 dB re 1 m(2) was defined, and acoustic surveys were purposefully extended to the selected fish assemblages (i.e., endemic Coreius species) that was acquired by the size and species selectivity of the gillnet sampling. The relative proportion of fish species in acoustic surveys was allocated based on the composition (%) of the harvest in the gillnet surveys. Geostatistical simulations were likewise used to generate spatial patterns of fish distribution, and to determine the absolute abundance of the selected fish assemblages. We observed both the species composition and the spatial distribution of the selected fish assemblages changed significantly after implementation of new flow regulation in the TGR, wherein an immediate sharp population decline in the Coreius occurred. Our results strongly suggested that the new flow regulation in the TGR impoundment adversely affected downstream fish species, particularly the endemic Coreius species. To determine the factors responsible for the decline, we associated the variation in the fish assemblage patterns with changes in the environment and determined that substrate erosion resulting from trapping practices in the TGR likely played a key role.

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.

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.

Molecular genetics and targeted therapeutics in biliary tract carcinoma

PubMed Central

Marks, Eric I; Yee, Nelson S

2016-01-01

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract. PMID:26819503

Molecular genetics and targeted therapeutics in biliary tract carcinoma.

PubMed

Marks, Eric I; Yee, Nelson S

2016-01-28

The primary malignancies of the biliary tract, cholangiocarcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma (BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

A WDM-PON with DPSK modulated downstream and OOK modulated upstream signals based on symmetric 10 Gbit/s wavelength reused bidirectional reflective SOA

NASA Astrophysics Data System (ADS)

El-Nahal, Fady I.

2017-01-01

We investigate a wavelength-division-multiplexing passive optical network (WDM-PON) with centralized lightwave and direct detection. The system is demonstrated for symmetric 10 Gbit/s differential phase-shift keying (DPSK) downstream signals and on-off keying (OOK) upstream signals, respectively. A wavelength reused scheme is employed to carry the upstream data by using a reflective semiconductor optical amplifier (RSOA) as an intensity modulator at the optical network unit (ONU). The constant-intensity property of the DPSK modulation format can keep high extinction ratio ( ER) of downstream signal and reduce the crosstalk to the upstream signal. The bit error rate ( BER) performance of our scheme shows that the proposed 10 Gbit/s symmetric WDM-PON can achieve error free transmission over 25-km-long fiber transmission with low power penalty.

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways*

PubMed Central

Kovacevic, Zaklina; Menezes, Sharleen V.; Sahni, Sumit; Kalinowski, Danuta S.; Bae, Dong-Hun; Lane, Darius J. R.; Richardson, Des R.

2016-01-01

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

SWATH2stats: An R/Bioconductor Package to Process and Convert Quantitative SWATH-MS Proteomics Data for Downstream Analysis Tools.

PubMed

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.

Retention of ferrofluid aggregates at the target site during magnetic drug targeting

NASA Astrophysics Data System (ADS)

Asfer, Mohammed; Saroj, Sunil Kumar; Panigrahi, Pradipta Kumar

2017-08-01

The present study reports the retention dynamics of a ferrofluid aggregate localized at the target site inside a glass capillary (500 × 500 μm2 square cross section) against a bulk flow of DI water (Re = 0.16 and 0.016) during the process of magnetic drug targeting (MDT). The dispersion dynamics of iron oxide nanoparticles (IONPs) into bulk flow for different initial size of aggregate at the target site is reported using the brightfield visualization technique. The flow field around the aggregate during the retention is evaluated using the μPIV technique. IONPs at the outer boundary experience a higher shear force as compared to the magnetic force, resulting in dispersion of IONPs into the bulk flow downstream to the aggregate. The blockage effect and the roughness of the outer boundary of the aggregate resulting from chain like clustering of IONPs contribute to the flow recirculation at the downstream region of the aggregate. The entrapment of seeding particles inside the chain like clusters of IONPs at the outer boundary of the aggregate reduces the degree of roughness resulting in a streamlined aggregate at the target site at later time. The effect of blockage, structure of the aggregate, and disturbed flow such as recirculation around the aggregate are the primary factors, which must be investigated for the effectiveness of the MDT process for in vivo applications.

RNA from the 5' end of the R2 retrotransposon controls R2 protein binding to and cleavage of its DNA target site.

PubMed

Christensen, Shawn M; Ye, Junqiang; Eickbush, Thomas H

2006-11-21

Non-LTR retrotransposons insert into eukaryotic genomes by target-primed reverse transcription (TPRT), a process in which cleaved DNA targets are used to prime reverse transcription of the element's RNA transcript. Many of the steps in the integration pathway of these elements can be characterized in vitro for the R2 element because of the rigid sequence specificity of R2 for both its DNA target and its RNA template. R2 retrotransposition involves identical subunits of the R2 protein bound to different DNA sequences upstream and downstream of the insertion site. The key determinant regulating which DNA-binding conformation the protein adopts was found to be a 320-nt RNA sequence from near the 5' end of the R2 element. In the absence of this 5' RNA the R2 protein binds DNA sequences upstream of the insertion site, cleaves the first DNA strand, and conducts TPRT when RNA containing the 3' untranslated region of the R2 transcript is present. In the presence of the 320-nt 5' RNA, the R2 protein binds DNA sequences downstream of the insertion site. Cleavage of the second DNA strand by the downstream subunit does not appear to occur until after the 5' RNA is removed from this subunit. We postulate that the removal of the 5' RNA normally occurs during reverse transcription, and thus provides a critical temporal link to first- and second-strand DNA cleavage in the R2 retrotransposition reaction.

Philippines' downstream sector poised for growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

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.

Prediction of target genes for miR-140-5p in pulmonary arterial hypertension using bioinformatics methods.

PubMed

Li, Fangwei; Shi, Wenhua; Wan, Yixin; Wang, Qingting; Feng, Wei; Yan, Xin; Wang, Jian; Chai, Limin; Zhang, Qianqian; Li, Manxiang

2017-12-01

The expression of microRNA (miR)-140-5p is known to be reduced in both pulmonary arterial hypertension (PAH) patients and monocrotaline-induced PAH models in rat. Identification of target genes for miR-140-5p with bioinformatics analysis may reveal new pathways and connections in PAH. This study aimed to explore downstream target genes and relevant signaling pathways regulated by miR-140-5p to provide theoretical evidences for further researches on role of miR-140-5p in PAH. Multiple downstream target genes and upstream transcription factors (TFs) of miR-140-5p were predicted in the analysis. Gene ontology (GO) enrichment analysis indicated that downstream target genes of miR-140-5p were enriched in many biological processes, such as biological regulation, signal transduction, response to chemical stimulus, stem cell proliferation, cell surface receptor signaling pathways. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis found that downstream target genes were mainly located in Notch, TGF-beta, PI3K/Akt, and Hippo signaling pathway. According to TF-miRNA-mRNA network, the important downstream target genes of miR-140-5p were PPI, TGF-betaR1, smad4, JAG1, ADAM10, FGF9, PDGFRA, VEGFA, LAMC1, TLR4, and CREB. After thoroughly reviewing published literature, we found that 23 target genes and seven signaling pathways were truly inhibited by miR-140-5p in various tissues or cells; most of these verified targets were in accordance with our present prediction. Other predicted targets still need further verification in vivo and in vitro .

A floating trap for sampling downstream migrant fishes.

Treesearch

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

1989-01-01

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

Prolyl isomerase Pin1 acts downstream of miR-200 to promote cancer stem-like cell traits in breast cancer

PubMed Central

Luo, Man-Li; Gong, Chang; Chen, Chun-Hau; Lee, Daniel Y.; Hu, Hai; Huang, Pengyu; Yao, Yandan; Guo, Wenjun; Reinhardt, Ferenc; Wulf, Gerburg; Lieberman, Judy; Zhou, Xiao Zhen; Song, Erwei; Lu, Kun Ping

2014-01-01

Breast cancer stem-like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness and tumorigenicity, defining it as a key target of miR-200c which is known to be a critical regluator in BSCS. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial-mesenchymal transition (EMT). Conversely, genetic or pharmaacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR-200c-resistant Pin1 rescued the BCSC defect in miR-200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells isolated from clinical samples inhibited the expansion, self-renewal activity and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR-200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC. PMID:24786790

Unit 6, downstream from Ferndale Bridge Johnstown Local Flood ...

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

Unit 6, downstream from Ferndale Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 2, downstream from Coppersdale Bridge Johnstown Local Flood ...

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

Unit 2, downstream from Coppersdale Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 3, downstream from Point Park Johnstown Local Flood ...

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

Unit 3, downstream from Point Park - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 1, downstream from Laurel Run Johnstown Local Flood ...

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

Unit 1, downstream from Laurel Run - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 5, downstream from Hickory Street Bridge Johnstown Local ...

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

Unit 5, downstream from Hickory Street Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 6, downstream from Horner Street Bridge Johnstown Local ...

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

Unit 6, downstream from Horner Street Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 3, downstream from Fourth Avenue Bridge Johnstown Local ...

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

Unit 3, downstream from Fourth Avenue Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 5, downstream from Haynes Street Bridge Johnstown Local ...

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

Unit 5, downstream from Haynes Street Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 4, downstream from Johns Street Bridge Johnstown Local ...

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

Unit 4, downstream from Johns Street Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

Unit 4, downstream from First Street Bridge Johnstown Local ...

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

Unit 4, downstream from First Street Bridge - Johnstown Local Flood Protection Project, Beginning on Conemaugh River approx 3.8 miles downstream from confluence of Little Conemaugh & Stony Creek Rivers at Johnstown, Johnstown, Cambria County, PA

The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis.

PubMed

Mao, Yimin; Kuo, Su-Wei; Chen, Le; Heckman, C J; Jiang, M C

2017-01-01

Amyotrophic Lateral Sclerosis (ALS) is a devastative neurodegenerative disease characterized by selective loss of motoneurons. While several breakthroughs have been made in identifying ALS genetic defects, the detailed molecular mechanisms are still unclear. These genetic defects involve in numerous biological processes, which converge to a common destiny: motoneuron degeneration. In addition, the common comorbid Frontotemporal Dementia (FTD) further complicates the investigation of ALS etiology. In this study, we aimed to explore the protein-protein interaction network built on known ALS-causative genes to identify essential proteins and common downstream proteins between classical ALS and ALS+FTD (classical ALS + ALS/FTD) groups. The results suggest that classical ALS and ALS+FTD share similar essential protein set (VCP, FUS, TDP-43 and hnRNPA1) but have distinctive functional enrichment profiles. Thus, disruptions to these essential proteins might cause motoneuron susceptible to cellular stresses and eventually vulnerable to proteinopathies. Moreover, we identified a common downstream protein, ubiquitin-C, extensively interconnected with ALS-causative proteins (22 out of 24) which was not linked to ALS previously. Our in silico approach provides the computational background for identifying ALS therapeutic targets, and points out the potential downstream common ground of ALS-causative mutations.

Targeting the RAS oncogene

PubMed Central

Takashima, Asami

2013-01-01

Introduction The Ras proteins (K-Ras, N-Ras, H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells. Areas covered The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: 1) Ras itself, 2) Ras downstream pathways, and 3) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI3K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application. Expert opinion The challenges of current and emerging therapeutics include the lack of “tumor specificity” and their limitation to those cancers which are “dependent” upon aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies. PMID:23360111

The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer

PubMed Central

Smith, Anna L.; Iwanaga, Ritsuko; Drasin, David J.; Micalizzi, Douglas S.; Vartuli, Rebecca L; Tan, Aik-Choon; Ford, Heide L.

2012-01-01

The role of TGF-β signaling in tumorigenesis is paradoxical: it can be tumor suppressive or tumor promotional, depending on context. The metastatic regulator, Six1, was recently shown to mediate this switch, providing a novel means to explain this elusive “TGF-β paradox”. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-β signaling, via its ability to upregulate the miR-106b-25 microRNA cluster, and further identify a novel function for this cluster of microRNAs. While expression of the miR-106b-25 cluster is known to overcome TGF-β-mediated growth suppression via targeting p21 and BIM, we demonstrate for the first time that this same cluster can additionally target the inhibitory Smad7 protein, resulting in increased levels of the TGF-β type I receptor (TβRI) and downstream activation of TGF-β signaling. We further show that the miR-106b-25 cluster is sufficient to induce an epithelial to mesenchymal transition and a tumor initiating cell phenotype, and that it is required downstream of Six1 to induce these phenotypes. Finally, we demonstrate a significant correlation between miR-106b, Six1, and activated TGF-β signaling in human breast cancers, and further show that high levels of miR-106b and miR-93 in breast tumors significantly predicts shortened time to relapse. These findings expand the spectrum of oncogenic functions of miR-106b-25, and may provide a novel molecular explanation, through the Six1 regulated miR-106b-25 cluster, by which TGF-β signaling shifts from tumor suppressive to tumor promoting. PMID:22286770

MDM4 is a key therapeutic target in cutaneous melanoma

PubMed Central

Gembarska, Agnieszka; Luciani, Flavie; Fedele, Clare; Russell, Elisabeth A; Dewaele, Michael; Villar, Stéphanie; Zwolinska, Aleksandra; Haupt, Sue; de Lange, Job; Yip, Dana; Goydos, James; Haigh, Jody J; Haupt, Ygal; Larue, Lionel; Jochemsen, Aart; Shi, Hubing; Moriceau, Gatien; Lo, Roger S; Ghanem, Ghanem; Shackleton, Mark; Bernal, Federico; Marine, Jean-Christophe

2013-01-01

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma—a highly chemotherapy-resistant disease—TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I–IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy. PMID:22820643

Purinergic System Dysfunction in Mood Disorders: A Key Target for Developing Improved Therapeutics

PubMed Central

Ortiz, Robin; Ulrich, Henning; Zarate, Carlos A; Machado-Vieira, Rodrigo

2014-01-01

Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system particularly the modulation of P1 and P2 receptor subtypes—plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects. PMID:25445063

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.

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.

A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib

PubMed Central

Yang, Lida; Kaur, Harmandeep; Pestel, Jenny; Looso, Mario; Nolte, Hendrik; Krishnan, Ramesh K.; Bünemann, Moritz; Offermanns, Stefan; Swiercz, Jakub M.

2017-01-01

Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration. PMID:28007914

A Study of the Ion Hose Instability in the DARHT-II Downstream Transport Region

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCarrick, J F

18.4 MeV over a distance of about fifty meters. Then the true downstream transport begins: the beam drifts through a matching section in preparation for the kicker, over some ten meters; the long-pulse beam then travels about four more meters from the kicker to the main dump. In the accelerator, the beam energy is obviously not constant; the transport is emittance-dominated and done through nearly continuous solenoidal focusing. In the downstream section, there are only two discrete solenoids over the entire fourteen meters and the transport is largely ballistic. Since ion hose has been studied in the accelerator [3] and since the lack of continuous focusing is considered a concern with respect to ion hose in the downstream section, the focus of this study is only from the exit of the accelerator to the main dump. A more in-depth description of the baseline (ion-free) DARHT-II downstream transport, including description of the actual transport elements and their use, will not be presented in this document; such details can be found in the documents cited in the References. The study of these effects will be done in stages. In the next section, the nature of the residual gas in the vacuum system will be considered, along with the various assumptions made in characterizing the creation of ions. Then the ion hose instability will be described in its simplest form. In the fourth section, additional features of ion hose will then be presented which attempt to capture some of the key behavior. Then a much more complete model using particle-in-cell (PIC) numerical techniques will be described, followed by details of the specific implementation used here. In section seven, the code will be benchmarked against results published in the literature. Section eight has the most relevant material: the actual study of the effects of ion hose and background gas focusing in the DARHT-II downstream transport region. In section nine, a simple experiment which can be tacked on to

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.

Featured collection introduction: Connectivity of streams and wetlands to downstream waters

USGS Publications Warehouse

Alexander, Laurie C.; Fritz, Ken M.; Schofield, Kate; Autrey, Bradley; DeMeester, Julie; Golden, Heather E.; Goodrich, David C.; Kepner, William G.; Kiperwas, Hadas R.; Lane, Charles R.; LeDuc, Stephen D.; Leibowitz, Scott; McManus, Michael G.; Pollard, Amina I.; Ridley, Caroline E.; Vanderhoof, Melanie; Wigington, Parker J.

2018-01-01

Connectivity is a fundamental but highly dynamic property of watersheds. Variability in the types and degrees of aquatic ecosystem connectivity presents challenges for researchers and managers seeking to accurately quantify its effects on critical hydrologic, biogeochemical, and biological processes. However, protecting natural gradients of connectivity is key to protecting the range of ecosystem services that aquatic ecosystems provide. In this featured collection, we review the available evidence on connections and functions by which streams and wetlands affect the integrity of downstream waters such as large rivers, lakes, reservoirs, and estuaries. The reviews in this collection focus on the types of waters whose protections under the U.S. Clean Water Act have been called into question by U.S. Supreme Court cases. We synthesize 40+ years of research on longitudinal, lateral, and vertical fluxes of energy, material, and biota between aquatic ecosystems included within the Act's frame of reference. Many questions about the roles of streams and wetlands in sustaining downstream water integrity can be answered from currently available literature, and emerging research is rapidly closing data gaps with exciting new insights into aquatic connectivity and function at local, watershed, and regional scales. Synthesis of foundational and emerging research is needed to support science‐based efforts to provide safe, reliable sources of fresh water for present and future generations.

Computational Systems Biology Approach Predicts Regulators and Targets of microRNAs and Their Genomic Hotspots in Apoptosis Process.

PubMed

Alanazi, Ibrahim O; Ebrahimie, Esmaeil

2016-07-01

Novel computational systems biology tools such as common targets analysis, common regulators analysis, pathway discovery, and transcriptomic-based hotspot discovery provide new opportunities in understanding of apoptosis molecular mechanisms. In this study, after measuring the global contribution of microRNAs in the course of apoptosis by Affymetrix platform, systems biology tools were utilized to obtain a comprehensive view on the role of microRNAs in apoptosis process. Network analysis and pathway discovery highlighted the crosstalk between transcription factors and microRNAs in apoptosis. Within the transcription factors, PRDM1 showed the highest upregulation during the course of apoptosis, with more than 9-fold expression increase compared to non-apoptotic condition. Within the microRNAs, MIR1208 showed the highest expression in non-apoptotic condition and downregulated by more than 6 fold during apoptosis. Common regulators algorithm showed that TNF receptor is the key upstream regulator with a high number of regulatory interactions with the differentially expressed microRNAs. BCL2 and AKT1 were the key downstream targets of differentially expressed microRNAs. Enrichment analysis of the genomic locations of differentially expressed microRNAs led us to the discovery of chromosome bands which were highly enriched (p < 0.01) with the apoptosis-related microRNAs, such as 13q31.3, 19p13.13, and Xq27.3 This study opens a new avenue in understanding regulatory mechanisms and downstream functions in the course of apoptosis as well as distinguishing genomic-enriched hotspots for apoptosis process.

A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18*

PubMed Central

Yang, Zhaoshou; Hou, Yongheng; Hao, Taofang; Rho, Hee-Sool; Wan, Jun; Luan, Yizhao; Gao, Xin; Yao, Jianping; Pan, Aihua; Xie, Zhi; Qian, Jiang; Liao, Wanqin; Zhu, Heng; Zhou, Xingwang

2017-01-01

Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates, we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions, including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1, were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser-187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and provide new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface. PMID:28087594

Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types.

PubMed

Gonzalez-Perez, Abel

2016-01-20

Large tumor genome sequencing projects have now uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies. One of the main challenges emerging from this catalog of drivers is how to make sense of their heterogeneity in most cancer types. This is key not only to understand how carcinogenesis appears and develops in these malignancies to be able to early diagnose them, but also to open up the possibility to employ therapeutic strategies targeting a driver protein to counteract the alteration of another connected driver. Here, I focus on driver transcription factors and their connection to tumorigensis in several tumor types through the alteration of the expression of their targets. First, I explore their involvement in tumorigenesis as mutational drivers in 28 different tumor types. Then, I collect a list of downstream targets of the all driver transcription factors (TFs), and identify which of them exhibit a differential expression upon alterations of driver transcription factors. I identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap. Furthermore, I am able to identify other driver genes that cause tumorigenesis through the alteration of very similar sets of targets. I thus uncover these circuits of connected drivers which cause tumorigenesis through the perturbation of overlapping cellular pathways in a pan-cancer manner across 15 malignancies. The systematic detection of these circuits may be key to propose novel therapeutic strategies indirectly targeting driver alterations in tumors.

The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules.

PubMed

Simon, Katharina; Hennen, Stephanie; Merten, Nicole; Blättermann, Stefanie; Gillard, Michel; Kostenis, Evi; Gomeza, Jesus

2016-01-08

Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the Gαi/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Connectivity of Streams and Wetlands to Downstream Waters ...

EPA Pesticide Factsheets

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

Integrative analysis of RUNX1 downstream pathways and target genes

PubMed Central

Michaud, Joëlle; Simpson, Ken M; Escher, Robert; Buchet-Poyau, Karine; Beissbarth, Tim; Carmichael, Catherine; Ritchie, Matthew E; Schütz, Frédéric; Cannon, Ping; Liu, Marjorie; Shen, Xiaofeng; Ito, Yoshiaki; Raskind, Wendy H; Horwitz, Marshall S; Osato, Motomi; Turner, David R; Speed, Terence P; Kavallaris, Maria; Smyth, Gordon K; Scott, Hamish S

2008-01-01

Background The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFβ, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both

Downstream promoter interactions of TFIID TAFs facilitate transcription reinitiation

PubMed Central

Joo, Yoo Jin; Ficarro, Scott B.; Soares, Luis M.; Chun, Yujin; Marto, Jarrod A.; Buratowski, Stephen

2017-01-01

TFIID binds promoter DNA to recruit RNA polymerase II and other basal factors for transcription. Although the TATA-binding protein (TBP) subunit of TFIID is necessary and sufficient for in vitro transcription, the TBP-associated factor (TAF) subunits recognize downstream promoter elements, act as coactivators, and interact with nucleosomes. In yeast nuclear extracts, transcription induces stable TAF binding to downstream promoter DNA, promoting subsequent activator-independent transcription reinitiation. In vivo, promoter responses to TAF mutations correlate with the level of downstream, rather than overall, Taf1 cross-linking. We propose a new model in which TAFs function as reinitiation factors, accounting for the differential responses of promoters to various transcription factor mutations. PMID:29203645

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

BIN1/M-Amphiphysin2 induces clustering of phosphoinositides to recruit its downstream partner dynamin

NASA Astrophysics Data System (ADS)

Picas, Laura; Viaud, Julien; Schauer, Kristine; Vanni, Stefano; Hnia, Karim; Fraisier, Vincent; Roux, Aurélien; Bassereau, Patricia; Gaits-Iacovoni, Frédérique; Payrastre, Bernard; Laporte, Jocelyn; Manneville, Jean-Baptiste; Goud, Bruno

2014-12-01

Phosphoinositides play a central role in many physiological processes by assisting the recruitment of proteins to membranes through specific phosphoinositide-binding motifs. How this recruitment is coordinated in space and time is not well understood. Here we show that BIN1/M-Amphiphysin2, a protein involved in T-tubule biogenesis in muscle cells and frequently mutated in centronuclear myopathies, clusters PtdIns(4,5)P2 to recruit its downstream partner dynamin. By using several mutants associated with centronuclear myopathies, we find that the N-BAR and the SH3 domains of BIN1 control the kinetics and the accumulation of dynamin on membranes, respectively. We show that phosphoinositide clustering is a mechanism shared by other proteins that interact with PtdIns(4,5)P2, but do not contain a BAR domain. Our numerical simulations point out that clustering is a diffusion-driven process in which phosphoinositide molecules are not sequestered. We propose that this mechanism plays a key role in the recruitment of downstream phosphoinositide-binding proteins.

The role of headwater streams in downstream water quality

USGS Publications Warehouse

Alexander, R.B.; Boyer, E.W.; Smith, R.A.; Schwarz, G.E.; Moore, R.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

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

DENSITY FLUCTUATIONS UPSTREAM AND DOWNSTREAM OF INTERPLANETARY SHOCKS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pitňa, A.; Šafránková, J.; Němeček, Z.

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 inmore » 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.« less

Sediment-phosphorus dynamics can shift aquatic ecology and cause downstream legacy effects after wildfire in large river systems.

PubMed

Emelko, Monica B; Stone, Micheal; Silins, Uldis; Allin, Don; Collins, Adrian L; Williams, Chris H S; Martens, Amanda M; Bladon, Kevin D

2016-03-01

Global increases in the occurrence of large, severe wildfires in forested watersheds threaten drinking water supplies and aquatic ecology. Wildfire effects on water quality, particularly nutrient levels and forms, can be significant. The longevity and downstream propagation of these effects as well as the geochemical mechanisms regulating them remain largely undocumented at larger river basin scales. Here, phosphorus (P) speciation and sorption behavior of suspended sediment were examined in two river basins impacted by a severe wildfire in southern Alberta, Canada. Fine-grained suspended sediments (<125 μm) were sampled continuously during ice-free conditions over a two-year period (2009-2010), 6 and 7 years after the wildfire. Suspended sediment samples were collected from upstream reference (unburned) river reaches, multiple tributaries within the burned areas, and from reaches downstream of the burned areas, in the Crowsnest and Castle River basins. Total particulate phosphorus (TPP) and particulate phosphorus forms (nonapatite inorganic P, apatite P, organic P), and the equilibrium phosphorus concentration (EPC0 ) of suspended sediment were assessed. Concentrations of TPP and the EPC0 were significantly higher downstream of wildfire-impacted areas compared to reference (unburned) upstream river reaches. Sediments from the burned tributary inputs contained higher levels of bioavailable particulate P (NAIP) - these effects were also observed downstream at larger river basin scales. The release of bioavailable P from postfire, P-enriched fine sediment is a key mechanism causing these effects in gravel-bed rivers at larger basin scales. Wildfire-associated increases in NAIP and the EPC0 persisted 6 and 7 years after wildfire. Accordingly, this work demonstrated that fine sediment in gravel-bed rivers is a significant, long-term source of in-stream bioavailable P that contributes to a legacy of wildfire impacts on downstream water quality, aquatic ecology, and

Msx genes are important apoptosis effectors downstream of the Shh/Gli3 pathway in the limb.

PubMed

Lallemand, Yvan; Bensoussan, Vardina; Cloment, Cécile Saint; Robert, Benoît

2009-07-15

In tetrapods, the anteroposterior (AP) patterning of the limb is under the control of the antagonistic activities of the secreted factor Sonic hedgehog (Shh) and Gli3R, the truncated repressor form of the transcription factor Gli3. In this report, we show that Msx1 and Msx2 are targets and downstream effectors of Gli3R. Consequently, in Shh null mutants, Msx genes are overexpressed and, furthermore, partially responsible for the limb phenotype. This is exemplified by the fact that reducing Msx activity in Shh mutants partially restores a normal limb development. Finally, we show that the main action of the Msx genes, in both normal and Shh(-/-) limb development, is to control cell death in the mesenchyme. We propose that, in the limb, Msx genes act downstream of the Shh/Gli3 pathway by transducing BMP signaling and that, in the absence of Shh signaling, their deregulation contributes to the extensive apoptosis that impairs limb development.

A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib.

PubMed

Sun, Tianliang; Yang, Lida; Kaur, Harmandeep; Pestel, Jenny; Looso, Mario; Nolte, Hendrik; Krasel, Cornelius; Heil, Daniel; Krishnan, Ramesh K; Santoni, Marie-Josée; Borg, Jean-Paul; Bünemann, Moritz; Offermanns, Stefan; Swiercz, Jakub M; Worzfeld, Thomas

2017-01-02

Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration. © 2017 Sun et al.

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

PubMed Central

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

2017-01-01

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

The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription.

PubMed

Chan, Baca; Gonçalves Magalhães, Vladimir; Lemmermann, Niels A W; Juranić Lisnić, Vanda; Stempel, Markus; Bussey, Kendra A; Reimer, Elisa; Podlech, Jürgen; Lienenklaus, Stefan; Reddehase, Matthias J; Jonjić, Stipan; Brinkmann, Melanie M

2017-05-01

The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host.

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.

Solanum tuberosum StCDPK1 is regulated by miR390 at the posttranscriptional level and phosphorylates the auxin efflux carrier StPIN4 in vitro, a potential downstream target in potato development.

PubMed

Santin, Franco; Bhogale, Sneha; Fantino, Elisa; Grandellis, Carolina; Banerjee, Anjan K; Ulloa, Rita M

2017-02-01

Among many factors that regulate potato tuberization, calcium and calcium-dependent protein kinases (CDPKs) play an important role. CDPK activity increases at the onset of tuber formation with StCDPK1 expression being strongly induced in swollen stolons. However, not much is known about the transcriptional and posttranscriptional regulation of StCDPK1 or its downstream targets in potato development. To elucidate further, we analyzed its expression in different tissues and stages of the life cycle. Histochemical analysis of StCDPK1::GUS (β-glucuronidase) plants demonstrated that StCDPK1 is strongly associated with the vascular system in stems, roots, during stolon to tuber transition, and in tuber sprouts. In agreement with the observed GUS profile, we found specific cis-acting elements in StCDPK1 promoter. In silico analysis predicted miR390 to be a putative posttranscriptional regulator of StCDPK1. Quantitative real time-polymerase chain reaction (qRT-PCR) analysis showed ubiquitous expression of StCDPK1 in different tissues which correlated well with Western blot data except in leaves. On the contrary, miR390 expression exhibited an inverse pattern in leaves and tuber eyes suggesting a possible regulation of StCDPK1 by miR390. This was further confirmed by Agrobacterium co-infiltration assays. In addition, in vitro assays showed that recombinant StCDPK1-6xHis was able to phosphorylate the hydrophilic loop of the auxin efflux carrier StPIN4. Altogether, these results indicate that StCDPK1 expression is varied in a tissue-specific manner having significant expression in vasculature and in tuber eyes; is regulated by miR390 at posttranscriptional level and suggest that StPIN4 could be one of its downstream targets revealing the overall role of this kinase in potato development. © 2016 Scandinavian Plant Physiology Society.

Kinetics of Hydrogen Oxidation Downstream of Lean Propane and Hydrogen Flames

NASA Technical Reports Server (NTRS)

Fine, Burton

1961-01-01

The decay of hydrogen was measured downstream of lean, flat, premixed hydrogen and propane-air flames seated on cooled porous burners. Experimental variables included temperature, pressure, initial equivalence ratio and diluent. Sampling of burned gas was done through uncooled quartz orifice probes, and the analysis was based on gas chromatography. An approximate treatment of the data in which diffusion was neglected led to the following rate expression for the zone downstream of hydrogen flames d[H (sub 2)] divided by (d times t) equals 1.7 times 10 (sup 10) [H (sub 2)] (sup 3) divided by (sub 2) [O (sub 2)]e (sup (-8100 divided by RT)) moles per liters per second. On the basis of a rate expression of this form, the specific rate constant for the reaction downstream of hydrogen flames was about three times as great as that determined downstream of propane flames. This result was explained on the basis of the existence of a steady state between hydrogen and carbon monoxide in the burned gas downstream of propane flames.

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

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

PubMed Central

Svalina, Matthew N.; Kikuchi, Ken; Abraham, Jinu; Lal, Sangeet; Davare, Monika A.; Settelmeyer, Teagan P.; Young, Michael C.; Peckham, Jennifer L.; Cho, Yoon-Jae; Michalek, Joel E.; Hernandez, Brian S.; Berlow, Noah E.; Jackson, Melanie; Guillaume, Daniel J.; Selden, Nathan R.; Bigner, Darell D.; Nazemi, Kellie J.; Green, Sarah C.; Corless, Christopher L.; Gultekin, Sakir; Mansoor, Atiya; Rubin, Brian P.; Woltjer, Randall; Keller, Charles

2016-01-01

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma. PMID:27255663

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma.

PubMed

Svalina, Matthew N; Kikuchi, Ken; Abraham, Jinu; Lal, Sangeet; Davare, Monika A; Settelmeyer, Teagan P; Young, Michael C; Peckham, Jennifer L; Cho, Yoon-Jae; Michalek, Joel E; Hernandez, Brian S; Berlow, Noah E; Jackson, Melanie; Guillaume, Daniel J; Selden, Nathan R; Bigner, Darell D; Nazemi, Kellie J; Green, Sarah C; Corless, Christopher L; Gultekin, Sakir; Mansoor, Atiya; Rubin, Brian P; Woltjer, Randall; Keller, Charles

2016-06-03

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.

The insulin receptor substrate (IRS)-1 pleckstrin homology domain functions in downstream signaling.

PubMed

Vainshtein, I; Kovacina, K S; Roth, R A

2001-03-16

The pleckstrin homology (PH) domain of the insulin receptor substrate-1 (IRS-1) plays a role in directing this molecule to the insulin receptor, thereby regulating its tyrosine phosphorylation. In this work, the role of the PH domain in subsequent signaling was studied by constructing constitutively active forms of IRS-1 in which the inter-SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase was fused to portions of the IRS-1 molecule. Chimeric molecules containing the PH domain were found to activate the downstream response of stimulating the Ser/Thr kinase Akt. A chimera containing point mutations in the PH domain that abolished the ability of this domain to bind phosphatidylinositol 4,5-bisphosphate prevented these molecules from activating Akt. These mutations also decreased by about 70% the amount of the constructs present in a particulate fraction of the cells. These results indicate that the PH domain of IRS-1, in addition to directing this protein to the receptor for tyrosine phosphorylation, functions in the ability of this molecule to stimulate subsequent responses. Thus, compromising the function of the PH domain, e.g. in insulin-resistant states, could decrease both the ability of IRS-1 to be tyrosine phosphorylated by the insulin receptor and to link to subsequent downstream targets.

Evidence-Based Identification of Key Beliefs Explaining Infant Male Circumcision Motivation Among Expectant Parents in Zimbabwe: Targets for Behavior Change Messaging.

PubMed

Montaño, Daniel E; Tshimanga, Mufuta; Hamilton, Deven T; Gorn, Gerald; Kasprzyk, Danuta

2018-02-01

Slow adult male circumcision uptake is one factor leading some to recommend increased priority for infant male circumcision (IMC) in sub-Saharan African countries. This research, guided by the integrated behavioral model (IBM), was carried out to identify key beliefs that best explain Zimbabwean parents' motivation to have their infant sons circumcised. A quantitative survey, designed from qualitative elicitation study results, was administered to independent representative samples of 800 expectant mothers and 795 expectant fathers in two urban and two rural areas in Zimbabwe. Multiple regression analyses found IMC motivation among fathers was explained by instrumental attitude, descriptive norm and self-efficacy; while motivation among mothers was explained by instrumental attitude, injunctive norm, descriptive norm, self-efficacy, and perceived control. Regression analyses of beliefs underlying IBM constructs found some overlap but many differences in key beliefs explaining IMC motivation among mothers and fathers. We found differences in key beliefs among urban and rural parents. Urban fathers' IMC motivation was explained best by behavioral beliefs, while rural fathers' motivation was explained by both behavioral and efficacy beliefs. Urban mothers' IMC motivation was explained primarily by behavioral and normative beliefs, while rural mothers' motivation was explained mostly by behavioral beliefs. The key beliefs we identified should serve as targets for developing messages to improve demand and maximize parent uptake as IMC programs are rolled out. These targets need to be different among urban and rural expectant mothers and fathers.

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.

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

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

PubMed

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

2012-05-08

Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single-neuron mRNA profiling of PVD. Selectively photoactivating PVD, FLP, and downstream interneurons via Channelrhodopsin-2 (ChR2) enabled the functional dissection of this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca(2+) channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD's dynamic range and that GTL-1 may amplify its signals. These channels act cell autonomously in PVD, downstream of primary mechanosensory molecules. Our work implicates TRPM channels in modifying excitability of and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologs, if functionally conserved, may denote valid targets for novel analgesics. Copyright © 2012 Elsevier Ltd. All rights reserved.

Downstream anastomotic hyperplasia. A mechanism of failure in Dacron arterial grafts.

PubMed Central

LoGerfo, F W; Quist, W C; Nowak, M D; Crawshaw, H M; Haudenschild, C C

1983-01-01

The precise location and progression of anastomotic hyperplasia and its possible relationship to flow disturbances was investigated in femoro-femoral Dacron grafts in 28 dogs. In 13 grafts, the outflow from the end-to-side downstream anastomosis was bidirectional (BDO), and in 15 it was unidirectional (UDO) (distally). Grafts were electively removed at intervals of two to 196 days or at the time of thrombosis. Each anastomosis and adjacent artery was perfusion-fixed and sectioned sagittally. The mean sagittal section was projected onto a digitized pad, and the total area of hyperplasia internal to the arterial internal elastic lamina and within the adjacent graft was integrated by computer. The location of the hyperplasia was compared with previously established sites of flow separation and stagnation. The observation was made that hyperplasia is significantly greater at the downstream, as compared with the upstream, anastomosis in both groups (BDO = p less than 0.001 and UDO = p less than 0.001) (analysis of variance for independent groups). Furthermore, this downstream hyperplasia was progressive with time (BDO p less than 0.01) (UDO p less than 0.01); Spearman Rank Correlation. There was no significant increase in the extent of downstream hyperplasia where flow separation was known to be greater (BDO). Five grafts failed (three BDO, two UDO), as a result of complete occlusion of the downstream anastomosis by fibrous hyperplasia. Transmission electron microscopy showed the hyperplasia to consist of collagen-producing smooth muscle cells. Anastomotic hyperplasia is significantly greater at the downstream anastomosis, is progressive with time, and is the primary cause of failure of Dacron arterial grafts in this model. Quantitative analysis of downstream anastomotic hyperplasia may be a valuable measure of the biocompatibility of Dacron grafts. Images Fig. 2. Fig. 3. Fig. 5. Fig. 6. Fig. 7. Fig. 8. PMID:6219641

p38β, A novel regulatory target of Pokemon in hepatic cells.

PubMed

Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-06-27

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.

p38β, A Novel Regulatory Target of Pokemon in Hepatic Cells

PubMed Central

Chen, Zhe; Liu, Feng; Zhang, Nannan; Cao, Deliang; Liu, Min; Tan, Ying; Jiang, Yuyang

2013-01-01

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. PMID:23807508

A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC).

PubMed

Sandoval, Imelda T; Delacruz, Richard Glenn C; Miller, Braden N; Hill, Shauna; Olson, Kristofor A; Gabriel, Ana E; Boyd, Kevin; Satterfield, Christeena; Remmen, Holly Van; Rutter, Jared; Jones, David A

2017-04-11

Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1) , a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc .

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

Core Promoter Functions in the Regulation of Gene Expression of Drosophila Dorsal Target Genes*

PubMed Central

Zehavi, Yonathan; Kuznetsov, Olga; Ovadia-Shochat, Avital; Juven-Gershon, Tamar

2014-01-01

Developmental processes are highly dependent on transcriptional regulation by RNA polymerase II. The RNA polymerase II core promoter is the ultimate target of a multitude of transcription factors that control transcription initiation. Core promoters consist of core promoter motifs, e.g. the initiator, TATA box, and the downstream core promoter element (DPE), which confer specific properties to the core promoter. Here, we explored the importance of core promoter functions in the dorsal-ventral developmental gene regulatory network. This network includes multiple genes that are activated by different nuclear concentrations of Dorsal, an NFκB homolog transcription factor, along the dorsal-ventral axis. We show that over two-thirds of Dorsal target genes contain DPE sequence motifs, which is significantly higher than the proportion of DPE-containing promoters in Drosophila genes. We demonstrate that multiple Dorsal target genes are evolutionarily conserved and functionally dependent on the DPE. Furthermore, we have analyzed the activation of key Dorsal target genes by Dorsal, as well as by another Rel family transcription factor, Relish, and the dependence of their activation on the DPE motif. Using hybrid enhancer-promoter constructs in Drosophila cells and embryo extracts, we have demonstrated that the core promoter composition is an important determinant of transcriptional activity of Dorsal target genes. Taken together, our results provide evidence for the importance of core promoter composition in the regulation of Dorsal target genes. PMID:24634215

NF-κB Signaling Pathway and its Potential as a Target for Therapy in Lymphoid Neoplasms

PubMed Central

Yu, Li; Li, Ling; Medeiros, L. Jeffrey; Young, Ken H.

2016-01-01

The NF-κB pathway, a critical regulator of apoptosis, plays a key role in many normal cellular functions. Genetic alterations and other mechanisms leading to constitutive activation of the NF-κB pathway contribute to cancer development, progression and therapy resistance by activation of downstream anti-apoptotic pathways, unfavorable microenvironment interactions, and gene dysregulation. Not surprisingly, given its importance to normal and cancer cell function, the NF-κB pathway has emerged as a target for therapy. In the review, we present the physiologic role of the NF-κB pathway and recent advances in better understanding of the pathologic roles of the NF-κB pathway in major types of lymphoid neoplasms. We also provide an update of clinical trials that use NF-κB pathway inhibitors. These trials are exploring the clinical efficiency of combining NF-κB pathway inhibitors with various agents that target diverse mechanisms of action with the goal being to optimize novel therapeutic opportunities for targeting oncogenic pathways to eradicate cancer cells. PMID:27773462

Wave and ion evolution downstream of quasi-perpendicular bow shocks

NASA Technical Reports Server (NTRS)

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

1995-01-01

Distribution functions of ions heated in quasi-perpendicular bow shocks have a large perpendicular temperature anisotropy that provides free energy for the growth of Alfven ion cyclotron (AIC) waves and mirror waves. Both types of waves have been observed in the Earth's magnetosheath downstream of quasi-perpendicular shocks. We use a two-dimensional hybrid simulations to give a self-consistent description of the evolution of the wave spectra downstream of quasi-perpendicular shocks. Both mirror and AIC waves are identified in the simulated magnetosheath. They are generated at or near the shock front and convected away from it by the sheath plasma. Near the shock, the waves have a broad spectrum, but downstream of the shock, shorter-wavelength modes are heavily damped and only longer-wavelength modes persist. The characteristics of these surviving modes can be predicted with reasonable accuracy by linear kinetic theory appropriate for downstream conditions. We also follow the evolution of the ion distribution function. The shocked ions that provide the free energy for wave growth have a two-component distribution function. The halo is initially gyrophase-bunched and extremely anisotropic. Within a relatively short distance downstream of the shock (of the order of 10 ion inertial lengths), wave-particle interactions remove these features from the halo and reduce the anisotropy of the distribution to near-threshold levels for the mirror and AIC instabilities. A similar evolution has been observed for ions at the Earth's bow shock.

Properties of targeted preamplification in DNA and cDNA quantification.

PubMed

Andersson, Daniel; Akrap, Nina; Svec, David; Godfrey, Tony E; Kubista, Mikael; Landberg, Göran; Ståhlberg, Anders

2015-01-01

Quantification of small molecule numbers often requires preamplification to generate enough copies for accurate downstream enumerations. Here, we studied experimental parameters in targeted preamplification and their effects on downstream quantitative real-time PCR (qPCR). To evaluate different strategies, we monitored the preamplification reaction in real-time using SYBR Green detection chemistry followed by melting curve analysis. Furthermore, individual targets were evaluated by qPCR. The preamplification reaction performed best when a large number of primer pairs was included in the primer pool. In addition, preamplification efficiency, reproducibility and specificity were found to depend on the number of template molecules present, primer concentration, annealing time and annealing temperature. The amount of nonspecific PCR products could also be reduced about 1000-fold using bovine serum albumin, glycerol and formamide in the preamplification. On the basis of our findings, we provide recommendations how to perform robust and highly accurate targeted preamplification in combination with qPCR or next-generation sequencing.

Photoperiod control of downstream movements of Atlantic salmon Salmo salar smolts

USGS Publications Warehouse

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

2014-01-01

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

Intracellular signaling by phospholipase D as a therapeutic target.

PubMed

Steed, P M; Chow, A H

2001-09-01

The pharmaceutical industry has recently focused on intracellular signaling as a means to integrate the multiple facets of complex disease states, such as inflammation, because these pathways respond to numerous extracellular signals and coordinate a collection of cell responses contributing to pathology. One critical aspect of intracellular signaling is regulation of key cell functions by lipid mediators, in particular the generation of a key mediator, phosphatidic acid (PA) via the hydrolysis of phosphatidylcholine by phospholipase D (PLD). Research in this field has intensified, due in part to the recent cloning and partial characterization of the two PLD isoforms in mammalian cells, and this work has contributed significantly to our understanding of events downstream of PA generation. It is these effector functions of PLD activity that make this pathway attractive as a therapeutic target while the biochemical properties of the PLD isozymes make them amenable to small molecule intervention. Recent studies indicate that PA, and its immediate metabolites diacylglycerol and lyso-PA, affect numerous cellular pathways including ligand-mediated secretion, cytoskeletal reorganisations, respiratory burst, prostaglandin release, cell migration, cytokine release, and mitogenesis. This review summarises the data implicating signaling via PLD in these cell functions, obtained from: (i) molecular analyses of PLD/effector interactions, (ii) correlation between PA production and cell responses, (iii) experimental manipulation of PA levels, (iv) inhibition of PLD regulators, and (v) direct inhibition of PA production. The utility of targeting PLD signaling for the treatment of acute/chronic inflammation and other indications is discussed in light of these data.

Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events

PubMed Central

Ashouri, Arghavan; Sayin, Volkan I.; Van den Eynden, Jimmy; Singh, Simranjit X.; Papagiannakopoulos, Thales; Larsson, Erik

2016-01-01

Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers. PMID:28959951

DOWNSTREAM-WATER-LEVEL CONTROL TEST RESULTS ON THE WM LATERAL CANAL

USDA-ARS?s Scientific Manuscript database

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...

42 CFR § 512.510 - Downstream distribution arrangements under the EPM.

Code of Federal Regulations, 2010 CFR

2017-10-01

... HEALTH AND HUMAN SERVICES (CONTINUED) HEALTH CARE INFRASTRUCTURE AND MODEL PROGRAMS EPISODE PAYMENT MODEL... distribution payment it receives from the EPM collaborator only in accordance with a downstream distribution... make or receive a downstream distribution payment must not be conditioned directly or indirectly on the...

Antidepressive effects of targeting ELK-1 signal transduction.

PubMed

Apazoglou, Kallia; Farley, Séverine; Gorgievski, Victor; Belzeaux, Raoul; Lopez, Juan Pablo; Grenier, Julien; Ibrahim, El Chérif; El Khoury, Marie-Anne; Tse, Yiu C; Mongredien, Raphaele; Barbé, Alexandre; de Macedo, Carlos E A; Jaworski, Wojciech; Bochereau, Ariane; Orrico, Alejandro; Isingrini, Elsa; Guinaudie, Chloé; Mikasova, Lenka; Louis, Franck; Gautron, Sophie; Groc, Laurent; Massaad, Charbel; Yildirim, Ferah; Vialou, Vincent; Dumas, Sylvie; Marti, Fabio; Mechawar, Naguib; Morice, Elise; Wong, Tak P; Caboche, Jocelyne; Turecki, Gustavo; Giros, Bruno; Tzavara, Eleni T

2018-05-07

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted 2-4 . The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation 5-7 , but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps

PubMed Central

Cichocki, Joseph A.; Guyton, Kathryn Z.; Guha, Neela; Chiu, Weihsueh A.

2016-01-01

Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high–production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure. PMID:27511820

Transition duct with divided upstream and downstream portions

DOE Office of Scientific and Technical Information (OSTI.GOV)

McMahan, Kevin Weston; LeBegue, Jeffrey Scott; Maldonado, Jaime Javier

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 themore » upstream portion and the downstream portion.« less

A Data-Driven Evaluation of the Stop TB Global Partnership Strategy of Targeting Key Populations at Greater Risk for Tuberculosis

PubMed Central

Schnippel, Kathryn; Sharp, Alana

2016-01-01

Objective Identifying those infected with tuberculosis (TB) is an important component of any strategy for reducing TB transmission and population prevalence. The Stop TB Global Partnership recently launched an initiative with a focus on key populations at greater risk for TB infection or poor clinical outcomes, due to housing and working conditions, incarceration, low household income, malnutrition, co-morbidities, exposure to tobacco and silica dust, or barriers to accessing medical care. To achieve operational targets, the global health community needs effective, low cost, and large-scale strategies for identifying key populations. Using South Africa as a test case, we assess the feasibility and effectiveness of targeting active case finding to populations with TB risk factors identified from regularly collected sources of data. Our approach is applicable to all countries with TB testing and census data. It allows countries to tailor their outreach activities to the particular risk factors of greatest significance in their national context. Methods We use a national database of TB test results to estimate municipality-level TB infection prevalence, and link it to Census data to measure population risk factors for TB including rates of urban households, informal settlements, household income, unemployment, and mobile phone ownership. To examine the relationship between TB prevalence and risk factors, we perform linear regression analysis and plot the set of population characteristics against TB prevalence and TB testing rate by municipality. We overlay lines of best fit and smoothed curves of best fit from locally weighted scatter plot smoothing. Findings Higher TB prevalence is statistically significantly associated with more urban municipalities (slope coefficient β1 = 0.129, p < 0.0001, R2 = 0.133), lower mobile phone access (β1 = -0.053, p < 0.001, R2 = 0.089), lower unemployment rates (β1 = -0.020, p = 0.003, R2 = 0.048), and a lower proportion of low

A Data-Driven Evaluation of the Stop TB Global Partnership Strategy of Targeting Key Populations at Greater Risk for Tuberculosis.

PubMed

McLaren, Zoë M; Schnippel, Kathryn; Sharp, Alana

2016-01-01

Identifying those infected with tuberculosis (TB) is an important component of any strategy for reducing TB transmission and population prevalence. The Stop TB Global Partnership recently launched an initiative with a focus on key populations at greater risk for TB infection or poor clinical outcomes, due to housing and working conditions, incarceration, low household income, malnutrition, co-morbidities, exposure to tobacco and silica dust, or barriers to accessing medical care. To achieve operational targets, the global health community needs effective, low cost, and large-scale strategies for identifying key populations. Using South Africa as a test case, we assess the feasibility and effectiveness of targeting active case finding to populations with TB risk factors identified from regularly collected sources of data. Our approach is applicable to all countries with TB testing and census data. It allows countries to tailor their outreach activities to the particular risk factors of greatest significance in their national context. We use a national database of TB test results to estimate municipality-level TB infection prevalence, and link it to Census data to measure population risk factors for TB including rates of urban households, informal settlements, household income, unemployment, and mobile phone ownership. To examine the relationship between TB prevalence and risk factors, we perform linear regression analysis and plot the set of population characteristics against TB prevalence and TB testing rate by municipality. We overlay lines of best fit and smoothed curves of best fit from locally weighted scatter plot smoothing. Higher TB prevalence is statistically significantly associated with more urban municipalities (slope coefficient β1 = 0.129, p < 0.0001, R2 = 0.133), lower mobile phone access (β1 = -0.053, p < 0.001, R2 = 0.089), lower unemployment rates (β1 = -0.020, p = 0.003, R2 = 0.048), and a lower proportion of low-income households (β1 = -0

Basal Ganglia Circuits as Targets for Neuromodulation in Parkinson Disease.

PubMed

DeLong, Mahlon R; Wichmann, Thomas

2015-11-01

The revival of stereotactic surgery for Parkinson disease (PD) in the 1990s, with pallidotomy and then with high-frequency deep brain stimulation (DBS), has led to a renaissance in functional surgery for movement and other neuropsychiatric disorders. To examine the scientific foundations and rationale for the use of ablation and DBS for treatment of neurologic and psychiatric diseases, using PD as the primary example. A summary of the large body of relevant literature is presented on anatomy, physiology, pathophysiology, and functional surgery for PD and other basal ganglia disorders. The signs and symptoms of movement disorders appear to result largely from signature abnormalities in one of several parallel and largely segregated basal ganglia thalamocortical circuits (ie, the motor circuit). The available evidence suggests that the varied movement disorders resulting from dysfunction of this circuit result from propagated disruption of downstream network activity in the thalamus, cortex, and brainstem. Ablation and DBS act to free downstream networks to function more normally. The basal ganglia thalamocortical circuit may play a key role in the expression of disordered movement, and the basal ganglia-brainstem projections may play roles in akinesia and disturbances of gait. Efforts are under way to target circuit dysfunction in brain areas outside of the traditionally implicated basal ganglia thalamocortical system, in particular, the pedunculopontine nucleus, to address gait disorders that respond poorly to levodopa and conventional DBS targets. Deep brain stimulation is now the treatment of choice for many patients with advanced PD and other movement disorders. The success of DBS and other forms of neuromodulation for neuropsychiatric disorders is the result of the ability to modulate circuit activity in discrete functional domains within the basal ganglia circuitry with highly focused interventions, which spare uninvolved areas that are often disrupted with

Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy*.

PubMed

Richardson, Kenneth E; Tannous, Paul; Berenji, Kambeez; Nolan, Bridgid; Bayless, Kayla J; Davis, George E; Rothermel, Beverly A; Hill, Joseph A

2005-12-01

There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rac1 and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.

The Vasa Homolog RDE-12 engages target mRNA and multiple argonaute proteins to promote RNAi in C. elegans.

PubMed

Shirayama, Masaki; Stanney, William; Gu, Weifeng; Seth, Meetu; Mello, Craig C

2014-04-14

Argonaute (AGO) proteins are key nuclease effectors of RNAi. Although purified AGOs can mediate a single round of target RNA cleavage in vitro, accessory factors are required for small interfering RNA (siRNA) loading and to achieve multiple-target turnover. To identify AGO cofactors, we immunoprecipitated the C. elegans AGO WAGO-1, which engages amplified small RNAs during RNAi. These studies identified a robust association between WAGO-1 and a conserved Vasa ATPase-related protein RDE-12. rde-12 mutants are deficient in RNAi, including viral suppression, and fail to produce amplified secondary siRNAs and certain endogenous siRNAs (endo-siRNAs). RDE-12 colocalizes with WAGO-1 in germline P granules and in cytoplasmic and perinuclear foci in somatic cells. These findings and our genetic studies suggest that RDE-12 is first recruited to target mRNA by upstream AGOs (RDE-1 and ERGO-1), where it promotes small RNA amplification and/or WAGO-1 loading. Downstream of these events, RDE-12 forms an RNase-resistant (target mRNA-independent) complex with WAGO-1 and may thus have additional functions in target mRNA surveillance and silencing. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

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.

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

NASA Astrophysics Data System (ADS)

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

2014-12-01

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

Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

PubMed

Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

2015-09-15

Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.

Downstream energetic proton and alpha particles during quasi-parallel interplanetary shock events

NASA Technical Reports Server (NTRS)

Tan, L. C.; Mason, G. M.; Gloeckler, G.; Ipavich, F. M.

1988-01-01

This paper considers the energetic particle populations in the downstream region of three quasi-parallel interplanetary shock events, which was explored using the ISEE 3 Ultra Low Energy Charge Analyzer sensor, which unambiguously identifies protons and alpha particles using the electrostatic deflection versus residual energy technique. The downstream particles were found to exhibit anisotropies due largely to convection in the solar wind. The spectral indices of the proton and the alpha-particle distribution functions were found to be remarkably constant during the downstream period, being generally insensitive to changes in particle flux levels, magnetic field direction, and solar wind densities. In two of the three events, the proton and the alpha spectra were the same throughout the entire downstream period, supporting the prediction of diffusive shock acceleration theory.

Beta-arrestin inhibits CAMKKbeta-dependent AMPK activation downstream of protease-activated-receptor-2.

PubMed

Wang, Ping; Jiang, Yong; Wang, Yinsheng; Shyy, John Y; DeFea, Kathryn A

2010-09-21

Proteinase-activated-receptor-2 (PAR2) is a seven transmembrane receptor that can activate two separate signaling arms: one through Gαq and Ca2+ mobilization, and a second through recruitment of β-arrestin scaffolds. In some cases downstream targets of the Gαq/Ca2+ signaling arm are directly inhibited by β-arrestins, while in other cases the two pathways are synergistic; thus β-arrestins act as molecular switches capable of modifying the signal generated by the receptor. Here we demonstrate that PAR2 can activate adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy balance, through Ca2+-dependent Kinase Kinase β (CAMKKβ), while inhibiting AMPK through interaction with β-arrestins. The ultimate outcome of PAR2 activation depended on the cell type studied; in cultured fibroblasts with low endogenous β-arrestins, PAR2 activated AMPK; however, in primary fat and liver, PAR2 only activated AMPK in β-arrestin-2-/- mice. β-arrestin-2 could be co-immunoprecipitated with AMPK and CAMKKβ under baseline conditions from both cultured fibroblasts and primary fat, and its association with both proteins was increased by PAR2 activation. Addition of recombinant β-arrestin-2 to in vitro kinase assays directly inhibited phosphorylation of AMPK by CAMKKβ on Thr172. Studies have shown that decreased AMPK activity is associated with obesity and Type II Diabetes, while AMPK activity is increased with metabolically favorable conditions and cholesterol lowering drugs. These results suggest a role for β-arrestin in the inhibition of AMPK signaling, raising the possibility that β-arrestin-dependent PAR2 signaling may act as a molecular switch turning a positive signal to AMPK into an inhibitory one.

Suspended sediments from upstream tributaries as the source of downstream river sites

NASA Astrophysics Data System (ADS)

Haddadchi, Arman; Olley, Jon

2014-05-01

Understanding the efficiency with which sediment eroded from different sources is transported to the catchment outlet is a key knowledge gap that is critical to our ability to accurately target and prioritise management actions to reduce sediment delivery. Sediment fingerprinting has proven to be an efficient approach to determine the sources of sediment. This study examines the suspended sediment sources from Emu Creek catchment, south eastern Queensland, Australia. In addition to collect suspended sediments from different sites of the streams after the confluence of tributaries and outlet of the catchment, time integrated suspended samples from upper tributaries were used as the source of sediment, instead of using hillslope and channel bank samples. Totally, 35 time-integrated samplers were used to compute the contribution of suspended sediments from different upstream waterways to the downstream sediment sites. Three size fractions of materials including fine sand (63-210 μm), silt (10-63 μm) and fine silt and clay (<10 μm) were used to find the effect of particle size on the contribution of upper sediments as the sources of sediment after river confluences. And then samples were analysed by ICP-MS and -OES to find 41 sediment fingerprints. According to the results of Student's T-distribution mixing model, small creeks in the middle and lower part of the catchment were major source in different size fractions, especially in silt (10-63 μm) samples. Gowrie Creek as covers southern-upstream part of the catchment was a major contributor at the outlet of the catchment in finest size fraction (<10 μm) Large differences between the contributions of suspended sediments from upper tributaries in different size fractions necessitate the selection of appropriate size fraction on sediment tracing in the catchment and also major effect of particle size on the movement and deposition of sediments.

A novel virtual hub approach for multisource downstream service integration

NASA Astrophysics Data System (ADS)

Previtali, Mattia; Cuca, Branka; Barazzetti, Luigi

2016-08-01

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

DEPDC5 as a potential therapeutic target for epilepsy.

PubMed

Myers, Kenneth A; Scheffer, Ingrid E

2017-06-01

Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism; disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy. Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors. Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.

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

USGS Publications Warehouse

Van Wilson, 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.

Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy.

PubMed

Shi, Yunli; Liu, Shengnan; Ahmad, Shabir; Gao, Qingzhi

2018-05-22

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps.

PubMed

Cichocki, Joseph A; Guyton, Kathryn Z; Guha, Neela; Chiu, Weihsueh A; Rusyn, Ivan; Lash, Lawrence H

2016-10-01

Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Identification of key target genes and pathways in laryngeal carcinoma

PubMed Central

Liu, Feng; Du, Jintao; Liu, Jun; Wen, Bei

2016-01-01

The purpose of the present study was to screen the key genes associated with laryngeal carcinoma and to investigate the molecular mechanism of laryngeal carcinoma progression. The gene expression profile of GSE10935 [Gene Expression Omnibus (GEO) accession number], including 12 specimens from laryngeal papillomas and 12 specimens from normal laryngeal epithelia controls, was downloaded from the GEO database. Differentially expressed genes (DEGs) were screened in laryngeal papillomas compared with normal controls using Limma package in R language, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed using Cytoscape software and modules were analyzed using MCODE plugin from the PPI network. Furthermore, significant biological pathway regions (sub-pathway) were identified by using iSubpathwayMiner analysis. A total of 67 DEGs were identified, including 27 up-regulated genes and 40 down-regulated genes and they were involved in different GO terms and pathways. PPI network analysis revealed that Ras association (RalGDS/AF-6) domain family member 1 (RASSF1) was a hub protein. The sub-pathway analysis identified 9 significantly enriched sub-pathways, including glycolysis/gluconeogenesis and nitrogen metabolism. Genes such as phosphoglycerate kinase 1 (PGK1), carbonic anhydrase II (CA2), and carbonic anhydrase XII (CA12) whose node degrees were >10 were identified in the disease risk sub-pathway. Genes in the sub-pathway, such as RASSF1, PGK1, CA2 and CA12 were presumed to serve critical roles in laryngeal carcinoma. The present study identified DEGs and their sub-pathways in the disease, which may serve as potential targets for treatment of laryngeal carcinoma. PMID:27446427

Stereotyped responses of Drosophila peptidergic neuronal ensemble depend on downstream neuromodulators

PubMed Central

Mena, Wilson; Diegelmann, Sören; Wegener, Christian; Ewer, John

2016-01-01

Neuropeptides play a key role in the regulation of behaviors and physiological responses including alertness, social recognition, and hunger, yet, their mechanism of action is poorly understood. Here, we focus on the endocrine control ecdysis behavior, which is used by arthropods to shed their cuticle at the end of every molt. Ecdysis is triggered by ETH (Ecdysis triggering hormone), and we show that the response of peptidergic neurons that produce CCAP (crustacean cardioactive peptide), which are key targets of ETH and control the onset of ecdysis behavior, depends fundamentally on the actions of neuropeptides produced by other direct targets of ETH and released in a broad paracrine manner within the CNS; by autocrine influences from the CCAP neurons themselves; and by inhibitory actions mediated by GABA. Our findings provide insights into how this critical insect behavior is controlled and general principles for understanding how neuropeptides organize neuronal activity and behaviors. DOI: http://dx.doi.org/10.7554/eLife.19686.001 PMID:27976997

Molecular Approach to Targeted Therapy for Multiple Sclerosis.

PubMed

Sherbet, Gajanan V

2016-01-01

The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems.

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.

Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila.

PubMed

Hing, H; Xiao, J; Harden, N; Lim, L; Zipursky, S L

1999-06-25

The SH2/SH3 adaptor protein Dock has been proposed to transduce signals from guidance receptors to the actin cytoskeleton in Drosophila photoreceptor (R cell) growth cones. Here, we demonstrate that Drosophila p21-activated kinase (Pak) is required in a Dock pathway regulating R cell axon guidance and targeting. Dock and Pak colocalize to R cell axons and growth cones, physically interact, and their loss-of-function phenotypes are indistinguishable. Normal patterns of R cell connectivity require Pak's kinase activity and binding sites for both Dock and Cdc42/Rac. A membrane-tethered form of Pak (Pak(myr) acts as a dominant gain-of-function protein. Retinal expression of Pak(myr) rescues the R cell connectivity phenotype in dock mutants. These data establish Pak as a critical regulator of axon guidance and a downstream effector of Dock in vivo.

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

NASA Astrophysics Data System (ADS)

Hsieh, T.

1986-10-01

Investigation of downstream boundary effects on the frequency of self-excited oscillations in two-dimensional, separated transonic diffuser flows were conducted numerically by solving the compressible, Reynolds-averaged, thin-layer Navier-Stokes equation with two equation turbulence models. It was found that the flow fields 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. The existence of a suction slot in the experimental setpup obscures the physical downstream boundary and therefore presents a difficulty for quantitative comparisons between computation and experiment.

Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling.

PubMed

Wei, Xiaofan; Wang, Xiang; Xia, Yang; Tang, Yan; Li, Feng; Fang, Weigang; Zhang, Hongquan

2014-01-01

Kindlin-2 is an adaptor protein that contributes to renal tubulointerstitial fibrosis (TIF). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells was regarded as one of the key events in TIF. To determine whether kindlin-2 is involved in the EMT process, we investigated its regulation of EMT in human kidney tubular epithelial cells (TECs) and explored the underlying mechanism. In this study, we found that overexpression of kindlin-2 suppressed epithelial marker E-cadherin and increased the expression of fibronectin and the myofibroblast marker α-smooth muscle actin (SMA). Kindlin-2 significantly activated ERK1/2 and Akt, and inhibition of ERK1/2 or Akt reversed kindlin-2-induced EMT in human kidney TECs. Mechanistically, kindlin-2 interacted with Ras and son of sevenless (Sos)-1. Furthermore, overexpression of kindlin-2 increased Ras activation through recruiting Sos-1. Treatment with a Ras inhibitor markedly repressed kindlin-2-induced ERK1/2 and Akt activation, leading to restraint of EMT. We further demonstrated that knockdown of kindlin-2 inhibited EGF-induced Ras-Sos-1 interaction, resulting in reduction of Ras activation and suppression of EMT stimulated by EGF. Importantly, we found that depletion of kindlin-2 significantly inhibited activation of ERK1/2 and Akt signaling in mice with unilateral ureteral obstruction. We conclude that kindlin-2, through activating Ras and the downstream ERK1/2 and Akt signaling pathways, plays an important role in regulating renal tubular EMT and could be a potential therapeutic target for the treatment of fibrotic kidney diseases.

How far downstream do dams impact streamflow?

NASA Astrophysics Data System (ADS)

Troy, T.

2017-12-01

Water infrastructure can be a double-edged sword. For example, dams can provide significant flood protection and stable water supplies, but they negatively impact river ecosystems. As the United States enters an era of dam decommissioning instead of dam building, it raises the question of how far downstream dams provide protection against flood peaks and sustaining environmental flows. This study uses USGS streamflow observations, the National Inventory of Dams, and VIC-modeled streamflow as a proxy for naturalized streamflow to evaluate the scale at which dams impact a variety of hydrologic signatures such as flood return period flows, streamflow variability, and low flows. Results over the Delaware River show that the impact of dams quickly dissipates as one moves downstream, but this is due to the basin's characteristics. This analysis is performed over the contiguous United States, quantifying the length scale of impact as a function of dam capacity, position on the river network, and the hydroclimatology.

Analytical prediction of the unsteady lift on a rotor caused by downstream struts

NASA Technical Reports Server (NTRS)

Taylor, A. C., III; Ng, W. F.

1987-01-01

A two-dimensional, inviscid, incompressible procedure is presented for predicting the unsteady lift on turbomachinery blades caused by the upstream potential disturbance of downstream flow obstructions. Using the Douglas-Neumann singularity superposition potential flow computer program to model the downstream flow obstructions, classical equations of thin airfoil theory are then employed, to compute the unsteady lift on the upstream rotor blades. The method is applied to a particular geometry which consists of a rotor, a downstream stator, and downstream struts which support the engine casing. Very good agreement between the Douglas-Neumann program and experimental measurements was obtained for the downstream stator-strut flow field. The calculations for the unsteady lift due to the struts were in good agreement with the experiments in showing that the unsteady lift due to the struts decays exponentially with increased axial separation of the rotor and the struts. An application of the method showed that for a given axial spacing between the rotor and the strut, strut-induced unsteady lift is a very weak function of the axial or circumferential position of the stator.

Rational design and optimization of downstream processes of virus particles for biopharmaceutical applications: current advances.

PubMed

Vicente, Tiago; Mota, José P B; Peixoto, Cristina; Alves, Paula M; Carrondo, Manuel J T

2011-01-01

The advent of advanced therapies in the pharmaceutical industry has moved the spotlight into virus-like particles and viral vectors produced in cell culture holding great promise in a myriad of clinical targets, including cancer prophylaxis and treatment. Even though a couple of cases have reached the clinic, these products have yet to overcome a number of biological and technological challenges before broad utilization. Concerning the manufacturing processes, there is significant research focusing on the optimization of current cell culture systems and, more recently, on developing scalable downstream processes to generate material for pre-clinical and clinical trials. We review the current options for downstream processing of these complex biopharmaceuticals and underline current advances on knowledge-based toolboxes proposed for rational optimization of their processing. Rational tools developed to increase the yet scarce knowledge on the purification processes of complex biologicals are discussed as alternative to empirical, "black-boxed" based strategies classically used for process development. Innovative methodologies based on surface plasmon resonance, dynamic light scattering, scale-down high-throughput screening and mathematical modeling for supporting ion-exchange chromatography show great potential for a more efficient and cost-effective process design, optimization and equipment prototyping. Copyright © 2011 Elsevier Inc. All rights reserved.

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets.

PubMed

Tenhagen, M; van Diest, P J; Ivanova, I A; van der Wall, E; van der Groep, P

2012-08-01

Cancer treatments are increasingly focusing on the molecular mechanisms underlying the oncogenic processes present in tumors of individual patients. Fibroblast growth factor receptors (FGFRs) are among the many molecules that are involved in oncogenesis and are currently under investigation for their potential as drug targets in breast cancer patients. These receptor tyrosine kinases play a role in several processes including proliferation, angiogenesis, and migration. Alterations in these basal processes can contribute to the development and progression of tumors. Among breast cancer patients, several subgroups have been shown to harbor genetic aberrations in FGFRs, including amplifications of FGFR1, FGFR2, and FGFR4 and mutations in FGFR2 and FGFR4. Here, we review in vitro and in vivo models that have partly elucidated the molecular implications of these different genetic aberrations, the resulting tumor characteristics, and the potential of FGFRs as therapeutic targets for breast cancer treatment.

Continuous-variable quantum authentication of physical unclonable keys

NASA Astrophysics Data System (ADS)

Nikolopoulos, Georgios M.; Diamanti, Eleni

2017-04-01

We propose a scheme for authentication of physical keys that are materialized by optical multiple-scattering media. The authentication relies on the optical response of the key when probed by randomly selected coherent states of light, and the use of standard wavefront-shaping techniques that direct the scattered photons coherently to a specific target mode at the output. The quadratures of the electromagnetic field of the scattered light at the target mode are analysed using a homodyne detection scheme, and the acceptance or rejection of the key is decided upon the outcomes of the measurements. The proposed scheme can be implemented with current technology and offers collision resistance and robustness against key cloning.

Pollutant Transport and Fate: Relations Between Flow-paths and Downstream Impacts of Human Activities

NASA Astrophysics Data System (ADS)

Thorslund, J.; Jarsjo, J.; Destouni, G.

2017-12-01

The quality of freshwater resources is increasingly impacted by human activities. Humans also extensively change the structure of landscapes, which may alter natural hydrological processes. To manage and maintain freshwater of good water quality, it is critical to understand how pollutants are released into, transported and transformed within the hydrological system. Some key scientific questions include: What are net downstream impacts of pollutants across different hydroclimatic and human disturbance conditions, and on different scales? What are the functions within and between components of the landscape, such as wetlands, on mitigating pollutant load delivery to downstream recipients? We explore these questions by synthesizing results from several relevant case study examples of intensely human-impacted hydrological systems. These case study sites have been specifically evaluated in terms of net impact of human activities on pollutant input to the aquatic system, as well as flow-path distributions trough wetlands as a potential ecosystem service of pollutant mitigation. Results shows that although individual wetlands have high retention capacity, efficient net retention effects were not always achieved at a larger landscape scale. Evidence suggests that the function of wetlands as mitigation solutions to pollutant loads is largely controlled by large-scale parallel and circular flow-paths, through which multiple wetlands are interconnected in the landscape. To achieve net mitigation effects at large scale, a large fraction of the polluted large-scale flows must be transported through multiple connected wetlands. Although such large-scale flow interactions are critical for assessing water pollution spreading and fate through the landscape, our synthesis shows a frequent lack of knowledge at such scales. We suggest ways forward for addressing the mismatch between the large scales at which key pollutant pressures and water quality changes take place and the

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schulze, Martin E.

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

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer.

PubMed

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T

2017-04-01

Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.

The Vasa homolog RDE-12 engages target mRNA and multiple Argonaute proteins to promote RNAi in C. elegans

PubMed Central

Shirayama, Masaki; Stanney, William; Gu, Weifeng; Seth, Meetu; Mello, Craig C.

2014-01-01

Summary Argonaute proteins (AGOs) are key nuclease effectors of RNA interference (RNAi) [1]. Although purified AGOs can mediate a single round of target-RNA cleavage in vitro, accessory factors are required for short-interfering (si)RNAs loading and to achieve multiple-target turnover [2, 3]. To identify AGO co-factors we immunoprecipitated the C. elegans AGO WAGO-1, which engages amplified small RNAs during RNAi [4]. These studies identified a robust association between WAGO-1 and a conserved Vasa ATPase-related protein RDE-12. rde-12 mutants are deficient in RNAi including viral suppression, and fail to produce amplified secondary siRNAs and certain endogenous siRNAs (endo-siRNAs). RDE-12 co-localizes with WAGO-1 in germline P-granules and in cytoplasmic and peri-nuclear foci in somatic cells. These findings and our genetic studies suggest that RDE-12 is first recruited to target mRNA by upstream AGOs (RDE-1 and ERGO-1) where it promotes small-RNA amplification and/or WAGO-1 loading. Downstream of these events, RDE-12 forms an RNase-resistant (target mRNA-independent) complex with WAGO-1 and may thus have additional functions in target mRNA surveillance and silencing. PMID:24684931

Assessing downstream flood impacts due to a potential GLOF from Imja Lake in Nepal

NASA Astrophysics Data System (ADS)

Somos-Valenzuela, M. A.; McKinney, D. C.; Byers, A. C.; Rounce, D. R.; Portocarrero, C.; Lamsal, D.

2014-11-01

Glacial-dominated areas pose unique challenges to downstream communities in adapting to recent and continuing global climate change, including increased threats of glacial lake outburst floods (GLOFs) that can increase risk due to flooding of downstream communities and cause substantial impacts on regional social, environmental and economic systems. The Imja glacial lake in Nepal, with potential to generate a GLOF, was studied using a two-dimensional debris flow inundation model in order to evaluate the effectiveness of proposed measures to reduce possible flooding impacts to downstream communities by lowering the lake level. The results indicate that only minor flood impact reduction is achieved in the downstream community of Dingboche with modest (~3 m) lake lowering. Lowering the lake by 10 m shows a significant reduction in inundated area. However, lowering the lake by 20 m almost eliminates all flood impact at Dingboche. Further downstream at Phakding, the impact of the GLOF is significant and similar reductions in inundation are likely as a result of lake lowering.

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.

Protecting Podocytes: A Key Target for Therapy of Focal Segmental Glomerulosclerosis.

PubMed

Campbell, Kirk N; Tumlin, James A

2018-05-31

Focal segmental glomerulosclerosis (FSGS) is a histologic pattern of injury demonstrated by renal biopsy that can arise from a diverse range of causes and mechanisms. It has an estimated incidence of 7 per 1 million and is the most common primary glomerular disorder leading to end-stage renal disease in the United States. This review focuses on damage to the podocyte and the consequences of this injury in patients with FSGS, the genetics of FSGS, and approaches to treatment with a focus on the effects on podocytes. The podocyte is central to the glomerular filtration barrier and is particularly vulnerable because of its highly differentiated post-mitotic phenotype. The progressive structural changes involved in the pathology of FSGS include podocyte foot process effacement, death of podocytes and exposure of the glomerular basement membrane, filtration of nonspecific plasma proteins, expansion of capillaries, misdirected filtration at points of synechiae, and mesangial matrix proliferation. Although damage to and death of podocytes can result from single-gene disorders, evidence also suggests a role for soluble factors, such as soluble urokinase-type plasminogen activator receptor, cardiotrophin-like cytokine-1, and anti-CD40 antibodies, that promote FSGS recurrence post transplant. Several classes of medications, including corticosteroids, calcineurin inhibitors, endothelin receptor antagonists, adrenocorticotropic hormone, and rituximab, have been shown to be effective for the treatment of FSGS and have been demonstrated to have significant protective effects on podocytes. Key Messages: Greater understanding of podocyte biology is essential to the identification of new treatment targets and medications for the management of patients with FSGS. © 2018 S. Karger AG, Basel.

C, N, P export regimes from headwater catchments to downstream reaches

NASA Astrophysics Data System (ADS)

Dupas, R.; Musolff, A.; Jawitz, J. W.; Rao, P. S.; Jaeger, C. G.; Fleckenstein, J. H.; Rode, M.; Borchardt, D.

2017-12-01

Excessive amounts of nutrients and dissolved organic matter in freshwater bodies affect aquatic ecosystems. In this study, the spatial and temporal variability in nitrate (NO3), dissolved organic carbon (DOC) and soluble reactive phosphorus (SRP) was analyzed in the Selke river continuum from headwaters draining 1 - 3 km² catchments to downstream reaches representing spatially integrated signals from 184 - 456 km² catchments (part of TERENO - Terrestrial Environmental Observatories, in Germany). Three headwater catchments were selected as archetypes of the main landscape units (land use x lithology) present in the Selke catchment. Export regimes in headwater catchments were interpreted in terms of NO3, DOC and SRP land-to-stream transfer processes. Headwater signals were subtracted from downstream signals, with the differences interpreted in terms of in-stream processes and contribution of point-source emissions. The seasonal dynamics for NO3 were opposite those of DOC and SRP in all three headwater catchments, and spatial differences also showed NO3 contrasting with DOC and SRP. These dynamics were interpreted as the result of the interplay of hydrological and biogeochemical processes, for which riparian zones were hypothesized to play a determining role. In the two downstream reaches, NO3 was transported almost conservatively, whereas DOC was consumed and produced in the upper and lower river sections, respectively. The natural export regime of SRP in the three headwater catchments mimicked a point-source signal, which may lead to overestimation of domestic contributions in the downstream reaches. Monitoring the river continuum from headwaters to downstream reaches proved effective to investigate jointly land-to-stream and in-stream transport and transformation processes.

MicroRNA as therapeutic targets for treatment of depression

PubMed Central

Hansen, Katelin F; Obrietan, Karl

2013-01-01

Depression is a potentially life-threatening mental disorder affecting approximately 300 million people worldwide. Despite much effort, the molecular underpinnings of clinical depression remain poorly defined, and current treatments carry limited therapeutic efficacy and potentially burdensome side effects. Recently, small noncoding RNA molecules known as microRNA (miRNA) have gained prominence as a target for therapeutic intervention, given their capacity to regulate neuronal physiology. Further, mounting evidence suggests a prominent role for miRNA in depressive molecular signaling. Recent studies have demonstrated that dysregulation of miRNA expression occurs in animal models of depression, and in the post-mortem tissue of clinically depressed patients. Investigations into depression-associated miRNA disruption reveals dramatic effects on downstream targets, many of which are thought to contribute to depressive symptoms. Furthermore, selective serotonin reuptake inhibitors, as well as other antidepressant drugs, have the capacity to reverse aberrant depressive miRNA expression and their downstream targets. Given the powerful effects that miRNA have on the central nervous system transcriptome, and the aforementioned studies, there is a compelling rationale to begin to assess the potential contribution of miRNA to depressive etiology. Here, we review the molecular biology of miRNA, our current understanding of miRNA in relation to clinical depression, and the utility of targeting miRNA for antidepressant treatment. PMID:23935365

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 thatmore » 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.« less

Watershed sustainability: Downstream effects of timber harvest in the Ozarks of Missouri

USGS Publications Warehouse

Jacobson, Robert B.

2004-01-01

The downstream effects of timber harvest in the Ozarks of Missouri can be evaluated by analogy to other geographic areas and by historical analysis of responses to past land use activities. Based on research from other geographic regions, timber harvest in the Ozarks would be expected to have minor effects on annual water yield and dissolved-phase water quality. The potential exists for haul roads to increase stormflow discharges and sediment yields. Of the possible downstream effects, sediment yield is potentially the most severe and difficult to predict; siting and design of roads are probably the most critical management concerns for minimizing downstream effects. Historical analysis shows that Ozark streams have been destabilized by past land use practices, primarily in the riparian zone. Therefore, present-day timber harvest takes place in a landscape where streams have lowered resilience to disturbance. Predictions of future downstream effects of timber harvest in the Ozarks are complicated by the inherent complexity of cumulative watershed effects and the lack of detailed, long-term instrumental records at appropriate scales.

Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations.

PubMed

Palermo, Giulia; Miao, Yinglong; Walker, Ross C; Jinek, Martin; McCammon, J Andrew

2016-10-26

The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system recently emerged as a transformative genome-editing technology that is innovating basic bioscience and applied medicine and biotechnology. The endonuclease Cas9 associates with a guide RNA to match and cleave complementary sequences in double stranded DNA, forming an RNA:DNA hybrid and a displaced non-target DNA strand. Although extensive structural studies are ongoing, the conformational dynamics of Cas9 and its interplay with the nucleic acids during association and DNA cleavage are largely unclear. Here, by employing multi-microsecond time scale molecular dynamics, we reveal the conformational plasticity of Cas9 and identify key determinants that allow its large-scale conformational changes during nucleic acid binding and processing. We show how the "closure" of the protein, which accompanies nucleic acid binding, fundamentally relies on highly coupled and specific motions of the protein domains, collectively initiating the prominent conformational changes needed for nucleic acid association. We further reveal a key role of the non-target DNA during the process of activation of the nuclease HNH domain, showing how the nontarget DNA positioning triggers local conformational changes that favor the formation of a catalytically competent Cas9. Finally, a remarkable conformational plasticity is identified as an intrinsic property of the HNH domain, constituting a necessary element that allows for the HNH repositioning. These novel findings constitute a reference for future experimental studies aimed at a full characterization of the dynamic features of the CRISPR-Cas9 system, and-more importantly-call for novel structure engineering efforts that are of fundamental importance for the rational design of new genome-engineering applications.

Identification of potential therapeutic target genes, key miRNAs and mechanisms in oral lichen planus by bioinformatics analysis.

PubMed

Gong, Cuihua; Sun, Shangtong; Liu, Bing; Wang, Jing; Chen, Xiaodong

2017-06-01

The study aimed to identify the potential target genes and key miRNAs as well as to explore the underlying mechanisms in the pathogenesis of oral lichen planus (OLP) by bioinformatics analysis. The microarray data of GSE38617 were downloaded from Gene Expression Omnibus (GEO) database. A total of 7 OLP and 7 normal samples were used to identify the differentially expressed genes (DEGs) and miRNAs. The DEGs were then performed functional enrichment analyses. Furthermore, DEG-miRNA network and miRNA-function network were constructed by Cytoscape software. Total 1758 DEGs (598 up- and 1160 down-regulated genes) and 40 miRNAs (17 up- and 23 down-regulated miRNAs) were selected. The up-regulated genes were related to nuclear factor-Kappa B (NF-κB) signaling pathway, while down-regulated genes were mainly enriched in the function of ribosome. Tumor necrosis factor (TNF), caspase recruitment domain family, member 11 (CARD11) and mitochondrial ribosomal protein (MRP) genes were identified in these functions. In addition, miR-302 was a hub node in DEG-miRNA network and regulated cyclin D1 (CCND1). MiR-548a-2 was the key miRNA in miRNA-function network by regulating multiple functions including ribosomal function. The NF-κB signaling pathway and ribosome function may be the pathogenic mechanisms of OLP. The genes such as TNF, CARD11, MRP genes and CCND1 may be potential therapeutic target genes in OLP. MiR-548a-2 and miR-302 may play important roles in OLP development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of sediment storage on downstream delivery of contaminated sediment

USGS Publications Warehouse

Malmon, Daniel V.; Reneau, Steven L.; Dunne, Thomas; Katzman, Danny; Drakos, Paul 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.

Bombyx mori P-element Somatic Inhibitor (BmPSI) Is a Key Auxiliary Factor for Silkworm Male Sex Determination

PubMed Central

Chen, Shuqing; Zeng, Baosheng; James, Anthony A.; Tan, Anjiang; Huang, Yongping

2017-01-01

Manipulation of sex determination pathways in insects provides the basis for a wide spectrum of strategies to benefit agriculture and public health. Furthermore, insects display a remarkable diversity in the genetic pathways that lead to sex differentiation. The silkworm, Bombyx mori, has been cultivated by humans as a beneficial insect for over two millennia, and more recently as a model system for studying lepidopteran genetics and development. Previous studies have identified the B. mori Fem piRNA as the primary female determining factor and BmMasc as its downstream target, while the genetic scenario for male sex determination was still unclear. In the current study, we exploite the transgenic CRISPR/Cas9 system to generate a comprehensive set of knockout mutations in genes BmSxl, Bmtra2, BmImp, BmImpM, BmPSI and BmMasc, to investigate their roles in silkworm sex determination. Absence of Bmtra2 results in the complete depletion of Bmdsx transcripts, which is the conserved downstream factor in the sex determination pathway, and induces embryonic lethality. Loss of BmImp or BmImpM function does not affect the sexual differentiation. Mutations in BmPSI and BmMasc genes affect the splicing of Bmdsx and the female reproductive apparatus appeared in the male external genital. Intriguingly, we identify that BmPSI regulates expression of BmMasc, BmImpM and Bmdsx, supporting the conclusion that it acts as a key auxiliary factor in silkworm male sex determination. PMID:28103247

Improvement of film cooling effectiveness with a small downstream block body

NASA Astrophysics Data System (ADS)

Khorsi, A.; Guelailia, A.; Hamidou, M. K.

2016-07-01

The aim of this study is to predict the improvement in film cooling performance over a flat plate through a single row of cylindrical holes with different streamwise angles by using the Ansys CFX software package. In order to improve the film cooling effectiveness, a short crescent-shaped block is placed downstream of a cylindrical cooling hole. The numerical results of the cylindrical hole without the downstream short crescent-shaped block are compared with experimental data.

Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tu, Yingfeng; Liu, Li; Zhao, Dongliang

Recent studies reported miR-497 exhibited inhibitory effects in various cancers. However, whether miR-497 is involved in inhibiting angiogenesis, which is critical for tumor growth and metastasis, is still unknown. The purpose of this study was to investigate the potential role of miR-497 in tumor angiogenesis. In this work, cell proliferation and apoptosis analyses were conducted to explore the potential function of miR-497 in HUVECs by using MTT and TUNEL assays. Western blotting (WB) was employed to validate the downstream targets of miR-497. Furthermore, in order to disclose the role of miR-497 on angiogenesis, VEGFR2-luc transgenic mice were treated with miR-497more » mimic and applied to monitor tumor angiogenesis and growth by in vivo bioluminescent imaging (BLI). The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo. Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway. Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis. In summary, miR-497 inhibits tumor angiogenesis and growth via targeting VEGFR2, indicating miR-497 can be explored as a potential drug candidate for cancer therapy.« less

Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2

DOE PAGES

Tu, Yingfeng; Liu, Li; Zhao, Dongliang; ...

2015-09-08

Recent studies reported miR-497 exhibited inhibitory effects in various cancers. However, whether miR-497 is involved in inhibiting angiogenesis, which is critical for tumor growth and metastasis, is still unknown. The purpose of this study was to investigate the potential role of miR-497 in tumor angiogenesis. In this work, cell proliferation and apoptosis analyses were conducted to explore the potential function of miR-497 in HUVECs by using MTT and TUNEL assays. Western blotting (WB) was employed to validate the downstream targets of miR-497. Furthermore, in order to disclose the role of miR-497 on angiogenesis, VEGFR2-luc transgenic mice were treated with miR-497more » mimic and applied to monitor tumor angiogenesis and growth by in vivo bioluminescent imaging (BLI). The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo. Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway. Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis. In summary, miR-497 inhibits tumor angiogenesis and growth via targeting VEGFR2, indicating miR-497 can be explored as a potential drug candidate for cancer therapy.« less

Assessing downstream flood impacts due to a potential GLOF from Imja Tsho in Nepal

NASA Astrophysics Data System (ADS)

Somos-Valenzuela, M. A.; McKinney, D. C.; Byers, A. C.; Rounce, D. R.; Portocarrero, C.; Lamsal, D.

2015-03-01

Glacial-dominated areas pose unique challenges to downstream communities in adapting to recent and continuing global climate change, including increased threats of glacial lake outburst floods (GLOFs) that can increase risk due to flooding of downstream communities and cause substantial impacts on regional social, environmental and economic systems. The Imja glacial lake (or Imja Tsho) in Nepal, which has the potential to generate a GLOF, was studied using a two-dimensional debris-flow inundation model in order to evaluate the effectiveness of proposed measures to reduce possible flooding impacts to downstream communities by lowering the lake level. The results indicate that only minor flood impact reduction is achieved in the downstream community of Dingboche with modest (~3 m) lake lowering. Lowering the lake by 10 m shows a significant reduction in inundated area. However, lowering the lake by 20 m almost eliminates all flood impact at Dingboche. Further downstream at Phakding, the impact of the GLOF is significant and similar reductions in inundation are likely as a result of lake lowering.

MicroRNA-320a suppresses in GBM patients and modulates glioma cell functions by targeting IGF-1R.

PubMed

Guo, Tianzhu; Feng, Ying; Liu, Qingyang; Yang, Xue; Jiang, Tao; Chen, Yan; Zhang, Quangeng

2014-11-01

Glioblastoma (GBM) is the most aggressive and malignant glioma. Currently, a few modern surgical and medical therapeutic strategies are applied for GBM, but the prognosis of GBM patients remains poor, and the average median survival time is only 14.6 months. In this study, we for the first time found that the levels of miR-320a were decreased in both GBM patients and glioma cells. In GBM patients, elevated miR-320a expression was associated with better prognosis. In addition, insulin-like growth factor-1 receptor (IGF-1R) was identified as a key direct target of miR-320a. Overexpression of miR-320a led to the inhibition of cell proliferation, migration, invasion, as well as tumorigenesis by targeting IGF-1R, and thus regulated the signaling pathways downstream, including PI3K/AKT and MAPK/ERK. In tumor orthotopic xenograft experiment, the tumor growth was depressed and survival time of mice model was prolonged when miR-320a was overexpressed. Therefore, our results suggested that miR-320a could suppress tumor development and growth by targeting IGF-1R, and miR-320a might serve as a new effective target for anti-cancer therapy strategies.

Binary agonist surface patterns prime platelets for downstream adhesion in flowing whole blood.

PubMed

Eichinger, Colin D; Hlady, Vladimir

2017-04-28

As platelets encounter damaged vessels or biomaterials, they interact with a complex milieu of surface-bound agonists, from exposed subendothelium to adsorbed plasma proteins. It has been shown that an upstream, surface-immobilized agonist is capable of priming platelets for enhanced adhesion downstream. In this study, binary agonists were integrated into the upstream position of flow cells and the platelet priming response was measured by downstream adhesion in flowing whole blood. A nonadditive response was observed in which platelets transiently exposed to two agonists exhibited greater activation and downstream adhesion than that from the sum of either agonist alone. Antibody blocking of one of the two upstream agonists eliminated nonadditive activation and downstream adhesion. Crosstalk between platelet activation pathways likely led to a synergistic effect which created an enhanced activation response in the platelet population. The existence of synergy between platelet priming pathways is a concept that has broad implications for the field of biomaterials hemocompatibility and platelet activity testing.

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model.

PubMed

El-Hashim, Ahmed Z; Khajah, Maitham A; Renno, Waleed M; Babyson, Rhema S; Uddin, Mohib; Benter, Ibrahim F; Ezeamuzie, Charles; Akhtar, Saghir

2017-08-30

The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kδ/Akt (IC-87114) respectively, or an inhibitor of NF-κB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.

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

Observations of Hall Reconnection Physics Far Downstream of the X Line.

PubMed

Mistry, R; Eastwood, J P; Haggerty, C C; Shay, M A; Phan, T D; Hietala, H; Cassak, P A

2016-10-28

Observations made using the Wind spacecraft of Hall magnetic fields in solar wind reconnection exhausts are presented. These observations are consistent with the generation of Hall fields by a narrow ion inertial scale current layer near the separatrix, which is confirmed with an appropriately scaled particle-in-cell simulation that shows excellent agreement with observations. The Hall fields are observed thousands of ion inertial lengths downstream from the reconnection X line, indicating that narrow regions of kinetic dynamics can persist extremely far downstream.

GEC-targeted HO-1 expression reduces proteinuria in glomerular immune injury.

PubMed

Duann, Pu; Lianos, Elias A

2009-09-01

Induction of heme oxygenase (HO)-1 is a key defense mechanism against oxidative stress. Compared with tubules, glomeruli are refractory to HO-1 upregulation in response to injury. This can be a disadvantage as it may be associated with insufficient production of cytoprotective heme-degradation metabolites. We, therefore, explored whether 1) targeted HO-1 expression can be achieved in glomeruli without altering their physiological integrity and 2) this expression reduces proteinuria in immune injury induced by an anti-glomerular basement membrane (GBM) antibody (Ab). We employed a 4.125-kb fragment of a mouse nephrin promoter downstream to which a FLAG-tagged hHO-1 cDNA sequence was inserted and subsequently generated transgenic mice from the FVB/N parental strain. There was a 16-fold higher transgene expression in the kidney than nonspecific background (liver) while the transprotein immunolocalized in glomerular epithelial cells (GEC). There was no change in urinary protein excretion, indicating that GEC-targeted HO-1 expression had no effect on glomerular protein permeability. Urinary protein excretion in transgenic mice with anti-GBM Ab injury (days 3 and 6) was significantly lower compared with wild-type controls. There was no significant change in renal expression levels of profibrotic (TGF-beta1) or anti-inflammatory (IL-10) cytokines in transgenic mice with anti-GBM Ab injury. These observations indicate that GEC-targeted HO-1 expression does not alter glomerular physiological integrity and reduces proteinuria in glomerular immune injury.

GEC-targeted HO-1 expression reduces proteinuria in glomerular immune injury

PubMed Central

Duann, Pu; Lianos, Elias A.

2009-01-01

Induction of heme oxygenase (HO)-1 is a key defense mechanism against oxidative stress. Compared with tubules, glomeruli are refractory to HO-1 upregulation in response to injury. This can be a disadvantage as it may be associated with insufficient production of cytoprotective heme-degradation metabolites. We, therefore, explored whether 1) targeted HO-1 expression can be achieved in glomeruli without altering their physiological integrity and 2) this expression reduces proteinuria in immune injury induced by an anti-glomerular basement membrane (GBM) antibody (Ab). We employed a 4.125-kb fragment of a mouse nephrin promoter downstream to which a FLAG-tagged hHO-1 cDNA sequence was inserted and subsequently generated transgenic mice from the FVB/N parental strain. There was a 16-fold higher transgene expression in the kidney than nonspecific background (liver) while the transprotein immunolocalized in glomerular epithelial cells (GEC). There was no change in urinary protein excretion, indicating that GEC-targeted HO-1 expression had no effect on glomerular protein permeability. Urinary protein excretion in transgenic mice with anti-GBM Ab injury (days 3 and 6) was significantly lower compared with wild-type controls. There was no significant change in renal expression levels of profibrotic (TGF-β1) or anti-inflammatory (IL-10) cytokines in transgenic mice with anti-GBM Ab injury. These observations indicate that GEC-targeted HO-1 expression does not alter glomerular physiological integrity and reduces proteinuria in glomerular immune injury. PMID:19587144

FGF23 Actions on Target Tissues—With and Without Klotho

PubMed Central

Richter, Beatrice; Faul, Christian

2018-01-01

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might—at least partially—underlie the pleiotropic tissue-protective functions of klotho. PMID:29770125

Neurospora crassa transcriptomics reveals oxidative stress and plasma membrane homeostasis biology genes as key targets in response to chitosan

PubMed Central

Lopez-Moya, Federico; Kowbel, David; Nueda, Ma José; Palma-Guerrero, Javier; Glass, N. Louise; Lopez-Llorca, Luis Vicente

2016-01-01

Chitosan is a natural polymer with antimicrobial activity. Chitosan causes plasma membrane permeabilization and induction of intracellular reactive oxygen species (ROS) in Neurospora crassa. We have determined the transcriptional profile of N. crassa to chitosan and identified the main gene targets involved in the cellular response to this compound. Global network analyses showed membrane, transport and oxidoreductase activity as key nodes affected by chitosan. Activation of oxidative metabolism indicates the importance of ROS and cell energy together with plasma membrane homeostasis in N. crassa response to chitosan. Deletion strain analysis of chitosan susceptibility pointed, NCU03639 encoding a class 3 lipase, involved in plasma membrane repair by lipid replacement and NCU04537 a MFS monosaccharide transporter related with assimilation of simple sugars, as main gene targets of chitosan. NCU10521, a glutathione S-transferase-4 involved in the generation of reducing power for scavenging intracellular ROS is also a determinant chitosan gene target. Ca2+ increased tolerance to chitosan in N. crassa. Growth of NCU10610 (fig 1 domain) and SYT1 (a synaptotagmin) deletion strains was significantly increased by Ca2+ in presence of chitosan. Both genes play a determinant role in N. crassa membrane homeostasis. Our results are of paramount importance for developing chitosan as antifungal. PMID:26694141

Measurement of turbulent flow upstream and downstream of a circular pipe bend

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakakibara, Jun; Machida, Nobuteru

2012-04-15

We measured velocity distribution in cross sections of a fully developed turbulent pipe flow upstream and downstream of a 90 degree sign bend by synchronizing two sets of a particle image velocimetry (PIV) system. Unsteady undulation of Dean vortices formed downstream from the bend was characterized by the azimuthal position of the stagnation point found on the inner and outer sides of the bend. Linear stochastic estimation was applied to capture the upstream flow field conditioned by the azimuthal location of the stagnation point downstream from the bend. When the inner-side stagnation point stayed below (above) the symmetry plane, themore » conditional streamwise velocity upstream from the bend exhibited high-speed streaks extended in a quasi-streamwise direction on the outer side of the curvature above (below) the symmetry plane.« less

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

PubMed Central

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T.

2018-01-01

Introduction Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted. PMID:28271910

Upstream and Downstream Influence in STBLI Instability

NASA Astrophysics Data System (ADS)

Martin, Pino; Priebe, Stephan; Helm, Clara

2016-11-01

Priebe and Martín (JFM, 2012) show that the low-frequency unsteadiness in shockwave and turbulent boundary layer interactions (STBLI) is governed by an inviscid instability. Priebe, Tu, Martín and Rowley (JFM, 2016) show that the instability is an inviscid centrifugal one, i.e Görtlerlike vortices. Previous works had given differing conclusions as to whether the low-frequency unsteadiness in STBLI is caused by an upstream or downstream mechanism. In this paper, we reconcile these opposite views and show that upstream and downstream correlations co-exist in the context of the nature of Görtler vortices. We find that the instability is similar to that in separated subsonic and laminar flows. Since the turbulence is modulated but passive to the global mode, the turbulent separated flows are amenable to linear global analysis. As such, the characteristic length and time scales, and the receptivity of the global mode might be determined, and low-order models that represent the low-frequency dynamics in STBLI might be developed. The centrifugal instability persists even under hypersonic conditions. This work is funded by the AFOSR Grant Number AF9550-15-1-0284 with Dr. Ivett Leyva.

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.

Endurance testing of downstream cathodes on a low-power MPD thruster

NASA Technical Reports Server (NTRS)

Burkhart, J. A.; Rose, J. R.

1974-01-01

A low-power MPD thruster with downstream cathode was tested for endurance with a series of hollow cathode designs. Failure modes and failure mechanisms were identified. A new hollow cathode (with rod inserts) has emerged which shows promise for long life. The downstream positioning of the cathode was also changed from an on-axis location to an off-axis location. Data are presented for a 1332-hour life test of this new hollow cathode located at the new off-axis location. Xenon propellant was used.

Transverse beam splitting made operational: Key features of the multiturn extraction at the CERN Proton Synchrotron

NASA Astrophysics Data System (ADS)

Huschauer, A.; Blas, A.; Borburgh, J.; Damjanovic, S.; Gilardoni, S.; Giovannozzi, M.; Hourican, M.; Kahle, K.; Le Godec, G.; Michels, O.; Sterbini, G.; Hernalsteens, C.

2017-06-01

Following a successful commissioning period, the multiturn extraction (MTE) at the CERN Proton Synchrotron (PS) has been applied for the fixed-target physics programme at the Super Proton Synchrotron (SPS) since September 2015. This exceptional extraction technique was proposed to replace the long-serving continuous transfer (CT) extraction, which has the drawback of inducing high activation in the ring. MTE exploits the principles of nonlinear beam dynamics to perform loss-free beam splitting in the horizontal phase space. Over multiple turns, the resulting beamlets are then transferred to the downstream accelerator. The operational deployment of MTE was rendered possible by the full understanding and mitigation of different hardware limitations and by redesigning the extraction trajectories and nonlinear optics, which was required due to the installation of a dummy septum to reduce the activation of the magnetic extraction septum. This paper focuses on these key features including the use of the transverse damper and the septum shadowing, which allowed a transition from the MTE study to a mature operational extraction scheme.

A computational fluid dynamics modeling study of guide walls for downstream fish passage

USGS Publications Warehouse

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

2017-01-01

A partial-depth, impermeable guidance structure (or guide wall) for downstream fish passage is typically constructed as a series of panels attached to a floating boom and anchored across a water body (e.g. river channel, reservoir, or power canal). The downstream terminus of the wall is generally located nearby to a fish bypass structure. If guidance is successful, the fish will avoid entrainment in a dangerous intake structure (i.e. turbine intakes) while passing from the headpond to the tailwater of a hydroelectric facility through a safer passage route (i.e. the bypass). The goal of this study is to determine the combination of guide wall design parameters that will most likely increase the chance of surface-oriented fish being successfully guided to the bypass. To evaluate the flow field immediately upstream of a guide wall, a parameterized computational fluid dynamics model of an idealized power canal was constructed in © ANSYS Fluent v 14.5 (ANSYS Inc., 2012). The design parameters investigated were the angle and depth of the guide wall and the average approach velocity in the power canal. Results call attention to the importance of the downward to sweeping flow ratio and demonstrate how a change in guide wall depth and angle can affect this important hydraulic cue to out-migrating fish. The key findings indicate that a guide wall set at a small angle (15° is the minimum in this study) and deep enough such that sweeping flow dominant conditions prevail within the expected vertical distribution of fish approaching the structure will produce hydraulic conditions that are more likely to result in effective passage.

KEY COMPARISON: CCQM-K61: Quantitation of a linearised plasmid DNA, based on a matched standard in a matrix of non-target DNA

NASA Astrophysics Data System (ADS)

Woolford, Alison; Holden, Marcia; Salit, Marc; Burns, Malcolm; Ellison, Stephen L. R.

2009-01-01

Key comparison CCQM-K61 was performed to demonstrate and document the capability of interested national metrology institutes in the determination of the quantity of specific DNA target in an aqueous solution. The study provides support for the following measurement claim: "Quantitation of a linearised plasmid DNA, based on a matched standard in a matrix of non-target DNA". The comparison was an activity of the Bioanalysis Working Group (BAWG) of the Comité Consultatif pour la Quantité de Matière and was coordinated by NIST (Gaithersburg, USA) and LGC (Teddington, UK). The following laboratories (in alphabetical order) participated in this key comparison. DMSC (Thailand); IRMM (European Union); KRISS (Republic of Korea); LGC (UK); NIM (China); NIST (USA); NMIA (Australia); NMIJ (Japan); VNIIM (Russian Federation) Good agreement was observed between the reported results of all nine of the participants. Uncertainty estimates did not account fully for the dispersion of results even after allowance for possible inhomogeneity in calibration materials. Preliminary studies suggest that the effects of fluorescence threshold setting might contribute to the excess dispersion, and further study of this topic is suggested Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (MRA).

Risk Factors and Therapeutic Targets in Pancreatic Cancer

PubMed Central

Wörmann, Sonja Maria; Algül, Hana

2013-01-01

Pancreatic cancer (PC) is one of the most challenging tumor entities worldwide, characterized as a highly aggressive disease with dismal overall prognosis and an incidence rate equalling mortality rate. Over the last decade, substantial progress has been made to define the morphological changes and key genetic events in pancreatic carcinogenesis. And yet, it is still unclear what factors trigger PC. Some risk factors appear to be associated with sex, age, race/ethnicity, or other rare genetic conditions. Additionally, modifying factors such as smoking, obesity, diabetes, occupational risk factors, etc., increase the potential for acquiring genetic mutations that may result in PC. Another hallmark of PC is its poor response to radio- and chemo-therapy. Current chemotherapeutic regimens could not provide substantial survival benefit with a clear increase in overall survival. Recently, several new approaches to significantly improve the clinical outcome of PC have been described involving downstream signaling cascades desmoplasia and stromal response as well as tumor microenvironment, immune response, vasculature, and angiogenesis. This review summarizes major risk factors for PC and tries to illuminate relevant targets considerable for new therapeutic approaches. PMID:24303367

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.

Cell Density Affects the Detection of Chk1 Target Engagement by the Selective Inhibitor V158411.

PubMed

Geneste, Clara C; Massey, Andrew J

2018-02-01

Understanding drug target engagement and the relationship to downstream pharmacology is critical for drug discovery. Here we have evaluated target engagement of Chk1 by the small-molecule inhibitor V158411 using two different target engagement methods (autophosphorylation and cellular thermal shift assay [CETSA]). Target engagement measured by these methods was subsequently related to Chk1 inhibitor-dependent pharmacology. Inhibition of autophosphorylation was a robust method for measuring V158411 Chk1 target engagement. In comparison, while target engagement determined using CETSA appeared robust, the V158411 CETSA target engagement EC 50 values were 43- and 19-fold greater than the autophosphorylation IC 50 values. This difference was attributed to the higher cell density in the CETSA assay configuration. pChk1 (S296) IC 50 values determined using the CETSA assay conditions were 54- and 33-fold greater than those determined under standard conditions and were equivalent to the CETSA EC 50 values. Cellular conditions, especially cell density, influenced the target engagement of V158411 for Chk1. The effects of high cell density on apparent compound target engagement potency should be evaluated when using target engagement assays that necessitate high cell densities (such as the CETSA conditions used in this study). In such cases, the subsequent relation of these data to downstream pharmacological changes should therefore be interpreted with care.

Impacts of large dams on downstream flow conditions of rivers: Aggradation and reduction of the Medjerda channel capacity downstream of the Sidi Salem dam (Tunisia)

NASA Astrophysics Data System (ADS)

Zahar, Yadh; Ghorbel, Abdelmajid; Albergel, Jean

2008-04-01

SummarySince the opening of the Sidi Salem dam on the watercourse of the Medjerda, in 1981, an alarming narrowing of the riverbed in the lower valley has been observed. This geo-morphological change is attributed to different factors ranking from the reduction in the discharge flows, which used to clean out the riverbed to the periodic releases of turbid water undertaken to remove the silt deposition inside the reservoir, which increased the sediment deposition in the downstream channel. Other smaller hydraulic projects are also held responsible for the loss of the water velocity including a series of concrete sills meant to raise water levels, numerous cross bridges and the management of the downstream Laroussia dam regulating the discharge from the Cap Bon canal. The above anthropogenic factors, in conjunction with natural topographical conditions characterized by a generally shallow slope and a very sinuous watercourse, led to an extremely rapid aggradation of the downstream channel-bed. This paper proposes an analysis of this process and argues that the resulting reduction in channel capacity is one of the major causes of the large floods experienced in the country since 1996.

Briefing book: Major projects in the upstream, downstream, petrochemical and power sectors of Vietnam. Final definitional mission report. Export trade information

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1998-04-06

The purpose of the briefing book is to provide project information to U.S. Businesses who seek cooperative partnerships with Vietnamese officials on a number of major development projects. The report is divided into the following sections: (1) Executive Summary; (2) Overview of Vietnam; (3) Overview of the Upstream Sector; (4) Overview of the Downstream Sector; (5) Overview of the Petrochemical Sector; (6) Overview of the Electric Energy Sector; (7) Project Development Processes; (8) Project Financing; (9) Foreign Competition and U.S. Competitiveness; (10) Project Profiles; (11) Key Contracts; (12) U.S. Commercial Service.

STAT3 Target Genes Relevant to Human Cancers

PubMed Central

Carpenter, Richard L.; Lo, Hui-Wen

2014-01-01

Since its discovery, the STAT3 transcription factor has been extensively studied for its function as a transcriptional regulator and its role as a mediator of development, normal physiology, and pathology of many diseases, including cancers. These efforts have uncovered an array of genes that can be positively and negatively regulated by STAT3, alone and in cooperation with other transcription factors. Through regulating gene expression, STAT3 has been demonstrated to play a pivotal role in many cellular processes including oncogenesis, tumor growth and progression, and stemness. Interestingly, recent studies suggest that STAT3 may behave as a tumor suppressor by activating expression of genes known to inhibit tumorigenesis. Additional evidence suggested that STAT3 may elicit opposing effects depending on cellular context and tumor types. These mixed results signify the need for a deeper understanding of STAT3, including its upstream regulators, parallel transcription co-regulators, and downstream target genes. To help facilitate fulfilling this unmet need, this review will be primarily focused on STAT3 downstream target genes that have been validated to associate with tumorigenesis and/or malignant biology of human cancers. PMID:24743777

Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization.

PubMed

Dubrac, Alexandre; Genet, Gael; Ola, Roxana; Zhang, Feng; Pibouin-Fragner, Laurence; Han, Jinah; Zhang, Jiasheng; Thomas, Jean-Léon; Chedotal, Alain; Schwartz, Martin A; Eichmann, Anne

2016-01-26

Sprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here, we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2. Mice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2- and VEGF-induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, and pathological ocular neovascularization and wound healing, as well. These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2, and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis. © 2015 American Heart Association, Inc.

Drug targeting of oncogenic pathways in melanoma.

PubMed

Fecher, Leslie A; Amaravadi, Ravi K; Schuchter, Lynn M; Flaherty, Keith T

2009-06-01

Melanoma continues to be one of the most aggressive and morbid malignancies once metastatic. Overall survival for advanced unresectable melanoma has not changed over the past several decades. However, the presence of some long-term survivors of metastatic melanoma highlights the heterogeneity of this disease and the potential for improved outcomes. Current research is uncovering the molecular and genetic scaffolding of normal and aberrant cell function. The known oncogenic pathways in melanoma and the attempts to develop therapy for them are discussed. The targeting of certain cellular processes, downstream of the common genetic alterations, for which the issues of target and drug validation are somewhat distinct, are also highlighted.

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

PubMed Central

Tang, Yujie; Gholamin, Sharareh; Schubert, Simone; Willardson, Minde I.; Lee, Alex; Bandopadhayay, Pratiti; Bergthold, Guillame; Masoud, Sabran; Nguyen, Brian; Vue, Nujsaubnusi; Balansay, Brianna; Yu, Furong; Oh, Sekyung; Woo, Pamelyn; Chen, Spenser; Ponnuswami, Anitha; Monje, Michelle; Atwood, Scott X.; Whitson, Ramon J.; Mitra, Siddhartha; Cheshier, Samuel H.; Qi, Jun; Beroukhim, Rameen; Tang, Jean Y.; Wechsler-Reya, Rob; Oro, Anthony E.; Link, Brian A.; Bradner, James E.; Cho, Yoon-Jae

2014-01-01

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. PMID:24973920

Favorable fragmentation: river reservoirs can impede downstream expansion of riparian weeds.

PubMed

Rood, Stewart B; Braatne, Jeffrey H; Goater, Lori A

2010-09-01

River valleys represent biologically rich corridors characterized by natural disturbances that create moist and barren sites suitable for colonization by native riparian plants, and also by weeds. Dams and reservoirs interrupt the longitudinal corridors and we hypothesized that this could restrict downstream weed expansion. To consider this "reservoir impediment" hypothesis we assessed the occurrences and abundances of weeds along a 315-km river valley corridor that commenced with an unimpounded reach of the Snake River and extended through Brownlee, Oxbow, and Hells Canyon reservoirs and dams, and downstream along the Snake River. Sampling along 206 belt transects with 3610 quadrats revealed 16 noxious and four invasive weed species. Ten weeds were upland plants, with Canada thistle (Cirsium arvense) restricted to the upstream reaches, where field morning glory (Convolvulus arvensis) was also more common. In contrast, St. John's wort (Hypericum perforatum) was more abundant below the dams, and medusahead wildrye (Taeniatherum caput-medusae) occurred primarily along the reservoirs. All seven riparian species were abundant in the upstream zones but sparse or absent below the dams. This pattern was observed for the facultative riparian species, poison hemlock (Conium maculatum) and perennial pepperweed (Lepidium latifolium), the obligate riparian, yellow nut sedge (Cyperus esculentus), the invasive perennial, reed canary grass (Phalaris arundinacea), and three invasive riparian trees, Russian olive (Elaeagnus angustifolia), false indigo (Amorpha fruticosa), and tamarisk (Tamarix spp.). The hydrophyte purple loosestrife (Lythrum salicaria) was also restricted to the upstream zone. These longitudinal patterns indicate that the reservoirs have impeded the downstream expansion of riparian weeds, and this may especially result from the repetitive draw-down and refilling of Brownlee Reservoir that imposes a lethal combination of drought and flood stress. The dams and

A systems biology approach for elucidating the interaction of curcumin with Fanconi anemia FANC G protein and the key disease targets of leukemia.

PubMed

Mahato, David; Samanta, Dipayan; Mukhopadhyay, Sudit S; Krishnaraj, R Navanietha

2017-06-01

Fanconi anemia (FA) is an autosomal recessive disorder with a high risk of malignancies including acute myeloid leukemia and squamous cell carcinoma. There is a constant search out of new potential therapeutic molecule to combat this disorder. In most cases, patients with FA develop haematological malignancies with acute myeloid leukemia and acute lymphoblastic leukemia. Identifying drugs which can efficiently block the pathways of both these disorders can be an ideal and novel strategy to treat FA. The curcumin, a natural compound obtained from turmeric is an interesting therapeutic molecule as it has been reported in the literature to combat both FA as well as leukemia. However, its complete mechanism is not elucidated. Herein, a systems biology approach for elucidating the therapeutic potential of curcumin against FA and leukemia is investigated by analyzing the computational molecular interactions of curcumin ligand with FANC G of FA and seven other key disease targets of leukemia. The proteins namely DOT1L, farnesyl transferase (FDPS), histone decetylase (EP3000), Polo-like kinase (PLK-2), aurora-like kinase (AUKRB), tyrosine kinase (ABL1), and retinoic acid receptor alpha (RARA) were chosen as disease targets for leukemia and modeled structure of FANC G protein as the disease target for FA. The docking investigations showed that curcumin had a very high binding affinity of -8.1 kcal/mol with FANC G protein. The key disease targets of leukemia namely tyrosine kinase (ABL1), aurora-like kinase (AUKRB), and polo-like kinase (PLK-2) showed that they had the comparable binding affinities of -9.7 k cal/mol, -8.7 k cal/mol, and -8.6 k cal/mol, respectively with curcumin. Further, the percentage similarity scores obtained from PAM50 using EMBOSS MATCHER was shown to provide a clue to understand the structural relationships to an extent and to predict the binding affinity. This investigation shows that curcumin effectively interacts with the disease targets of both

Constriction of isolated collecting lymphatic vessels in response to acute increases in downstream pressure

PubMed Central

Scallan, Joshua P; Wolpers, John H; Davis, Michael J

2013-01-01

Collecting lymphatic vessels generate pressure to transport lymph downstream to the subclavian vein against a significant pressure head. To investigate their response to elevated downstream pressure, collecting lymphatic vessels containing one valve (incomplete lymphangion) or two valves (complete lymphangion) were isolated from the rat mesentery and tied to glass cannulae capable of independent pressure control. Downstream pressure was selectively raised to various levels, either stepwise or ramp-wise, while keeping upstream pressure constant. Diameter and valve positions were tracked under video microscopy, while intralymphangion pressure was measured concurrently with a servo-null micropipette. Surprisingly, a potent lymphatic constriction occurred in response to the downstream pressure gradient due to (1) a pressure-dependent myogenic constriction and (2) a frequency-dependent decrease in diastolic diameter. The myogenic index of the lymphatic constriction (−3.3 ± 0.6, in mmHg) was greater than that of arterioles or collecting lymphatic vessels exposed to uniform increases in pressure (i.e. upstream and downstream pressures raised together). Additionally, the constriction was transmitted to the upstream lymphatic vessel segment even though it was protected from changes in pressure by a closed intraluminal valve; the conducted constriction was blocked by loading only the pressurized half of the vessel with either ML-7 (0.5 mm) to block contraction, or cromakalim (3 μm) to hyperpolarize the downstream muscle layer. Finally, we provide evidence that the lymphatic constriction is important to maintain normal intraluminal valve closure during each contraction cycle in the face of an adverse pressure gradient, which probably protects the lymphatic capillaries from lymph backflow. PMID:23045335

Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations

PubMed Central

LoPiccolo, Jaclyn; Blumenthal, Gideon M.; Bernstein, Wendy B.; Dennis, Phillip A.

2008-01-01

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection. PMID:18166498

Headwater Influences on Downstream Water Quality

PubMed Central

Oakes, Robert M.

2007-01-01

We investigated the influence of riparian and whole watershed land use as a function of stream size on surface water chemistry and assessed regional variation in these relationships. Sixty-eight watersheds in four level III U.S. EPA ecoregions in eastern Kansas were selected as study sites. Riparian land cover and watershed land use were quantified for the entire watershed, and by Strahler order. Multiple regression analyses using riparian land cover classifications as independent variables explained among-site variation in water chemistry parameters, particularly total nitrogen (41%), nitrate (61%), and total phosphorus (63%) concentrations. Whole watershed land use explained slightly less variance, but riparian and whole watershed land use were so tightly correlated that it was difficult to separate their effects. Water chemistry parameters sampled in downstream reaches were most closely correlated with riparian land cover adjacent to the smallest (first-order) streams of watersheds or land use in the entire watershed, with riparian zones immediately upstream of sampling sites offering less explanatory power as stream size increased. Interestingly, headwater effects were evident even at times when these small streams were unlikely to be flowing. Relationships were similar among ecoregions, indicating that land use characteristics were most responsible for water quality variation among watersheds. These findings suggest that nonpoint pollution control strategies should consider the influence of small upland streams and protection of downstream riparian zones alone is not sufficient to protect water quality. PMID:17999108

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

Neurospora crassa transcriptomics reveals oxidative stress and plasma membrane homeostasis biology genes as key targets in response to chitosan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lopez-Moya, Federico; Kowbel, David; Nueda, Ma Jose

Chitosan is a natural polymer with antimicrobial activity. Chitosan causes plasma membrane permeabilization and induction of intracellular reactive oxygen species (ROS) in Neurospora crassa. In this paper, we have determined the transcriptional profile of N. crassa to chitosan and identified the main gene targets involved in the cellular response to this compound. Global network analyses showed membrane, transport and oxidoreductase activity as key nodes affected by chitosan. Activation of oxidative metabolism indicates the importance of ROS and cell energy together with plasma membrane homeostasis in N. crassa response to chitosan. Deletion strain analysis of chitosan susceptibility pointed NCU03639 encoding amore » class 3 lipase, involved in plasma membrane repair by lipid replacement, and NCU04537 a MFS monosaccharide transporter related to assimilation of simple sugars, as main gene targets of chitosan. NCU10521, a glutathione S-transferase-4 involved in the generation of reducing power for scavenging intracellular ROS is also a determinant chitosan gene target. Ca 2+ increased tolerance to chitosan in N. crassa. Growth of NCU10610 (fig 1 domain) and SYT1 (a synaptotagmin) deletion strains was significantly increased by Ca 2+ in the presence of chitosan. Both genes play a determinant role in N. crassa membrane homeostasis. Finally, our results are of paramount importance for developing chitosan as an antifungal.« less

Neurospora crassa transcriptomics reveals oxidative stress and plasma membrane homeostasis biology genes as key targets in response to chitosan

DOE PAGES

Lopez-Moya, Federico; Kowbel, David; Nueda, Ma Jose; ...

2015-12-01

Chitosan is a natural polymer with antimicrobial activity. Chitosan causes plasma membrane permeabilization and induction of intracellular reactive oxygen species (ROS) in Neurospora crassa. In this paper, we have determined the transcriptional profile of N. crassa to chitosan and identified the main gene targets involved in the cellular response to this compound. Global network analyses showed membrane, transport and oxidoreductase activity as key nodes affected by chitosan. Activation of oxidative metabolism indicates the importance of ROS and cell energy together with plasma membrane homeostasis in N. crassa response to chitosan. Deletion strain analysis of chitosan susceptibility pointed NCU03639 encoding amore » class 3 lipase, involved in plasma membrane repair by lipid replacement, and NCU04537 a MFS monosaccharide transporter related to assimilation of simple sugars, as main gene targets of chitosan. NCU10521, a glutathione S-transferase-4 involved in the generation of reducing power for scavenging intracellular ROS is also a determinant chitosan gene target. Ca 2+ increased tolerance to chitosan in N. crassa. Growth of NCU10610 (fig 1 domain) and SYT1 (a synaptotagmin) deletion strains was significantly increased by Ca 2+ in the presence of chitosan. Both genes play a determinant role in N. crassa membrane homeostasis. Finally, our results are of paramount importance for developing chitosan as an antifungal.« less

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

PubMed

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.

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

Experiments on tip vortices interacting with downstream wings

NASA Astrophysics Data System (ADS)

Chen, C.; Wang, Z.; Gursul, I.

2018-05-01

The interaction of meandering tip vortices shed from a leading wing with a downstream wing was investigated experimentally in a water tunnel using flow visualization, particle image velocimetry measurements, and volumetric velocity measurements. Counter-rotating upstream vortices may exhibit sudden variations of the vortex core location when the wing-tip separation is within approximately twice the vortex core radius. This is caused by the formation of vortex dipoles near the wing tip. In contrast, co-rotating upstream vortices do not exhibit such sensitivity. Large spanwise displacement of the trajectory due to the image vortex is possible when the incident vortex is further inboard. For both co-rotating and counter-rotating vortices, as long as there is no direct impingement upon the wing, there is a little change in the structure of the time-averaged vortex past the wing, even though the tip vortex shed from the downstream wing may be substantially weakened or strengthened. In the absence of the downstream wing, as well as for weak interactions, the most energetic unsteady modes represent the first helical mode | m| = 1, which is estimated from the three-dimensional Proper Orthogonal Decomposition modes and has a very large wavelength, on the order of 102 times the vortex core radius, λ/ a = O(102). Instantaneous vorticity measurements as well as flow visualization suggest the existence of a smaller wavelength, λ/ a = 5-6, which is not among the most energetic modes. These two-orders of magnitude different wavelengths are in agreement with the previous measurements of tip vortices and also exhibit qualitative agreement with the transient energy growth analysis. The very long wavelength mode in the upstream vortex may persist during the interaction, and reveal coupling with the trailing vortex as well as increased meandering.

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.

Downstream movement of fish in a tributary of southern Lake Superior

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manion, P.J.

1977-01-01

The influence of two environmental factors, stream flow and water temperature, on the downstream movement of four fish species in the Big Garlic River over a 12-yr period is described. Brook trout (Salvelinus fontinalis) migrated after floods had subsided in the spring and during rising water in the fall at temperatures of about 10/sup 0/C. Brook sticklebacks (Culaea inconstans) moved downstream chiefly in winter. Mottled sculpins (Cottus bairdi) moved primarily in the winter and during floods. Yellow perch (Perca flavescens) appeared to move generally in the fall as water levels increased and water temperatures decreased.

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

The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: the Caerphilly Study.

PubMed

Patterson, Christopher C; Smith, Anne E; Yarnell, John W G; Rumley, Ann; Ben-Shlomo, Yoav; Lowe, Gordon D O

2010-04-01

Interleukin-6 (IL-6) is a key pro-inflammatory cytokine which mediates expression of several 'downstream' inflammatory markers and may play a role in atherothrombosis. However, it is not yet known whether IL-6 plays a role in mediating the associations of each marker with risk of coronary heart disease (CHD) or ischaemic stroke (IS). We examined the role of IL-6 and several "downstream" markers of inflammation (leucocyte counts, plasma and serum viscosity, fibrinogen, C-reactive protein, alpha1-antitrypsin and alpha2-macroglobulin) with risk of subsequent CHD, IS, and a combined endpoint (CHD/IS) in a population of British men. 2208 men aged 45-64 years were followed for a median of 13.4 years and 486 men had experienced a cardiovascular event. In age-adjusted analyses, most inflammatory markers were significantly associated with risk of CHD or CHD/IS, but for IS associations were weaker. On multivariable analyses, including conventional risk factors, associations of serum viscosity, alpha2-macroglobulin and leucocyte count became non-significant for CHD and CHD/IS, while no inflammatory marker retained a significant association with risk of IS. In contrast, IL-6 retained a significant association with CHD and CHD/IS and, after adjustment for IL-6, hazard ratios for downstream inflammatory markers were attenuated to non-significance. These findings suggest that IL-6 may play a role in mediating the associations of circulating inflammatory markers with risk of CHD in men. Further studies are required to assess whether this is also the case for risk of IS, and for CHD/IS in women. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

A biochemical approach to identifying microRNA targets

PubMed Central

Karginov, Fedor V.; Conaco, Cecilia; Xuan, Zhenyu; Schmidt, Bryan H.; Parker, Joel S.; Mandel, Gail; Hannon, Gregory J.

2007-01-01

Identifying the downstream targets of microRNAs (miRNAs) is essential to understanding cellular regulatory networks. We devised a direct biochemical method for miRNA target discovery that combined RNA-induced silencing complex (RISC) purification with microarray analysis of bound mRNAs. Because targets of miR-124a have been analyzed, we chose it as our model. We honed our approach both by examining the determinants of stable binding between RISC and synthetic target RNAs in vitro and by determining the dependency of both repression and RISC coimmunoprecipitation on miR-124a seed sites in two of its well characterized targets in vivo. Examining the complete spectrum of miR-124 targets in 293 cells yielded both a set that were down-regulated at the mRNA level, as previously observed, and a set whose mRNA levels were unaffected by miR-124a. Reporter assays validated both classes, extending the spectrum of mRNA targets that can be experimentally linked to the miRNA pathway. PMID:18042700

Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets

PubMed Central

Arango, Daniel; Morohashi, Kengo; Yilmaz, Alper; Kuramochi, Kouji; Parihar, Arti; Brahimaj, Bledi; Grotewold, Erich; Doseff, Andrea I.

2013-01-01

Flavonoids constitute the largest class of dietary phytochemicals, adding essential health value to our diet, and are emerging as key nutraceuticals. Cellular targets for dietary phytochemicals remain largely unknown, posing significant challenges for the regulation of dietary supplements and the understanding of how nutraceuticals provide health value. Here, we describe the identification of human cellular targets of apigenin, a flavonoid abundantly present in fruits and vegetables, using an innovative high-throughput approach that combines phage display with second generation sequencing. The 160 identified high-confidence candidate apigenin targets are significantly enriched in three main functional categories: GTPase activation, membrane transport, and mRNA metabolism/alternative splicing. This last category includes the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2), a factor involved in splicing regulation, mRNA stability, and mRNA transport. Apigenin binds to the C-terminal glycine-rich domain of hnRNPA2, preventing hnRNPA2 from forming homodimers, and therefore, it perturbs the alternative splicing of several human hnRNPA2 targets. Our results provide a framework to understand how dietary phytochemicals exert their actions by binding to many functionally diverse cellular targets. In turn, some of them may modulate the activity of a large number of downstream genes, which is exemplified here by the effects of apigenin on the alternative splicing activity of hnRNPA2. Hence, in contrast to small-molecule pharmaceuticals designed for defined target specificity, dietary phytochemicals affect a large number of cellular targets with varied affinities that, combined, result in their recognized health benefits. PMID:23697369

Integrated landscape-based approach of remote sensing, GIS, and physical modelling to study the hydrological connectivity of wetlands to the downstream water: progress and challenge

NASA Astrophysics Data System (ADS)

Yeo, I. Y.

2015-12-01

We report the recent progress on our effort to improve the mapping of wetland dynamics and the modelling of its functioning and hydrological connection to the downstream waters. Our study focused on the Coastal Plain of the Chesapeake Bay Watershed (CBW), the Delmarva Peninsula, where the most of wetlands in CBW are densely distributed. The wetland ecosystem plays crucial roles in improving water quality and ecological integrity for the downstream waters and the Chesapeake Bay, and headwater wetlands in the region, such as Delmarva Bay, are now subject to the legal protection under the Clean Water Rules. We developed new wetland maps using time series Landsat images and a highly accurate LiDAR map over last 30 years. These maps show the changes in surface water fraction at a 30-m grid cell at annual time scale. Using GIS, we analyse these maps to characterize changing dynamics of wetland inundation due to the physical environmental factors (e.g., weather variability, tide) and assessed the hydrological connection of wetlands to the downstream water at the watershed scale. Focusing on the two adjacent watersheds in the upper region of the Choptank River Basin, we study how wetland inundation dynamics and the hydrologic linkage of wetlands to downstream water would vary by the local hydrogeological setting and attempt to identify the key landscape factors affecting the wetland ecosystems and functioning. We then discuss the potential of using remote sensing products to improve the physical modelling of wetlands from our experience with SWAT (Soil and Water Assessment Tool).

Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neo-Vascularization

PubMed Central

Dubrac, Alexandre; Genet, Gael; Ola, Roxana; Zhang, Feng; Pibouin-Fragner, Laurence; Han, Jinah; Zhang, Jiasheng; Thomas, Jean-Léon; Chedotal, Alain; Schwartz, Martin A.; Eichmann, Anne

2015-01-01

Background Sprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2. Methods and Results Mice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2 and VEGF induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, as well as pathological ocular neovascularization and wound healing. Conclusions These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2 and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis. PMID:26659946

Toxicity assessment of sediments collected upstream and downstream from the White Dam in Clarke County, Georgia

USGS Publications Warehouse

Lasier, Peter J.

2018-06-06

The White Dam in Clarke County, Georgia, has been proposed for breaching. Efforts to determine potential risks to downstream biota included assessments of sediment collected in the vicinity of the dam. Sediments collected from sites upstream and downstream from the dam were evaluated for toxicity in 42-day exposures using the freshwater amphipod Hyalella azteca. Endpoints of the study were survival, growth, and reproduction of H. azteca. Results indicated no significant differences between the collected sediments and the water-only treatment used for comparison of the test endpoints. Therefore, based on the laboratory experiments in this study, sediment migration downstream from a breach of the Dam may not pose a toxicity risk to downstream biota.

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

Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames.

PubMed

Liang, Xue-Hai; Shen, Wen; Crooke, Stanley T

2017-01-01

A number of diseases are caused by low levels of key proteins; therefore, increasing the amount of specific proteins in human bodies is of therapeutic interest. Protein expression is downregulated by some structural or sequence elements present in the 5' UTR of mRNAs, such as upstream open reading frames (uORF). Translation initiation from uORF(s) reduces translation from the downstream primary ORF encoding the main protein product in the same mRNA, leading to a less efficient protein expression. Therefore, it is possible to use antisense oligonucleotides (ASOs) to specifically inhibit translation of the uORF by base-pairing with the uAUG region of the mRNA, redirecting translation machinery to initiate from the primary AUG site. Here we review the recent findings that translation of specific mRNAs can be enhanced using ASOs targeting uORF regions. Appropriately designed and optimized ASOs are highly specific, and they act in a sequence- and position-dependent manner, with very minor off-target effects. Protein levels can be increased using this approach in different types of human and mouse cells, and, importantly, also in mice. Since uORFs are present in around half of human mRNAs, the uORF-targeting ASOs may thus have valuable potential as research tools and as therapeutics to increase the levels of proteins for a variety of genes.

1. STONE BRIDGE, LOOKING EAST DOWNSTREAM Photocopy of photograph, summer ...

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

1. STONE BRIDGE, LOOKING EAST DOWNSTREAM Photocopy of photograph, summer 1932 National Park Service, National Capital Region files - Dumbarton Oaks Park, Thirty-second & R Streets Northwest, Washington, District of Columbia, DC

Bioassays with caged hyalella azteca to determine in situ toxicity downstream of two Saskatchewan, Canada, uranium operations.

PubMed

Robertson, Erin L; Liber, Karsten

2007-11-01

The main objectives of this in situ study were to evaluate the usefulness of an in situ bioassay to determine if downstream water bodies at the Key Lake and Rabbit Lake uranium operations (Saskatchewan, Canada) were toxic to Hyalella azteca and, if toxicity was observed, to differentiate between the contribution of surface water and sediment contamination to in situ toxicity. These objectives were achieved by performing 4-d in situ bioassays with laboratory-reared H. azteca confined in specially designed, paired, surface water and sediment exposure chambers. Results from the in situ bioassays revealed significant mortality, relative to the respective reference site, at the exposure sites at both Key Lake (p Key Lake (p = 0.232) or Rabbit Lake (p = 0.072). This suggests that surface water (the common feature of both types of exposure chambers) was the primary cause of in situ mortality of H. azteca at both operations, although this relationship was stronger at Key Lake. At Key Lake, the primary cause of aquatic toxicity to H. azteca did not appear to be correlated with the variables measured in this study, but most likely with a pulse of organic mill-process chemicals released during the time of the in situ study-a transient event that was caused by a problem with the mill's solvent extraction process. The suspected cause of in situ toxicity to H. azteca at Rabbit Lake was high levels of uranium in surface water, sediment, and pore water.

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

71. photographer unknown 9 September 1935 DOWNSTREAM SIDE OF POWERHOUSE ...

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

71. photographer unknown 9 September 1935 DOWNSTREAM SIDE OF POWERHOUSE SUBSTRUCTURE, SHOWING FISHWAY AND DRAFT TUBE OUTLETS. - Bonneville Project, Powerhouse No.1, Spanning Bradford Slough, from Bradford Island, Bonneville, Multnomah County, OR

16. DOWNSTREAM VIEW OF OUTLET STRUCTURE AND OUTLET CHANNEL, FROM ...

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

16. DOWNSTREAM VIEW OF OUTLET STRUCTURE AND OUTLET CHANNEL, FROM WEST END OF EMBANKMENT. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

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

Dissection of Signaling Events Downstream of the c-Mpl Receptor in Murine Hematopoietic Stem Cells Via Motif-Engineered Chimeric Receptors.

PubMed

Saka, Koichiro; Lai, Chen-Yi; Nojima, Masanori; Kawahara, Masahiro; Otsu, Makoto; Nakauchi, Hiromitsu; Nagamune, Teruyuki

2018-02-01

Hematopoietic stem cells (HSCs) are a valuable resource in transplantation medicine. Cytokines are often used to culture HSCs aiming at better clinical outcomes through enhancement of HSC reconstitution capability. Roles for each signal molecule downstream of receptors in HSCs, however, remain puzzling due to complexity of the cytokine-signaling network. Engineered receptors that are non-responsive to endogenous cytokines represent an attractive tool for dissection of signaling events. We here tested a previously developed chimeric receptor (CR) system in primary murine HSCs, target cells that are indispensable for analysis of stem cell activity. Each CR contains tyrosine motifs that enable selective activation of signal molecules located downstream of the c-Mpl receptor upon stimulation by an artificial ligand. Signaling through a control CR with a wild-type c-Mpl cytoplasmic tail sufficed to enhance HSC proliferation and colony formation in cooperation with stem cell factor (SCF). Among a series of CRs, only one compatible with selective Stat5 activation showed similar positive effects. The HSCs maintained ex vivo in these environments retained long-term reconstitution ability following transplantation. This ability was also demonstrated in secondary recipients, indicating effective transmission of stem cell-supportive signals into HSCs via these artificial CRs during culture. Selective activation of Stat5 through CR ex vivo favored preservation of lymphoid potential in long-term reconstituting HSCs, but not of myeloid potential, exemplifying possible dissection of signals downstream of c-Mpl. These CR systems therefore offer a useful tool to scrutinize complex signaling pathways in HSCs.

Comparison of pitot traverses taken at varying distances downstream of obstructions.

PubMed

Guffey, S E; Booth, D W

1999-01-01

This study determined the deviations between pitot traverses taken under "ideal" conditions--at least seven duct diameter's lengths (i.e., distance = 7D) from obstructions, elbows, junction fittings, and other disturbances to flows--with those taken downstream from commonplace disturbances. Two perpendicular 10-point, log-linear velocity pressure traverses were taken at various distances downstream of tested upstream conditions. Upstream conditions included a plain duct opening, a junction fitting, a single 90 degrees elbow, and two elbows rotated 90 degrees from each other into two orthogonal planes. Airflows determined from those values were compared with the values measured more than 40D downstream of the same obstructions under ideal conditions. The ideal measurements were taken on three traverse diameters in the same plane separated by 120 degrees in honed drawn-over-mandrel tubing. In all cases the pitot tubes were held in place by devices that effectively eliminated alignment errors and insertion depth errors. Duct velocities ranged from 1500 to 4500 ft/min. Results were surprisingly good if one employed two perpendicular traverses. When the averages of two perpendicular traverses was taken, deviations from ideal value were 6% or less even for traverses taken as close as 2D distance from the upstream disturbances. At 3D distance, deviations seldom exceeded 5%. With single diameter traverses, errors seldom exceeded 5% at 6D or more downstream from the disturbance. Interestingly, percentage deviations were about the same at high and low velocities. This study demonstrated that two perpendicular pitot traverses can be taken as close as 3D from these disturbances with acceptable (< or = 5%) deviations from measurements taken under ideal conditions.

Thailand's downstream projects proliferate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1991-06-03

Thailand continues to press expansion and modernization of its downstream sector. Among recent developments: Construction of an olefins unit at Thailand's second major petrochemical complex and a worldscale aromatics unit in Thailand is threatened by rising costs. Thailand's National Petrochemical Corp (NPC) let a 9 billion yen contract to Mitsui Engineering and Shipbuilding Co. and C. Itoh and Co. for a dual fuel cogeneration power plant at its Mab Ta Phud, Rayong province, petrochemical complex. Financing is in place to flash a green light for a $530 million Belgian-Thai joint venture sponsoring a worldscale polyvinyl chloride/vinyl chloride monomer plant inmore » Thailand. Work is more than 50% complete on the $345 million second phase expansion of Thai Oil's Sri Racha refinery in Chon Buri province. Petroleum Authority of Thailand (PTT) endorsed a plan to install two more natural gas processing plants in Thailand to meet rapidly growing domestic demand for petroleum gas.« less

Streamflow gain-loss characteristics of Elkhead Creek downstream from Elkhead Reservoir near Craig, Colorado, 2009

USGS Publications Warehouse

Ruddy, Barbara C.

2010-01-01

The U.S. Geological Survey (USGS), in cooperation with the Colorado Water Conservation Board, the Upper Colorado River Endangered Fish Recovery Program (UCREFRP), Colorado Division of Water Resources, and City of Craig studied the gain-loss characteristics of Elkhead Creek downstream from Elkhead Reservoir to the confluence with the Yampa River during August through October 2009. Earlier qualitative interpretation of streamflow data downstream from the reservoir indicated that there could be a transit loss of nearly 10 percent. This potential loss could be a significant portion of the releases from Elkhead Reservoir requested by UCREFRP during late summer and early fall for improving critical habitat for endangered fish downstream in the Yampa River. Information on the gain-loss characteristics was needed for the effective management of the reservoir releases. In order to determine streamflow gain-loss characteristics for Elkhead Creek, eight measurement sets were made at four strategic instream sites and at one diversion from August to early October 2009. An additional measurement set was made after the study period during low-flow conditions in November 2009. Streamflow measurements were made using an Acoustic Doppler Velocimeter to provide high accuracy and consistency, especially at low flows. During this study, streamflow ranged from about 5 cubic feet per second up to more than 90 cubic feet per second with step increments in between. Measurements were made at least 24 hours after a change in reservoir release (streamflow) during steady-state conditions. The instantaneous streamflow measurements and the streamflow volume comparisons show the reach of Elkhead Creek immediately downstream from Elkhead Reservoir to the streamflow-gaging station 09246500, Elkhead Creek near Craig, CO, is neither a gaining nor losing reach. The instantaneous measurements immediately downstream from the dam and the combined measurements of Norvell ditch plus streamflow

Power Plant Bromide Discharges and Downstream Drinking Water Systems in Pennsylvania.

PubMed

Good, Kelly D; VanBriesen, Jeanne M

2017-10-17

Coal-fired power plants equipped with wet flue gas desulfurization (FGD) systems have been implicated in increasing bromide levels and subsequent increases in disinfection byproducts at downstream drinking water plants. Bromide was not included as a regulated constituent in the recent steam electric effluent limitations guidelines and standards (ELGs) since the U.S. EPA analysis suggested few drinking water facilities would be affected by bromide discharges from power plants. The present analysis uses a watershed approach to identify Pennsylvania drinking water intakes downstream of wet FGD discharges and to assess the potential for bromide discharge effects. Twenty-two (22) public drinking water systems serving 2.5 million people were identified as being downstream of at least one wet FGD discharge. During mean August conditions (generally low-flow, minimal dilution) in receiving rivers, the median predicted bromide concentrations contributed by wet FGD at Pennsylvania intake locations ranged from 5.2 to 62 μg/L for the Base scenario (including only natural bromide in coal) and from 16 to 190 μg/L for the Bromide Addition scenario (natural plus added bromide for mercury control); ranges depend on bromide loads and receiving stream dilution capacity.

Integrated development of up- and downstream processes supported by the Cherry-Tag™ for real-time tracking of stability and solubility of proteins.

PubMed

Baumann, Pascal; Bluthardt, Nicolai; Renner, Sarah; Burghardt, Hannah; Osberghaus, Anna; Hubbuch, Jürgen

2015-04-20

Product analytics is the bottleneck of most processes in bioprocess engineering, as it is rather time-consuming. Real-time and in-line product tracing without sample pre-treatment is only possible for few products. The Cherry-Tag™ (Delphi Genetics, Belgium) which can be fused to any target protein allows for straightforward product analytics by VIS absorption measurements. When the fused protein becomes unstable or insoluble, the chromophore function of the group is lost, which makes this technology an ideal screening tool for solubility and stability in up- and downstream process development. The Cherry-Tag™ technology will be presented for the tagged enzyme glutathione-S-transferase (GST) from Escherichia coli in a combined up- and downstream process development study. High-throughput cultivations were carried out in a 48-well format in a BioLector system (m2p-Labs, Germany). The best cultivation setup of highest product titer was scaled up to a 2.5L shake flask culture, followed by a selective affinity chromatography product capturing step. In upstream applications the tag was capable of identifying conditions where insoluble and non-native inclusion bodies were formed. In downstream applications the red-colored product was found to be bound effectively to a GST affinity column. Thus, it was identified to be a native and active protein, as the binding mechanism relies on catalytic activity of the enzyme. The Cherry-Tag™ was found to be a reliable and quantitative tool for real-time tracking of stable and soluble proteins in up- and downstream processing applications. Denaturation and aggregation of the product can be detected in-line at any stage of the process. Critical stages can be identified and subsequently changed or replaced. Copyright © 2015 Elsevier B.V. All rights reserved.

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

5. View from the east of the bridge's southeast (downstream) ...

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

5. View from the east of the bridge's southeast (downstream) elevation - Big Cottonwood River Bridge No. 246, Spanning Big Cottonwood River at Cottonwood Street (City Road No. 165), New Ulm, Brown County, MN

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

Identification of thioredoxin-interacting protein (TXNIP) as a downstream target for IGF1 action.

PubMed

Nagaraj, Karthik; Lapkina-Gendler, Lena; Sarfstein, Rive; Gurwitz, David; Pasmanik-Chor, Metsada; Laron, Zvi; Yakar, Shoshana; Werner, Haim

2018-01-30

Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that TXNIP gene expression is negatively regulated by IGF1. These results were corroborated in animal studies. In addition, we show that oxidative and glucose stresses led to marked increases in TXNIP expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of TXNIP Augmented TXNIP expression in LS may account for cancer protection in this condition. Finally, TXNIP levels could be potentially useful in the clinic as a predictive or diagnostic biomarker for IGF1R-targeted therapies.

Does targeting key-containers effectively reduce Aedes aegypti population density?

PubMed

Maciel-de-Freitas, Rafael; Lourenço-de-Oliveira, Ricardo

2011-08-01

The elimination of Aedes aegypti breeding sites has been broadly adopted worldwide to keep vector population density below a critical threshold. We observed the effectiveness of targeting the most productive containers on adult A. aegypti females density, which was evaluated weekly. Adult mosquitoes were collected weekly over 55 weeks and pupal surveys were done in intervals of 4 months to determine container productivity and guidelines for interventions. Pupal surveys indicated that water tanks (72% of pupae in first survey) and metal drums (30.7% of pupae in second survey) were the most productive container types. We observed a dramatic but short-term decrease in weekly adult female A. aegypti density after covering 733 water tanks with nylon net. A long-term decrease in female adult population density was achieved only when we covered both water tanks and metal drums. Overall, pupae abundance and pupae standing crop diminished after netting water tanks and metal drums. Pupae per person, per hectare and per house decreased gradually between the first and the third pupal surveys, suggesting that targeting the most productive container types (water tanks and metal drums) produced a reduction in adult population density and infestation levels. Overall, targeting the most productive container types caused the adult mosquito density to decrease over time, supporting the assumption that this intervention is an effective tool for dengue control. However, this effect was observed only when both water tanks and metal drums were covered, possibly due to the functional similarity between these container types, which are large, often shaded, perennial water storage containers. © 2011 Blackwell Publishing Ltd.

Understanding the Key to Targeting the IGF Axis in Cancer: A Biomarker Assessment

PubMed Central

Lodhia, Kunal Amratlal; Tienchaiananda, Piyawan; Haluska, Paul

2015-01-01

Type 1 insulin like growth factor receptor (IGF-1R) targeted therapies showed compelling pre-clinical evidence; however, to date, this has failed to translate into patient benefit in Phase 2/3 trials in unselected patients. This was further complicated by the toxicity, including hyperglycemia, which largely results from the overlap between IGF and insulin signaling systems and associated feedback mechanisms. This has halted the clinical development of inhibitors targeting IGF signaling, which has limited the availability of biopsy samples for correlative studies to understand biomarkers of response. Indeed, a major factor contributing to lack of clinical benefit of IGF targeting agents has been difficulty in identifying patients with tumors driven by IGF signaling due to the lack of predictive biomarkers. In this review, we will describe the IGF system, rationale for targeting IGF signaling, the potential liabilities of targeting strategies, and potential biomarkers that may improve success. PMID:26217584

Energy-saving scheme based on downstream packet scheduling in ethernet passive optical networks

NASA Astrophysics Data System (ADS)

Zhang, Lincong; Liu, Yejun; Guo, Lei; Gong, Xiaoxue

2013-03-01

With increasing network sizes, the energy consumption of Passive Optical Networks (PONs) has grown significantly. Therefore, it is important to design effective energy-saving schemes in PONs. Generally, energy-saving schemes have focused on sleeping the low-loaded Optical Network Units (ONUs), which tends to bring large packet delays. Further, the traditional ONU sleep modes are not capable of sleeping the transmitter and receiver independently, though they are not required to transmit or receive packets. Clearly, this approach contributes to wasted energy. Thus, in this paper, we propose an Energy-Saving scheme that is based on downstream Packet Scheduling (ESPS) in Ethernet PON (EPON). First, we design both an algorithm and a rule for downstream packet scheduling at the inter- and intra-ONU levels, respectively, to reduce the downstream packet delay. After that, we propose a hybrid sleep mode that contains not only ONU deep sleep mode but also independent sleep modes for the transmitter and the receiver. This ensures that the energy consumed by the ONUs is minimal. To realize the hybrid sleep mode, a modified GATE control message is designed that involves 10 time points for sleep processes. In ESPS, the 10 time points are calculated according to the allocated bandwidths in both the upstream and the downstream. The simulation results show that ESPS outperforms traditional Upstream Centric Scheduling (UCS) scheme in terms of energy consumption and the average delay for both real-time and non-real-time packets downstream. The simulation results also show that the average energy consumption of each ONU in larger-sized networks is less than that in smaller-sized networks; hence, our ESPS is better suited for larger-sized networks.

3. View to southwest. Oblique view of downstream side of ...

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

3. View to southwest. Oblique view of downstream side of bridge and west pier. (135mm lens) - South Fork Trinity River Bridge, State Highway 299 spanning South Fork Trinity River, Salyer, Trinity County, CA

2. View to east. Oblique view of downstream side of ...

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

2. View to east. Oblique view of downstream side of bridge and east pier. (135mm lens) - South Fork Trinity River Bridge, State Highway 299 spanning South Fork Trinity River, Salyer, Trinity County, CA

Do insect repellents induce drift behaviour in aquatic non-target organisms?

PubMed

Fink, Patrick; Moelzner, Jana; Berghahn, Ruediger; von Elert, Eric

2017-01-01

Synthetic insect repellents are compounds applied to surfaces to discourage insects, mainly mosquitoes, from landing on those surfaces. As some of these repellents have repeatedly been detected in surface waters at significant concentrations, they may also exert repellent effects on aquatic non-target organisms. In running water systems, aquatic invertebrates actively enter downstream drift in order to avoid unfavourable environmental conditions. We thus tested the hypothesis that the widely used insect repellents DEET (N,N-Diethyl-m-toluamide), EBAAP (3-[N-butyl-N-acetyl]-aminopropionic acid ethyl ester) and Icaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropyl ester) induce downstream drift behaviour in the aquatic invertebrates Gammarus pulex (Crustacea, Amphipoda) and Cloeon dipterum (Insecta, Ephemeroptera), using a laboratory-scale drift assay. We found no clear increase in the drift behaviour of both invertebrate species across a concentration gradient of eight orders of magnitude and even beyond maximum environmental concentrations for any of the three repellents. We found no evidence for a direct drift-inducing activity of insect repellents on aquatic non-target organisms. Copyright © 2016 Elsevier Ltd. All rights reserved.

LOOKING EASTSOUTHEAST. Showing downstream side of completed bridge, from confluence ...

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

LOOKING EAST-SOUTHEAST. Showing downstream side of completed bridge, from confluence of Trinity and South Fork Trinity Rivers - South Fork Trinity River Bridge, State Highway 299 spanning South Fork Trinity River, Salyer, Trinity County, CA

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

4. DETAIL VIEW OF CCCBUILT RIVERCOBBLE WING WALL ON DOWNSTREAM ...

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

4. DETAIL VIEW OF CCC-BUILT RIVER-COBBLE WING WALL ON DOWNSTREAM SIDE OF OUTLET WORKS AT DAM 87, LOOKING WEST - Upper Souris National Wildlife Refuge, Dam 87, Souris River Basin, Foxholm, Surrey (England), ND

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

An Arabidopsis mutation in translation elongation factor 2 causes superinduction of CBF/DREB1 transcription factor genes but blocks the induction of their downstream targets under low temperatures.

PubMed

Guo, Yan; Xiong, Liming; Ishitani, Manabu; Zhu, Jian-Kang

2002-05-28

Low temperature regulates gene expression in bacteria, yeast, and animals as well as in plants. However, the signal transduction cascades mediating the low temperature responses are not well understood in any organism. To identify components in low temperature signaling genetically, we isolated Arabidopsis thaliana mutants in which cold-responsive genes are no longer induced by low temperatures. One of these mutations, los1-1, specifically blocks low temperature-induced transcription of cold-responsive genes. Surprisingly, cold-induced expression of the early response transcriptional activators, C-repeat/dehydration responsive element binding factors (CBF/DREB1s), is enhanced by the los1-1 mutation. The los1-1 mutation also reduces the capacity of plants to develop freezing tolerance but does not impair the vernalization response. Genetic analysis indicated that los1-1 is a recessive mutation in a single nuclear gene. The LOS1 gene encodes a translation elongation factor 2-like protein. Protein labeling studies show that new protein synthesis is blocked in los1-1 mutant plants specifically in the cold. These results reveal a critical role of new protein synthesis in the proper transduction of low temperature signals. Our results also suggest that cold-induced transcription of CBF/DREB1s is feedback inhibited by their gene products or by products of their downstream target genes.

An Arabidopsis mutation in translation elongation factor 2 causes superinduction of CBF/DREB1 transcription factor genes but blocks the induction of their downstream targets under low temperatures

PubMed Central

Guo, Yan; Xiong, Liming; Ishitani, Manabu; Zhu, Jian-Kang

2002-01-01

Low temperature regulates gene expression in bacteria, yeast, and animals as well as in plants. However, the signal transduction cascades mediating the low temperature responses are not well understood in any organism. To identify components in low temperature signaling genetically, we isolated Arabidopsis thaliana mutants in which cold-responsive genes are no longer induced by low temperatures. One of these mutations, los1–1, specifically blocks low temperature-induced transcription of cold-responsive genes. Surprisingly, cold-induced expression of the early response transcriptional activators, C-repeat/dehydration responsive element binding factors (CBF/DREB1s), is enhanced by the los1–1 mutation. The los1–1 mutation also reduces the capacity of plants to develop freezing tolerance but does not impair the vernalization response. Genetic analysis indicated that los1–1 is a recessive mutation in a single nuclear gene. The LOS1 gene encodes a translation elongation factor 2-like protein. Protein labeling studies show that new protein synthesis is blocked in los1–1 mutant plants specifically in the cold. These results reveal a critical role of new protein synthesis in the proper transduction of low temperature signals. Our results also suggest that cold-induced transcription of CBF/DREB1s is feedback inhibited by their gene products or by products of their downstream target genes. PMID:12032361

Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer.

PubMed

Wei, Shuo; Kozono, Shingo; Kats, Lev; Nechama, Morris; Li, Wenzong; Guarnerio, Jlenia; Luo, Manli; You, Mi-Hyeon; Yao, Yandan; Kondo, Asami; Hu, Hai; Bozkurt, Gunes; Moerke, Nathan J; Cao, Shugeng; Reschke, Markus; Chen, Chun-Hau; Rego, Eduardo M; Lo-Coco, Francesco; Cantley, Lewis C; Lee, Tae Ho; Wu, Hao; Zhang, Yan; Pandolfi, Pier Paolo; Zhou, Xiao Zhen; Lu, Kun Ping

2015-05-01

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.

Global preamplification simplifies targeted mRNA quantification

PubMed Central

Kroneis, Thomas; Jonasson, Emma; Andersson, Daniel; Dolatabadi, Soheila; Ståhlberg, Anders

2017-01-01

The need to perform gene expression profiling using next generation sequencing and quantitative real-time PCR (qPCR) on small sample sizes and single cells is rapidly expanding. However, to analyse few molecules, preamplification is required. Here, we studied global and target-specific preamplification using 96 optimised qPCR assays. To evaluate the preamplification strategies, we monitored the reactions in real-time using SYBR Green I detection chemistry followed by melting curve analysis. Next, we compared yield and reproducibility of global preamplification to that of target-specific preamplification by qPCR using the same amount of total RNA. Global preamplification generated 9.3-fold lower yield and 1.6-fold lower reproducibility than target-specific preamplification. However, the performance of global preamplification is sufficient for most downstream applications and offers several advantages over target-specific preamplification. To demonstrate the potential of global preamplification we analysed the expression of 15 genes in 60 single cells. In conclusion, we show that global preamplification simplifies targeted gene expression profiling of small sample sizes by a flexible workflow. We outline the pros and cons for global preamplification compared to target-specific preamplification. PMID:28332609

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

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

6. VIEW OF SHOWING DOWNSTREAM OUTLET PIPE AND COLLAR (12' ...

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

6. VIEW OF SHOWING DOWNSTREAM OUTLET PIPE AND COLLAR (12' DIAMETER CORRUGATED STEEL PIPE ENCASED IN 6' CONCRETE), LOOKING NORTH - High Mountain Dams in Bonneville Unit, Island Lake Dam, Wasatch National Forest, Kamas, Summit County, UT

24. TWIN FALLS MAIN CANAL HEADWORKS, DOWNSTREAM LOOKING TOWARD THE ...

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

24. TWIN FALLS MAIN CANAL HEADWORKS, DOWNSTREAM LOOKING TOWARD THE EAST. - Milner Dam & Main Canal: Twin Falls Canal Company, On Snake River, 11 miles West of city of Burley, Idaho, Twin Falls, Twin Falls County, ID

8. VIEW OF DOWNSTREAM OUTLET CULVERT AND WING RETAINING WALLS, ...

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

8. VIEW OF DOWNSTREAM OUTLET CULVERT AND WING RETAINING WALLS, LOOKING NORTHWEST - High Mountain Dams in Upalco Unit, Twin Pots Dam, Ashley National Forest, 10.1 miles North of Mountain Home, Mountain Home, Duchesne County, UT

Targeting FOXM1 Improves Cytotoxicity of Paclitaxel and Cisplatinum in Platinum-Resistant Ovarian Cancer.

PubMed

Westhoff, Gina L; Chen, Yi; Teng, Nelson N H

2017-10-01

Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.

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 system...

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

Code of Federal Regulations, 2014 CFR

2014-07-01

... 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 system...

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

Code of Federal Regulations, 2013 CFR

2013-07-01

... 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 system...

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

Code of Federal Regulations, 2011 CFR

2011-07-01

... 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 system...

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 refineries and importers? The sulfur standard for gasoline at any point in the gasoline distribution system...

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.

CCAAT-enhancer-binding protein β (C/EBPβ) and downstream human placental growth hormone genes are targets for dysregulation in pregnancies complicated by maternal obesity.

PubMed

Vakili, Hana; Jin, Yan; Menticoglou, Savas; Cattini, Peter A

2013-08-02

Human chorionic somatomammotropin (CS) and placental growth hormone variant (GH-V) act as metabolic adaptors in response to maternal insulin resistance, which occurs in "normal" pregnancy. Maternal obesity can exacerbate this "resistance," suggesting that CS, GH-V, or transcription factors that regulate their production might be targets. The human CS genes, hCS-A and hCS-B, flank the GH-V gene. A significant decrease in pre-term placental CS/GH-V RNA levels was observed in transgenic mice containing the CS/GH-V genes in a model of high fat diet (HFD)-induced maternal obesity. Similarly, a decrease in CS/GH-V RNA levels was detected in term placentas from obese (body mass index (BMI) ≥ 35 kg/m(2)) versus lean (BMI 20-25 kg/m(2)) women. A specific decrease in transcription factor CCAAT-enhancer-binding protein β (C/EBPβ) RNA levels was also seen with obesity; C/EBPβ is required for mouse placenta development and is expressed, like CS and GH-V, in syncytiotrophoblasts. Binding of C/EBPβ to the CS gene downstream enhancer regions, which by virtue of their position distally flank the GH-V gene, was reduced in placenta chromatin from mice on a HFD and in obese women; a corresponding decrease in RNA polymerase II associated with CS/GH-V promoters was also observed. Detection of decreased endogenous CS/GH-V RNA levels in human placental tumor cells treated with C/EBPβ siRNA is consistent with a direct effect. These data provide evidence for CS/GH-V dysregulation in acute HFD-induced obesity in mouse pregnancy and chronic obesity in human pregnancy and implicate C/EBPβ, a factor associated with CS regulation and placental development.

A Competency-Based Medical Student Curriculum Targeting Key Geriatric Syndromes

ERIC Educational Resources Information Center

van Zuilen, Maria H.; Rodriguez, Osvaldo; Mintzer, Michael J.; Paniagua, Miguel A.; Milanez, Marcos N.; Ruiz, Jorge G.; Kaiser, Robert M.; Roos, Bernard A.

2008-01-01

The University of Miami Miller School of Medicine (UMMSM) has developed and implemented a competency-based undergraduate medical education (UME) curriculum that targets 61 learning objectives for three geriattic syndromes: dementia, falls, and delirium. This curriculum redesign changed the educational focus from what is taught to what is learned.…

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development.

PubMed

Lu, Cecilia S; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-09-26

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development

PubMed Central

Lu, Cecilia S.; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-01-01

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins. PMID:25135978

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

31. VIEW OF TWIN FALLS MAIN CANAL BRIDGE FROM DOWNSTREAM ...

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

31. VIEW OF TWIN FALLS MAIN CANAL BRIDGE FROM DOWNSTREAM LOOKING UPSTREAM. - Milner Dam & Main Canal: Twin Falls Canal Company, On Snake River, 11 miles West of city of Burley, Idaho, Twin Falls, Twin Falls County, ID

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

15. DETAIL VIEW OF BUTTRESSES AND STRUTTIE BEAMS ON DOWNSTREAM ...

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

15. DETAIL VIEW OF BUTTRESSES AND STRUT-TIE BEAMS ON DOWNSTREAM SIDE OF DAM--1971 - Mountain Dell Dam, Parley's Canyon, Northwest side of I-80, West of State Route 39, Salt Lake City, Salt Lake County, UT

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

New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals.

PubMed

Qi, Jingjing; Yu, Yong; Akilli Öztürk, Özlem; Holland, Jane D; Besser, Daniel; Fritzmann, Johannes; Wulf-Goldenberg, Annika; Eckert, Klaus; Fichtner, Iduna; Birchmeier, Walter

2016-10-01

We have previously identified a 115-gene signature that characterises the metastatic potential of human primary colon cancers. The signature included the canonical Wnt target gene BAMBI, which promoted experimental metastasis in mice. Here, we identified three new direct Wnt target genes from the signature, and studied their functions in epithelial-mesenchymal transition (EMT), cell migration and experimental metastasis. We examined experimental liver metastases following injection of selected tumour cells into spleens of NOD/SCID mice. Molecular and cellular techniques were used to identify direct transcription target genes of Wnt/β-catenin signals. Microarray analyses and experiments that interfered with cell migration through inhibitors were performed to characterise downstream signalling systems. Three new genes from the colorectal cancer (CRC) metastasis signature, BOP1, CKS2 and NFIL3, were identified as direct transcription targets of β-catenin/TCF4. Overexpression and knocking down of these genes in CRC cells promoted and inhibited, respectively, experimental metastasis in mice, EMT and cell motility in culture. Cell migration was repressed by interfering with distinct signalling systems through inhibitors of PI3K, JNK, p38 mitogen-activated protein kinase and/or mTOR. Gene expression profiling identified a series of migration-promoting genes, which were induced by BOP1, CKS2 and NFIL3, and could be repressed by inhibitors that are specific to these pathways. We identified new direct Wnt/β-catenin target genes, BOP1, CKS2 and NFIL3, which induced EMT, cell migration and experimental metastasis of CRC cells. These genes crosstalk with different downstream signalling systems, and activate migration-promoting genes. These pathways and downstream genes may serve as therapeutic targets in the treatment of CRC metastasis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Ptn functions downstream of C/EBPβ to mediate the effects of cAMP on uterine stromal cell differentiation through targeting Hand2 in response to progesterone.

PubMed

Yu, Hai-Fan; Tao, Ran; Yang, Zhan-Qing; Wang, Kai; Yue, Zhan-Peng; Guo, Bin

2018-02-01

Ptn is a pleiotropic growth factor involving in the regulation of cellular proliferation and differentiation, but its biological function in uterine decidualization remains unknown. Here, we showed that Ptn was highly expressed in the decidual cells, and could induce the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1 which were two well-established differentiation markers for decidualization, suggesting an important role of Ptn in decidualization. In the uterine stromal cells, progesterone stimulated the expression of Ptn accompanied with an accumulation of intracellular cAMP level. Silencing of Ptn impeded the induction of progesterone and cAMP on the differentiation of uterine stromal cells. Administration of PKA inhibitor H89 resulted in a blockage of progesterone on Ptn expression. Further analysis evidenced that regulation of progesterone and cAMP on Ptn was mediated by C/EBPβ. During in vitro decidualization, knockdown of Ptn could weaken the up-regulation of Prl8a2 and Prl3c1 elicited by C/EBPβ overexpression, while constitutive activation of Ptn reversed the repressive effects of C/EBPβ siRNA on the expression of Prl8a2 and Prl3c1. Meanwhile, Ptn might mediate the regulation of C/EBPβ on Hand2 which was a downstream target of Ptn in the differentiation of uterine stromal cells. Attenuation of Ptn or C/EBPβ by specific siRNA blocked the stimulation of Hand2 by progesterone and cAMP. Collectively, Ptn may play a vital role in the progesterone-induced decidualization pathway. © 2017 Wiley Periodicals, Inc.

Scaling-up HIV responses with key populations in West Africa.

PubMed

Wheeler, Tisha; Wolf, R Cameron; Kapesa, Laurent; Cheng Surdo, Alison; Dallabetta, Gina

2015-03-01

Despite decades of HIV responses in pockets of West and Central Africa (WCA), the HIV response with key populations remains an understudied area. Recently, there has been a proliferation of studies highlighting epidemiologic and behavioral data that challenge attitudes of complacency among donors and country governments uncomfortable in addressing key populations. The articles in this series highlight new studies that provide a better understanding of the epidemiologic and structural burden facing key populations in the WCA region and how to improve responses through more effective targeting. Key populations face pervasive structural barriers including institutional and sexual violence and an intersection of stigma, criminalization, and marginalization as sexual minorities. Despite decades of smaller interventions that have shown the importance of integrated services for key populations, there remains incongruent provision of outreach or testing or family planning pointing to sustained risk. There remains an incongruent resource provision for key populations where they shoulder the burden of HIV and their access to services alone could turn around HIV epidemics within the region. These proximal and distal determinants must be addressed in regional efforts, led by the community, and resourced for scale, targeting those most at risk for the acquisition and transmission of HIV. This special issue builds the knowledge base for the region focusing on interventions that remove barriers to service access including treatment uptake for those living with HIV. Better analysis and use of data for strategic planning are shown to lead to more effective targeting of prevention, care, and HIV treatment programs with key populations. These articles further demonstrate the immediate need for comprehensive action to address HIV among key populations throughout the WCA region.

COMPLETED STRUCTURE. View is eastsoutheast of downstream side of bridge, ...

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

COMPLETED STRUCTURE. View is east-southeast of downstream side of bridge, from beyond confluence of Trinity and South Fork Trinity Rivers - South Fork Trinity River Bridge, State Highway 299 spanning South Fork Trinity River, Salyer, Trinity County, CA

9. A CLOSEUP VIEW LOOKING NORTH OF THE DOWNSTREAM SIDE ...

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

9. A CLOSE-UP VIEW LOOKING NORTH OF THE DOWNSTREAM SIDE OF PIER. ALSO VISIBLE IS THE NORTHWEST ABUTMENT AND WING WALL. - Cement Plant Road Bridge, Spanning Leatherwood Creek on County Road 50 South, Bedford, Lawrence County, IN

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

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

PubMed

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

2010-02-01

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

Targeting the eIF4F translation initiation complex: a critical nexus for cancer development.

PubMed

Pelletier, Jerry; Graff, Jeremy; Ruggero, Davide; Sonenberg, Nahum

2015-01-15

Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents. ©2014 American Association for Cancer Research.

Four MicroRNAs Promote Prostate Cell Proliferation with Regulation of PTEN and Its Downstream Signals In Vitro

PubMed Central

Xue, Jing-lun; Chen, Jin-zhong

2013-01-01

Background Phosphatase and tensin homologue (PTEN), as a tumor suppressor, plays vital roles in tumorigenesis and progression of prostate cancer. However, the mechanisms of PTEN regulation still need further investigation. We here report that a combination of four microRNAs (miR-19b, miR-23b, miR-26a and miR-92a) promotes prostate cell proliferation by regulating PTEN and its downstream signals in vitro. Methodology/Principal Findings We found that the four microRNAs (miRNAs) could effectively suppress PTEN expression by directly interacting with its 3’ UTR in prostate epithelial and cancer cells. Under-expression of the four miRNAs by antisense neutralization up-regulates PTEN expression, while overexpression of the four miRNAs accelerates epithelial and prostate cancer cell proliferation. Furthermore, the expression of the four miRNAs could, singly or jointly, alter the expression of the key components in the phosphoinositide 3-kinase (PI3K)/Akt pathway, including PIK3CA, PIK3CD, PIK3R1 and Akt, along with their downstream signal, cyclin D1. Conclusions These results suggested that the four miRNAs could promote prostate cancer cell proliferation by co-regulating the expression of PTEN, PI3K/Akt pathway and cyclin D1 in vitro. These findings increase understanding of the molecular mechanisms of prostate carcinogenesis and progression, even provide valuable insights into the diagnosis, prognosis, and rational design of novel therapeutics for prostate cancer. PMID:24098737

Downstream resource utilization following hybrid cardiac imaging with an integrated cadmium-zinc-telluride/64-slice CT device.

PubMed

Fiechter, Michael; Ghadri, Jelena R; Wolfrum, Mathias; Kuest, Silke M; Pazhenkottil, Aju P; Nkoulou, Rene N; Herzog, Bernhard A; Gebhard, Cathérine; Fuchs, Tobias A; Gaemperli, Oliver; Kaufmann, Philipp A

2012-03-01

Low yield of invasive coronary angiography and unnecessary coronary interventions have been identified as key cost drivers in cardiology for evaluation of coronary artery disease (CAD). This has fuelled the search for noninvasive techniques providing comprehensive functional and anatomical information on coronary lesions. We have evaluated the impact of implementation of a novel hybrid cadmium-zinc-telluride (CZT)/64-slice CT camera into the daily clinical routine on downstream resource utilization. Sixty-two patients with known or suspected CAD were referred for same-day single-session hybrid evaluation with CZT myocardial perfusion imaging (MPI) and coronary CT angiography (CCTA). Hybrid MPI/CCTA images from the integrated CZT/CT camera served for decision-making towards conservative versus invasive management. Based on the hybrid images patients were classified into those with and those without matched findings. Matched findings were defined as the combination of MPI defect with a stenosis by CCTA in the coronary artery subtending the respective territory. All patients with normal MPI and CCTA as well as those with isolated MPI or CCTA finding or combined but unmatched findings were categorized as "no match". All 23 patients with a matched finding underwent invasive coronary angiography and 21 (91%) were revascularized. Of the 39 patients with no match, 5 (13%, p < 0.001 vs matched) underwent catheterization and 3 (8%, p < 0.001 vs matched) were revascularized. Cardiac hybrid imaging in CAD evaluation has a profound impact on patient management and may contribute to optimal downstream resource utilization.

Decrease of miR-195 Promotes Chondrocytes Proliferation and Maintenance of Chondrogenic Phenotype via Targeting FGF-18 Pathway

PubMed Central

Wang, Yong; Yang, Tao; Liu, Yadong; Zhao, Wei; Zhang, Zhen; Lu, Ming; Zhang, Weiguo

2017-01-01

Slow growth and rapid loss of chondrogenic phenotypes are the major problems affecting chronic cartilage lesions. The role of microRNA-195 (miR-195) and its detailed working mechanism in the fore-mentioned process remains unknown. Fibroblastic growth factor 18 (FGF-18) plays a key role in cartilage homeostasis; whether miR-195 could regulate FGF-18 and its downstream signal pathway in chondrocyte proliferation and maintenance of chondrogenic phenotypes still remains unclear. The present research shows elevated miR-195 but depressed FGF-18 expressed in joint fluid specimens of 20 patients with chronic cartilage lesions and in CH1M and CH3M chondrocytes when compared with that in joint fluid specimens without cartilage lesions and in CH1W and CH2W chondrocytes, respectively. The following loss of function test revealed that downregulation of miR-195 by transfection of miR-195 inhibitors promoted chondrocyte proliferation and expression of a type II collagen α I chain (Col2a1)/aggrecan. Through the online informatics analysis we theoretically predicted that miR-195 could bind to a FGF-18 3′ untranslated region (3′UTR), also, we verified that a miR-195 could regulate the FGF-18 and its downstream pathway. The constructed dual luciferase assay further confirmed that FGF-18 was a direct target of miR-195. The executed anti-sense experiment displayed that miR-195 could regulate chondrocyte proliferation and Col2a1/aggrecan expression via the FGF-18 pathway. Finally, through an in vivo anterior cruciate ligament transection (ACLT) model, downregulation of miR-195 presented a significantly protective effect on chronic cartilage lesions. Evaluating all of the outcomes of the current research revealed that a decrease of miR-195 protected chronic cartilage lesions by promoting chondrocyte proliferation and maintenance of chondrogenic phenotypes via the targeting of the FGF-18 pathway and that the miR-195/FGF-18 axis could be a potential target in the treatment of

Decrease of miR-195 Promotes Chondrocytes Proliferation and Maintenance of Chondrogenic Phenotype via Targeting FGF-18 Pathway.

PubMed

Wang, Yong; Yang, Tao; Liu, Yadong; Zhao, Wei; Zhang, Zhen; Lu, Ming; Zhang, Weiguo

2017-05-04

Slow growth and rapid loss of chondrogenic phenotypes are the major problems affecting chronic cartilage lesions. The role of microRNA-195 (miR-195) and its detailed working mechanism in the fore-mentioned process remains unknown. Fibroblastic growth factor 18 (FGF-18) plays a key role in cartilage homeostasis; whether miR-195 could regulate FGF-18 and its downstream signal pathway in chondrocyte proliferation and maintenance of chondrogenic phenotypes still remains unclear. The present research shows elevated miR-195 but depressed FGF-18 expressed in joint fluid specimens of 20 patients with chronic cartilage lesions and in CH1M and CH3M chondrocytes when compared with that in joint fluid specimens without cartilage lesions and in CH1W and CH2W chondrocytes, respectively. The following loss of function test revealed that downregulation of miR-195 by transfection of miR-195 inhibitors promoted chondrocyte proliferation and expression of a type II collagen α I chain (Col2a1)/aggrecan. Through the online informatics analysis we theoretically predicted that miR-195 could bind to a FGF-18 3' untranslated region (3'UTR), also, we verified that a miR-195 could regulate the FGF-18 and its downstream pathway. The constructed dual luciferase assay further confirmed that FGF-18 was a direct target of miR-195. The executed anti-sense experiment displayed that miR-195 could regulate chondrocyte proliferation and Col2a1/aggrecan expression via the FGF-18 pathway. Finally, through an in vivo anterior cruciate ligament transection (ACLT) model, downregulation of miR-195 presented a significantly protective effect on chronic cartilage lesions. Evaluating all of the outcomes of the current research revealed that a decrease of miR-195 protected chronic cartilage lesions by promoting chondrocyte proliferation and maintenance of chondrogenic phenotypes via the targeting of the FGF-18 pathway and that the miR-195/FGF-18 axis could be a potential target in the treatment of cartilage

7. View to southeast. View of downstream side of bridge ...

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

7. View to southeast. View of downstream side of bridge from confluence of Trinity and South Fork Trinity Rivers. (90mm Lens) - South Fork Trinity River Bridge, State Highway 299 spanning South Fork Trinity River, Salyer, Trinity County, CA

The "WFD-effect" on upstream-downstream relations in international river basins - insights from the Rhine and the Elbe basins

NASA Astrophysics Data System (ADS)

Moellenkamp, S.

2007-06-01

The upstream-downstream relationship in international river basins is a traditional challenge in water management. Water use in upstream countries often has a negative impact on water use in downstream countries. This is most evident in the classical example of industrial pollution in upstream countries hindering drinking water production downstream. The European Water Framework Directive (WFD) gives new impetus to the river basin approach and to international co-operation in European catchments. It aims at transforming a mainly water quality oriented management into a more integrated approach of ecosystem management. After discussing the traditional upstream-downstream relationship, this article shows that the WFD has a balancing effect on upstream-downstream problems and that it enhances river basin solidarity in international basins. While it lifts the downstream countries to the same level as the upstream countries, it also leads to new duties for the downstream states. Following the ecosystem approach, measures taken by downstream countries become increasingly more important. For example, downstream countries need to take measures to allow for migrating fish species to reach upstream stretches of river systems. With the WFD, fish populations receive increased attention, as they are an important indicator for the ecological status. The European Commission acquires a new role of inspection and control in river basin management, which finally also leads to enhanced cooperation and solidarity among the states in a basin. In order to achieve better water quality and to mitigate upstream-downstream problems, also economic instruments can be applied and the WFD does not exclude the possibility of making use of financial compensations, if at the same time the polluter pays principle is taken into account. The results presented in this article originate from a broader study on integrated water resources management conducted at Bonn University and refer to the Rhine and

Organic compounds downstream from a treated-wastewater discharge near Dallas, Texas, March 1987

USGS Publications Warehouse

Buszka, P.M.; Barber, L.B.; Schroeder, M.P.; Becker, L.D.

1994-01-01

Comparison of instantaneous flux values of selected organic compounds in water from downstream sites indicates: (1) the formation of chloroform in the stream following the discharge of the treated effluent, and that (2) instream biodegradation may be decreasing concentrations of linear alkylbenzene compounds in water. The relative persistence of many of the selected organic compounds in Rowlett Creek downstream from the municipal wastewater-treatment plant indicates that they could be transported into Lake Ray Hubbard, a source of municipal water supply.

KRAS as a Therapeutic Target.

PubMed

McCormick, Frank

2015-04-15

KRAS proteins play a major role in human cancer, but have not yielded to therapeutic attack. New technologies in drug discovery and insights into signaling pathways that KRAS controls have promoted renewed efforts to develop therapies through direct targeting of KRAS itself, new ways of blocking KRAS processing, or by identifying targets that KRAS cancers depend on for survival. Although drugs that block the well-established downstream pathways, RAF-MAPK and PI3K, are being tested in the clinic, new efforts are under way to exploit previously unrecognized vulnerabilities, such as altered metabolic networks, or novel pathways identified through synthetic lethal screens. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer further hope that new ways of treating KRAS are finally coming into view. These issues are discussed in this edition of CCR Focus. ©2015 American Association for Cancer Research.

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

28. VIEW FROM IMMEDIATELY DOWNSTREAM OF TWIN FALLS MAIN CANAL ...

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

28. VIEW FROM IMMEDIATELY DOWNSTREAM OF TWIN FALLS MAIN CANAL HEADWORKS WITH CANAL BRIDGE IN DISTANCE. - Milner Dam & Main Canal: Twin Falls Canal Company, On Snake River, 11 miles West of city of Burley, Idaho, Twin Falls, Twin Falls County, ID

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

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

3. VIEW OF DOWNSTREAM ARCHES. MASONRY ABOVE ARCHES IN THE ...

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

3. VIEW OF DOWNSTREAM ARCHES. MASONRY ABOVE ARCHES IN THE SPANDREL WALL IS LAID IN A SEMI-COURSED RUBBLE PATTERN. - Core Creek County Bridge, Spanning Core Creek, approximately 1 mile South of State Route 332 (Newtown Bypass), Newtown, Bucks County, PA

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

10. EASTERLY VIEW OF THE ACCESS ROAD TO THE DOWNSTREAM ...

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

10. EASTERLY VIEW OF THE ACCESS ROAD TO THE DOWNSTREAM SIDE OF BIG DALTON DAM EXTENDING FROM THE FOOTBRIDGE TO THE GAGING STATION. BIG DALTON DAM IN BACKGROUND. - Big Dalton Dam, 2600 Big Dalton Canyon Road, Glendora, Los Angeles County, CA

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

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

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

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.

Subthalamic, not striatal, activity correlates with basal ganglia downstream activity in normal and parkinsonian monkeys

PubMed Central

Deffains, Marc; Iskhakova, Liliya; Katabi, Shiran; Haber, Suzanne N; Israel, Zvi; Bergman, Hagai

2016-01-01

The striatum and the subthalamic nucleus (STN) constitute the input stage of the basal ganglia (BG) network and together innervate BG downstream structures using GABA and glutamate, respectively. Comparison of the neuronal activity in BG input and downstream structures reveals that subthalamic, not striatal, activity fluctuations correlate with modulations in the increase/decrease discharge balance of BG downstream neurons during temporal discounting classical condition task. After induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), abnormal low beta (8-15 Hz) spiking and local field potential (LFP) oscillations resonate across the BG network. Nevertheless, LFP beta oscillations entrain spiking activity of STN, striatal cholinergic interneurons and BG downstream structures, but do not entrain spiking activity of striatal projection neurons. Our results highlight the pivotal role of STN divergent projections in BG physiology and pathophysiology and may explain why STN is such an effective site for invasive treatment of advanced Parkinson's disease and other BG-related disorders. DOI: http://dx.doi.org/10.7554/eLife.16443.001 PMID:27552049

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

STEEL ERECTION. View of downstream of bridge, looking southeast from ...

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

STEEL ERECTION. View of downstream of bridge, looking southeast from confluence of Trinity and South Fork Trinity rivers. The old suspension bridge is in background - South Fork Trinity River Bridge, State Highway 299 spanning South Fork Trinity River, Salyer, Trinity County, CA

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

7. VIEW SHOWING DOWNSTREAM FACE AND TOE OF DAM, WITH ...

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

7. VIEW SHOWING DOWNSTREAM FACE AND TOE OF DAM, WITH OUTLET CULVERT AND WING RETAINING WALLS, LOOKING NORTH - High Mountain Dams in Upalco Unit, Twin Pots Dam, Ashley National Forest, 10.1 miles North of Mountain Home, Mountain Home, Duchesne County, UT

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

Key Ingredients-Target Groups, Methods and Messages, and Evaluation-of Local-Level, Public Interventions to Counter Stigma and Discrimination: A Lived Experience Informed Selective Narrative Literature Review.

PubMed

Ashton, Laura J; Gordon, Sarah E; Reeves, Racheal A

2018-04-01

A proliferation of recent literature provides substantial direction as to the key ingredients-target groups, messages and methods, and evaluation-of local-level, public interventions to counter stigma and discrimination. This paper provides a selective narrative review of that literature from the perspective or standpoint of anti-stigma experts with lived experience of mental distress, the key findings of which have been synthesised and presented in diagrammatic overviews (infographics). These are intended to guide providers in planning, delivering and evaluating lived experience-directed local-level, public interventions to counter stigma and discrimination in accord with current best practice.

Computation of the turbulent boundary layer downstream of vortex generators

NASA Astrophysics Data System (ADS)

Chang, Paul K.

1987-12-01

The approximate analysis of three-dimensional incompressible turbulent boundary layer downstream of vortex generators is presented. Extensive numerical computations are carried out to assess the effectiveness of single-row, counter-rotating vane-type vortex generators to alleviate flow separation lines. Flow separation downstream of the vortex generators on a thick airfoil are determined in terms of size, location, and arrangement of the vortex generators. These lines are compared with the separation line without the vortex generators. High efficiency is obtained with the moderately slender rectangular blade of the generator. The results indicate that separations is alleviated more effectively in the region closer to the symmetry axis of the generator than in the outer region of the symmetry axis. No optimum conditions for the alleviation of flow separation are established in this investigation, and no comparisons are made with other analytical results and experimental data.

Continuous Manufacturing of Recombinant Therapeutic Proteins: Upstream and Downstream Technologies.

PubMed

Patil, Rohan; Walther, Jason

2017-03-07

Continuous biomanufacturing of recombinant therapeutic proteins offers several potential advantages over conventional batch processing, including reduced cost of goods, more flexible and responsive manufacturing facilities, and improved and consistent product quality. Although continuous approaches to various upstream and downstream unit operations have been considered and studied for decades, in recent years interest and application have accelerated. Researchers have achieved increasingly higher levels of process intensification, and have also begun to integrate different continuous unit operations into larger, holistically continuous processes. This review first discusses approaches for continuous cell culture, with a focus on perfusion-enabling cell separation technologies including gravitational, centrifugal, and acoustic settling, as well as filtration-based techniques. We follow with a review of various continuous downstream unit operations, covering categories such as clarification, chromatography, formulation, and viral inactivation and filtration. The review ends by summarizing case studies of integrated and continuous processing as reported in the literature.

FANCD2 functions as a critical factor downstream of MiTF to maintain the proliferation and survival of melanoma cells.

PubMed

Bourseguin, Julie; Bonet, Caroline; Renaud, Emilie; Pandiani, Charlotte; Boncompagni, Marina; Giuliano, Sandy; Pawlikowska, Patrycja; Karmous-Benailly, Houda; Ballotti, Robert; Rosselli, Filippo; Bertolotto, Corine

2016-11-09

Proteins involved in genetic stability maintenance and safeguarding DNA replication act not only against cancer initiation but could also play a major role in sustaining cancer progression. Here, we report that the FANC pathway is highly expressed in metastatic melanoma harboring the oncogenic microphthalmia-associated transcription factor (MiTF). We show that MiTF downregulation in melanoma cells lowers the expression of several FANC genes and proteins. Moreover, we observe that, similarly to the consequence of MiTF downregulation, FANC pathway silencing alters proliferation, migration and senescence of human melanoma cells. We demonstrate that the FANC pathway acts downstream MiTF and establish the existence of an epistatic relationship between MiTF and the FANC pathway. Our findings point to a central role of the FANC pathway in cellular and chromosomal resistance to both DNA damage and targeted therapies in melanoma cells. Thus, the FANC pathway is a promising new therapeutic target in melanoma treatment.

FANCD2 functions as a critical factor downstream of MiTF to maintain the proliferation and survival of melanoma cells

PubMed Central

Bourseguin, Julie; Bonet, Caroline; Renaud, Emilie; Pandiani, Charlotte; Boncompagni, Marina; Giuliano, Sandy; Pawlikowska, Patrycja; Karmous-Benailly, Houda; Ballotti, Robert; Rosselli, Filippo; Bertolotto, Corine

2016-01-01

Proteins involved in genetic stability maintenance and safeguarding DNA replication act not only against cancer initiation but could also play a major role in sustaining cancer progression. Here, we report that the FANC pathway is highly expressed in metastatic melanoma harboring the oncogenic microphthalmia-associated transcription factor (MiTF). We show that MiTF downregulation in melanoma cells lowers the expression of several FANC genes and proteins. Moreover, we observe that, similarly to the consequence of MiTF downregulation, FANC pathway silencing alters proliferation, migration and senescence of human melanoma cells. We demonstrate that the FANC pathway acts downstream MiTF and establish the existence of an epistatic relationship between MiTF and the FANC pathway. Our findings point to a central role of the FANC pathway in cellular and chromosomal resistance to both DNA damage and targeted therapies in melanoma cells. Thus, the FANC pathway is a promising new therapeutic target in melanoma treatment. PMID:27827420

Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: An important role of Insilco methods in multi target directed ligands design.

PubMed

Kumar, Akhil; Tiwari, Ashish; Sharma, Ashok

2018-03-15

Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So the current AD drug discovery research shifting towards new approach for better solution that simultaneously modulate more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs. Drug discovery project is tedious, costly and long term project. Moreover, multi target AD drug discovery added extra challenges such as good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off target side effect and crossing of the blood brain barrier. These hurdles may be addressed by insilico methods for efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here we are summarizing some of the most prominent and computationally explored single target against AD and further we discussed successful example of dual or multiple inhibitors for same targets. Moreover we focused on ligand and structure based computational approach to design MTDL against AD. However is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy are useful in future MTDLs drug discovery alone or in combination with fragment based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug

Impact of surfactants on the target recognition of Fab-conjugated PLGA nanoparticles.

PubMed

Kennedy, Patrick J; Perreira, Ines; Ferreira, Daniel; Nestor, Marika; Oliveira, Carla; Granja, Pedro L; Sarmento, Bruno

2018-06-01

Targeted drug delivery with nanoparticles (NPs) requires proper surface ligand presentation and availability. Surfactants are often used as stabilizers in the production of targeted NPs. Here, we evaluated the impact of surfactants on ligand functionalization and downstream molecular recognition. Our model system consisted of fluorescent poly(lactic-co-glycolic acid) (PLGA) NPs that were nanoprecipitated in one of a small panel of commonly-used surfactants followed by equivalent washes and conjugation of an engineered Fab antibody fragment. Size, polydispersity index and zeta potential were determined by dynamic light scattering and laser Doppler anemometry, and Fab presence on the NPs was assessed by enzyme-linked immunosorbent assay. Most importantly, Fab-decorated NP binding to the cell surface receptor was monitored by fluorescence-activated cell sorting. 2% polyvinyl alcohol, 1% sodium cholate, 0.5% Pluronic F127 (F127) and 2% Tween-80 were initially tested. Of the four surfactants tested, PLGA NPs in 0.5% F127 and 2% Tween-80 had the highest cell binding. These two surfactants were then retested in two different concentrations, 0.5% and 2%. The Fab-decorated PLGA NPs in 2% F127 had the highest cell binding. This study highlights the impact of common surfactants and their concentrations on the downstream targeting of ligand-decorated NPs. Similar principles should be applied in the development of future targeted nanosystems where surfactants are employed. Copyright © 2018 Elsevier B.V. All rights reserved.

Downstream movement of mature eels in a hydroelectric reservoir in New Zealand

USGS Publications Warehouse

Watene, E.M.; Boubee, J.A.T.; Haro, A.

2003-01-01

This study investigates the behavior of migrant eels as they approached the Patea hydroelectric dam on the West Coast of the North Island, New Zealand. Seventeen mature migrant eels (870-1,240 mm; 2,000-6,380 g) were implanted with coded acoustic transmitters and released. Their movements in the reservoir were monitored for 14 months with stationary data logging and manual tracking receivers. The downstream migration of sexually maturing eels was found to occur mainly at night, usually during, or immediately after, rainfall events. Eels tended to travel at the surface, within the upper 4 m of the water column, at speeds ranging from 16 to 89 cm/s. Upon reaching the headrace, eels typically spent time searching, presumably for an unobstructed downstream route. In order to aid downstream passage of eels at the Patea Dam, power station operators began spillway opening trials during peak migration periods. Although this allowed some migrant eels to safely pass over the dam, information on the relative effectiveness and cost of this method over other possible mitigation methods is still required. ?? Copyright by the American Fisheries Society 2003.

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

NASA Astrophysics Data System (ADS)

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

2017-04-01

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

Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

PubMed

Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

2016-04-15

Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Sex- and Tissue-specific Functions of Drosophila Doublesex Transcription Factor Target Genes

PubMed Central

Clough, Emily; Jimenez, Erin; Kim, Yoo-Ah; Whitworth, Cale; Neville, Megan C.; Hempel, Leonie; Pavlou, Hania J.; Chen, Zhen-Xia; Sturgill, David; Dale, Ryan; Smith, Harold E.; Przytycka, Teresa M.; Goodwin, Stephen F.; Van Doren, Mark; Oliver, Brian

2014-01-01

Primary sex determination “switches” evolve rapidly, but Doublesex (DSX) related transcription factors (DMRTs) act downstream of these switches to control sexual development in most animal species. Drosophila dsx encodes female- and male-specific isoforms (DSXF and DSXM), but little is known about how dsx controls sexual development, whether DSXF and DSXM bind different targets, or how DSX proteins direct different outcomes in diverse tissues. We undertook genome-wide analyses to identify DSX targets using in vivo occupancy, binding site prediction, and evolutionary conservation. We find that DSXF and DSXM bind thousands of the same targets in multiple tissues in both sexes, yet these targets have sex- and tissue-specific functions. Interestingly, DSX targets show considerable overlap with targets identified for mouse DMRT1. DSX targets include transcription factors and signaling pathway components providing for direct and indirect regulation of sex-biased expression. PMID:25535918

Status of downstream fish passage at hydroelectric projects in the northeast, USA

USGS Publications Warehouse

Odeh, Mufeed; Orvis, Curtis

1997-01-01

In the northeastern United States several guidance, protection, and conveyance methods have been employed to assist downstream migrating fish. Overlay racks, standard bar racks with close spacing, louvers, curtain walls, guide walls, netting, and other means have been used to guide and protect fish from entrainment. The design process of these facilities comprises consideration of various factors, including flow approach, attraction flow, guidance and protection devices, bypass location, conveyance mechanism, and plunge pool conditions. This paper presents the status of the design criteria for downstream fish passage facilities at hydroelectric sites in the northeast part of the United States. Examples of existing facilities are given.

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

PubMed

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

2013-01-01

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

Anticancer molecules targeting fibroblast growth factor receptors.

PubMed

Liang, Guang; Liu, Zhiguo; Wu, Jianzhang; Cai, Yuepiao; Li, Xiaokun

2012-10-01

The fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases: FGFR1-4. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. These FGFR cascades play crucial roles in tumor cell proliferation, angiogenesis, migration, and survival. The combination of knockdown studies and pharmaceutical inhibition in preclinical models demonstrates that FGFRs are attractive targets for therapeutic intervention in cancer. Multiple FGFR inhibitors with various structural skeletons have been designed, synthesized, and evaluated. Reviews on FGFRs have recently focused on FGFR signaling, pathophysiology, and functions in cancer or other diseases. In this article, we review recent advances in structure-activity relationships (SAR) of FGFR inhibitors, as well as the FGFR-targeting drug design strategies currently employed in targeting deregulated FGFRs by antibodies and small molecule inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

6. AN IMAGE OF LOOKING NORTHEAST FROM THE DOWNSTREAM SIDE ...

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

6. AN IMAGE OF LOOKING NORTHEAST FROM THE DOWNSTREAM SIDE OF THE BRIDGE, SHOWING THE ENTRADOS, SOLID-RAIL PARAPET, THE BEAM, THE NORTHWEST ABUTMENT AND PART OF THE PIER. - Cement Plant Road Bridge, Spanning Leatherwood Creek on County Road 50 South, Bedford, Lawrence County, IN

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. 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

Using stable isotopes to examine watershed connectivity to downstream waters

EPA Science Inventory

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

Downstream movement of fall Chinook salmon juveniles in the lower Snake River reservoirs during winter and early spring

USGS Publications Warehouse

Tiffan, Kenneth F.; Kock, Tobias J.; Connor, William P.; Mullins, Frank; Steinhorst, R. Kirk

2012-01-01

We conducted a 3-year radiotelemetry study in the lower Snake River to (1) determine whether juvenile fall Chinook salmon Oncorhynchus tshawytscha pass dams during winter, when bypass systems and structures designed to prevent mortality are not operated; (2) determine whether downstream movement rate varies annually, seasonally, and from reservoir to reservoir; and (3) identify some of the factors that contribute to annual, seasonal, and spatial variation in downstream movement rate. Fall Chinook salmon juveniles moved downstream up to 169 km and at a sufficiently fast rate (7.5 km/d) such that large percentages (up to 93%) of the fish passed one or more dams during the winter. Mean downstream movement rate varied annually (9.2–11.3 km/d), increased from winter (7.5 km/d) to spring (16.4 km/d), and increased (from 6.9 to 16.8 km/d) as fish moved downstream from reservoir to reservoir. Fish condition factor at tagging explained some of the annual variation in downstream movement rate, whereas water particle velocity and temperature explained portions of the seasonal variation. An increase in migrational disposition as fish moved downstream helped to explain the spatial variation. The potential cost of winter movement might be reduced survival due to turbine passage at a time when the bypass systems and spillway passage structures are not operated. Efforts to understand and increase passage survival of winter migrants in large impoundments might help to rehabilitate some imperiled anadromous salmonid populations.

Potential GLOF Hazards and Initiatives taken to minimize its Impacts on Downstream Communities and Infrastructures in Nepal Himalaya

NASA Astrophysics Data System (ADS)

Regmi, D.; Kargel, J. S.; Leonard, G. J.; Haritashya, U. K.; Karki, A.; Poudyal, S.

2017-12-01

With long-term temperature increases due to climate change, glacier lakes in several parts of the world are a fast-developing threat to infrastructure and downstream communities. There are more than 2000 glacier lakes in Nepal; while most pose no significant hazard to people, a comparative few are very dangerous, such as Tso Rolpa, Imja, Barun and Thulagi glacier lakes. The objectives of this study are to present 1) a review of prior glacier lake studies that have been carried out in the Nepal Himalaya; 2) recent research results, including bathymetric studies of the lakes; 3) a summary of possible infrastructure damages, especially multi-million-dollar hydropower projects, that are under threat of glacier lake outburst floods (GLOFs); 4) to present the outcome of the recently completed Imja lake lowering project, which is the highest altitude lake ever controlled by lowering the water level. This project is being undertaken as a response to a scientific ground-based bathymetric and geophysical survey funded by the United Nations Development Program and a satellite-based study of the long-term development of the lake (funded by NASA's SERVIR program, J. Kargel, PI). The objective of the Imja Lake GLOF mitigation project is to lower the water level by three meters to reduce the lake volume, increase the freeboard, and improve the safety of tourism, downstream communities, and the infrastructure of Nepal's Everest region. This GLOF mitigation step taken by Nepal's government to reduce the risk of an outburst flood is a good step to reduce the chances of a GLOF, and to reduce the magnitude of a disaster if a GLOF nonetheless occurs despite our best efforts. We will also present the prospects for the future of Imja Lake, including an outline of possible steps that could further reduce the hazards faced by downstream communities and infrastructure. Key words: Glacier Lakes; GLOF; Hydropower; Imja lake; lake lowering

11. A VIEW LOOKING WEST/SOUTHWEST AND DOWNSTREAM ALONG LEATHERWOOD CREEK, ...

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

11. A VIEW LOOKING WEST/SOUTHWEST AND DOWNSTREAM ALONG LEATHERWOOD CREEK, WAS TAKEN FROM THE BRIDGE ROADWAY. - Cement Plant Road Bridge, Spanning Leatherwood Creek on County Road 50 South, Bedford, Lawrence County, IN

40 CFR 80.1604 - Gasoline sulfur standards and requirements for parties downstream of refiners and importers.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 17 2014-07-01 2014-07-01 false Gasoline sulfur standards and... ADDITIVES Gasoline Sulfur § 80.1604 Gasoline sulfur standards and requirements for parties downstream of refiners and importers. (a) The sulfur standard for gasoline at any downstream location shall be determined...

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

PubMed

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

2017-12-01

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

Ciona intestinalis as a Marine Model System to Study Some Key Developmental Genes Targeted by the Diatom-Derived Aldehyde Decadienal

PubMed Central

Lettieri, Anna; Esposito, Rosaria; Ianora, Adrianna; Spagnuolo, Antonietta

2015-01-01

The anti-proliferative effects of diatoms, described for the first time in copepods, have also been demonstrated in benthic invertebrates such as polychaetes, sea urchins and tunicates. In these organisms PUAs (polyunsaturated aldehydes) induce the disruption of gametogenesis, gamete functionality, fertilization, embryonic mitosis, and larval fitness and competence. These inhibitory effects are due to the PUAs, produced by diatoms in response to physical damage as occurs during copepod grazing. The cell targets of these compounds remain largely unknown. Here we identify some of the genes targeted by the diatom PUA 2-trans-4-trans-decadienal (DD) using the tunicate Ciona intestinalis. The tools, techniques and genomic resources available for Ciona, as well as the suitability of Ciona embryos for medium-to high-throughput strategies, are key to their employment as model organisms in different fields, including the investigation of toxic agents that could interfere with developmental processes. We demonstrate that DD can induce developmental aberrations in Ciona larvae in a dose-dependent manner. Moreover, through a preliminary analysis, DD is shown to affect the expression level of genes involved in stress response and developmental processes. PMID:25789602

TBK1-targeted suppression of TRIF-dependent signaling pathway of Toll-like receptors by 6-shogaol, an active component of ginger.

PubMed

Park, Se-Jeong; Lee, Mi-Young; Son, Bu-Soon; Youn, Hyung-Sun

2009-07-01

Toll-like receptors (TLRs) are primary sensors that detect a wide variety of microbial components involving induction of innate immune responses. After recognition of microbial components, TLRs trigger the activation of myeloid differential factor 88 (MyD88) and Toll-interleukin-1 (IL-1) receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream signaling pathways. 6-Shoagol, an active ingredient of ginger, inhibits the MyD88-dependent signaling pathway by inhibiting inhibitor-kappaB kinase activity. Inhibitor-kappaB kinase is a key kinase in nuclear factor kappaB (NF-kappaB) activation. However, it is not known whether 6-shogaol inhibits the TRIF-dependent signaling pathway. Our goal was to identify the molecular target of 6-shogaol in the TRIF-dependent pathway of TLRs. 6-Shogaol inhibited the activation of interferon-regulatory factor 3 (IRF3) induced by lipopolysaccharide (LPS) and by polyriboinosinic polyribocytidylic acid (poly[I:C]), overexpression of TRIF, TANK-binding kinase1 (TBK1), and IRF3. Furthermore, 6-shogaol inhibited TBK1 activity in vitro. Together, these results suggest that 6-shogaol inhibits the TRIF-dependent signaling pathway of TLRs by targeting TBK1, and, they imply that 6-shogaol can modulate TLR-derived immune/inflammatory target gene expression induced by microbial infection.

Novel Techniques for Quantification of Correlation Between Primary Liquid Jet Breakup and Downstream Spray Characteristics

DTIC Science & Technology

2016-05-08

unlimited. 5 1. Introduction Several liquid -fuelled combustion systems, such as liquid propellant rocket engines and gas turbines...AFRL-AFOSR-JP-TR-2016-0084 Novel techniques for quantification of correlation between primary liquid jet breakup and downstream spray characteristics...to 17 Apr 2016 4.  TITLE AND SUBTITLE Novel techniques for quantification of correlation between primary liquid jet breakup and downstream spray

Novel Techniques for Quantification of Correlation Between Primary Liquid Jet Breakup and Downstream Spray Characteristics

DTIC Science & Technology

2016-10-05

unlimited. 5 1. Introduction Several liquid -fuelled combustion systems, such as liquid propellant rocket engines and gas turbines...AFRL-AFOSR-JP-TR-2016-0084 Novel techniques for quantification of correlation between primary liquid jet breakup and downstream spray characteristics...to 17 Apr 2016 4.  TITLE AND SUBTITLE Novel techniques for quantification of correlation between primary liquid jet breakup and downstream spray

Synthesis of downstream fish passage information at projects owned by the U.S. Army Corps of Engineers in the Willamette River Basin, Oregon

USGS Publications Warehouse

Hansen, Amy C.; Kock, Tobias J.; Hansen, Gabriel S.

2017-08-07

The U.S. Army Corps of Engineers (USACE) operates the Willamette Valley Project (Project) in northwestern Oregon, which includes a series of dams, reservoirs, revetments, and fish hatcheries. Project dams were constructed during the 1950s and 1960s on rivers that supported populations of spring Chinook salmon (Oncorhynchus tshawytscha), winter steelhead (O. mykiss), and other anadromous fish species in the Willamette River Basin. These dams, and the reservoirs they created, negatively affected anadromous fish populations. Efforts are currently underway to improve passage conditions within the Project and enhance populations of anadromous fish species. Research on downstream fish passage within the Project has occurred since 1960 and these efforts are documented in numerous reports and publications. These studies are important resources to managers in the Project, so the USACE requested a synthesis of existing literature that could serve as a resource for future decision-making processes. In 2016, the U.S. Geological Survey conducted an extensive literature review on downstream fish passage studies within the Project. We identified 116 documents that described studies conducted during 1960–2016. Each of these documents were obtained, reviewed, and organized by their content to describe the state-of-knowledge within four subbasins in the Project, which include the North Santiam, South Santiam, McKenzie, and Middle Fork Willamette Rivers. In this document, we summarize key findings from various studies on downstream fish passage in the Willamette Project. Readers are advised to review specific reports of interest to insure that study methods, results, and additional considerations are fully understood.

Circadian rhythms in healthy aging--effects downstream from the pacemaker

NASA Technical Reports Server (NTRS)

Monk, T. H.; Kupfer, D. J.

2000-01-01

Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms "downstream" from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24 h routine, sleeping at night) and unmasking (36 h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men).

A novel cell autolysis system for cost-competitive downstream processing.

PubMed

Hajnal, Ivan; Chen, Xiangbin; Chen, Guo-Qiang

2016-11-01

The industrial production of low value-added biological products poses significant challenges due to cost pressures. In recent years, it has been argued that synthetic biology approaches will lead to breakthroughs that eliminate price bottlenecks for the production of a wide range of biological products including bioplastics and biofuels. One significant bottleneck lies in the necessity to break the tough cell walls of microbes in order to release intracellular products. We here report the implementation of the first synthetic biology standard part based on the lambda phage SRRz genes and a synthetic ribosome binding site (RBS) that works in Escherichia coli and Halomonas campaniensis, which enables the producer strains to induce lysis after the addition of small amounts (1-5 %) of solvents or to spontaneously lyse during the stresses of downstream processing, and thus has the potential to eliminate the mechanical cell disruption step as both an efficiency bottleneck and a significant capex barrier when implementing downstream bioprocesses.

Downstream reduction of rural channel size with contrasting urban effects in small coastal streams of southeastern Australia

NASA Astrophysics Data System (ADS)

Nanson, G. C.; Young, R. W.

1981-07-01

Although most streams show a downstream increase in channel size corresponding to a downstream increase in flood discharges, those flowing off the Illawarra escarpment of New South Wales show a marked reduction of channel size, accompanied by a down-stream increase in flood frequency in their lower reaches. Within the confined and steeply sloping valleys of the escarpment foothills, bed and bank sediments are relatively coarse and uncohesive, and channels increase in size, corresponding to increasing discharge downstream. However, once these streams emerge into more open rural valleys at lower slopes and are accompanied by extensive floodplains formed of fine cohesive sediment, there is a dramatic reduction in channel size. This decrease in channel size apparently results from a sudden decline in channel slope and associated stream power, the cohesive nature of downstream alluvium, its retention on the channel banks by a dense cover of pasture grasses, and the availability of an extensive floodplain to carry displaced floodwater. Under these conditions floodwaters very frequently spill out over the floodplain and the downstream channel-flow becomes a relatively unimportant component of the total peak discharge. This emphasizes the importance of these floodplains as a part of the total channel system. In situations where urban development has increased peak runoff and reduced the available area of effective floodplain, stream channels formed in this fine alluvium rapidly entrench and increase in cross-sectional area by 2-3 times. Minor man-induced channel alteration and maintenance appears to trigger this enlargement.

Therapeutic antibody targeting of individual Notch receptors.

PubMed

Wu, Yan; Cain-Hom, Carol; Choy, Lisa; Hagenbeek, Thijs J; de Leon, Gladys P; Chen, Yongmei; Finkle, David; Venook, Rayna; Wu, Xiumin; Ridgway, John; Schahin-Reed, Dorreyah; Dow, Graham J; Shelton, Amy; Stawicki, Scott; Watts, Ryan J; Zhang, Jeff; Choy, Robert; Howard, Peter; Kadyk, Lisa; Yan, Minhong; Zha, Jiping; Callahan, Christopher A; Hymowitz, Sarah G; Siebel, Christian W

2010-04-15

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to

Downstream approaches to phosphorus management in agricultural landscapes: regional applicability and use.

PubMed

Kröger, R; Dunne, E J; Novak, J; King, K W; McLellan, E; Smith, D R; Strock, J; Boomer, K; Tomer, M; Noe, G B

2013-01-01

This review provides a critical overview 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. Specific practices that we discuss include the use of controlled drainage, chemical treatment of waters and soils, receiving ditch management, and wetlands. The review also focuses on the specific hydrology and biogeochemistry associated with each of those practices. The practices are structured sequentially along flowpaths as you move through the landscape, from the edge-of-field, to adjacent aquatic systems, and ultimately to downstream P retention. Often practices are region specific based on geology, cropping practices, and specific P related problems and thus require a right practice, and right place mentality to management. Each practice has fundamental P transport and retention processes by systems that can be optimized by management with the goal of reducing downstream P loading after P has left agricultural fields. The management of P requires a system-wide assessment of the stability of P in different biogeochemical forms (particulate vs. dissolved, organic vs. inorganic), in different storage pools (soil, sediment, streams etc.), and under varying biogeochemical and hydrological conditions that act to convert P from one form to another and promote its retention in or transport out of different landscape components. There is significant potential of hierarchically placing practices in the agricultural landscape and enhancing the associated P mitigation. But an understanding is needed of short- and long-term P retention mechanisms within a certain practice and incorporating maintenance schedules if necessary to improve P retention times and minimize exceeding retention capacity. Copyright © 2012 Elsevier B.V. All rights reserved.

ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

PubMed

Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

2018-05-01

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

Towards β-globin gene-targeting with integrase-defective lentiviral vectors.

PubMed

Inanlou, Davoud Nouri; Yakhchali, Bagher; Khanahmad, Hossein; Gardaneh, Mossa; Movassagh, Hesam; Cohan, Reza Ahangari; Ardestani, Mehdi Shafiee; Mahdian, Reza; Zeinali, Sirous

2010-11-01

We have developed an integrase-defective lentiviral (LV) vector in combination with a gene-targeting approach for gene therapy of β-thalassemia. The β-globin gene-targeting construct has two homologous stems including sequence upstream and downstream of the β-globin gene, a β-globin gene positioned between hygromycin and neomycin resistant genes and a herpes simplex virus type 1 thymidine kinase (HSVtk) suicide gene. Utilization of integrase-defective LV as a vector for the β-globin gene increased the number of selected clones relative to non-viral methods. This method represents an important step toward the ultimate goal of a clinical gene therapy for β-thalassemia.

Sprouty is a cytoplasmic target of adenoviral E1A oncoproteins to regulate the receptor tyrosine kinase signalling pathway

PubMed Central

2011-01-01

Background Oncoproteins encoded by the early region of adenoviruses have been shown to be powerful tools to study gene regulatory mechanisms, which affect major cellular events such as proliferation, differentiation, apoptosis and oncogenic transformation. They are possesing a key role to favor viral replication via their interaction with multiple cellular proteins. In a yeast two-hybrid screen we have identified Sprouty1 (Spry1) as a target of adenoviral E1A Oncoproteins. Spry proteins are central and complex regulators of the receptor tyrosine kinase (RTK) signalling pathway. The deregulation of Spry family members is often associated with alterations of the RTK signalling and its downstream effectors, leading to the ERK pathway. Results Here, we confirm our yeast two-hybrid data, showing the interaction between Spry1 and E1A in GST pull-down and immunoprecipitation assays. We also demonstrated the interaction of E1A with two further Spry isoforms. Using deletion mutants we identified the N-terminus and the CR conserved region (CR) 3 of E1A- and the C-terminal half of Spry1, which contains the highly conserved Spry domain, as the essential sites for direct interaction between Spry and E1A. Immunofluorescent microscopy data revealed a co-localization of E1A13S with Spry1 in the cytoplasm. SRE and TRE reporter assays demonstrated that co-expression of Spry1 with E1A13S abolishes the inhibitory function of Spry1 in RTK signalling, which is consequently accompanied with a decrease of E1A13S-induced gene expression. Conclusions These results establish Spry1 as a cytoplasmic localized cellular target for E1A oncoproteins to regulate the RTK signalling pathway, and consequently cellular events downstream of RTK that are essential for viral replication and transformation. PMID:21518456

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

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

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

Neoepitopes as cancer immunotherapy targets: key challenges and opportunities.

PubMed

Brennick, Cory A; George, Mariam M; Corwin, William L; Srivastava, Pramod K; Ebrahimi-Nik, Hakimeh

2017-03-01

Over the last half century, it has become well established that cancers can elicit a host immune response that can target them with high specificity. Only within the last decade, with the advances in high-throughput gene sequencing and bioinformatics approaches, are we now on the forefront of harnessing the host's immune system to treat cancer. Recently, some strides have been taken toward understanding effective tumor-specific MHC I restricted epitopes or neoepitopes. However, many fundamental questions still remain to be addressed before this therapy can live up to its full clinical potential. In this review, we discuss the major hurdles that lie ahead and the work being done to address them.

The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study.

PubMed

Burslem, George M; Smith, Blake E; Lai, Ashton C; Jaime-Figueroa, Saul; McQuaid, Daniel C; Bondeson, Daniel P; Toure, Momar; Dong, Hanqing; Qian, Yimin; Wang, Jing; Crew, Andrew P; Hines, John; Crews, Craig M

2018-01-18

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. Copyright © 2017 Elsevier Ltd. All rights reserved.

Summary report of responses of key resources to the 2000 Low Steady Summer Flow experiment, along the Colorado River downstream from Glen Canyon Dam, Arizona

USGS Publications Warehouse

Ralston, Barbara E.

2011-01-01

temperature, and quantifying useable shorelines). The part of the hydrograph that included a habitat maintenance flow (a 4-day spike at a powerplant capacity of 877 m3/s) and sustained high releases in April and May (averaging 509 m3/s) resulted in sediment export to Lake Mead, the reservoir downstream from Glen Canyon Dam, which is outside the study area. Some mid-elevation sandbar building (between 566 and 877 m3/s stage elevations) occurred from existing sediment deposits rather than from sediment inputs from tributaries during the previous winter. Low releases in the summer combined with low tributary sediment inputs resulted in minor sediment accumulation in the study area. The September habitat maintenance flow reworked accumulated sediment and resulted in increases in the area of some backwaters. The mainstem water temperatures in the reach near the Little Colorado River during the LSSF experiment varied little from previous years. Mainstem water temperatures in western Grand Canyon average 17 to 20 degrees C. During the LSSF, backwaters warmed more than other shoreline environments during the day, but most backwaters returned to mainstem water temperatures overnight. Shoreline surface water temperatures from river mile (RM) 30 to 72 varied between 9 and 28 degrees C in the middle of the day in July. These temperatures are within the optimal temperature range for humpback chub growth and spawning, which is between 15 and 24 degrees C. How surface water temperatures transfer to subsurface water temperatures is unknown. Data collection associated with the response of fish to the 2000 LSSF hydrograph focused on fish growth and abundance along the Colorado River in Grand Canyon. The target resource, humpback chub and other native fishes, did not respond in a strongly positive or strongly negative manner to the LSSF hydrograph during the sampling period, which extended from June to September 2000. In 2000, the mean total length of YOY native fishes was similar to the mean

Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project | Office of Cancer Genomics

Cancer.gov

TARGET researchers sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with activated kinase signaling, including Ph-like ALL, to establish the incidence of tyrosine kinase mutations in this cohort. The study confirmed previously identified somatic mutations in JAK and FLT3, but did not find novel alterations in any additional tyrosine kinases or downstream genes. The mechanism of kinase signaling activation in this high-risk subgroup of pediatric ALL remains largely unknown.

PAX3-FOXO1: Zooming in on an "undruggable" target.

PubMed

Wachtel, Marco; Schäfer, Beat W

2018-06-01

Driver oncogenes are prime targets for therapy in tumors many of which, including leukemias and sarcomas, express recurrent fusion transcription factors. One specific example for such a cancer type is alveolar rhabdomyosarcoma, which is associated in the majority of cases with the fusion protein PAX3-FOXO1. Since fusion transcription factors are challenging targets for development of small molecule inhibitors, indirect inhibitory strategies for this type of oncogenes represent a more promising approach. One can envision strategies at different molecular levels including upstream modifiers and activators, epigenetic and transcriptional co-regulators, and downstream effector targets. In this review, we will discuss the current knowledge regarding potential therapeutic targets that might contribute to indirect interference with PAX3-FOXO1 activity in alveolar rhabdomyosarcoma at the different molecular levels and extrapolate these findings to fusion transcription factors in general. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Novel Paradigms for Dialysis Vascular Access: Downstream Vascular Biology–Is There a Final Common Pathway?

PubMed Central

2013-01-01

Summary Vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of vascular access dysfunction is venous stenosis from neointimal hyperplasia within the perianastomotic region of an arteriovenous fistula and at the graft-vein anastomosis of an arteriovenous graft. There have been few, if any, effective treatments for vascular access dysfunction because of the limited understanding of the pathophysiology of venous neointimal hyperplasia formation. This review will (1) describe the histopathologic features of hemodialysis access stenosis; (2) discuss novel concepts in the pathogenesis of neointimal hyperplasia development, focusing on downstream vascular biology; (3) highlight future novel therapies for treating downstream biology; and (4) discuss future research areas to improve our understanding of downstream biology and neointimal hyperplasia development. PMID:23990166

Glycosaminoglycan-Mediated Downstream Signaling of CXCL8 Binding to Endothelial Cells

PubMed Central

Derler, Rupert; Weber, Corinna; Strutzmann, Elisabeth; Miller, Ingrid; Kungl, Andreas

2017-01-01

The recruitment of leukocytes, mediated by endothelium bound chemokine gradients, is a vital process in inflammation. The highly negatively charged, unbranched polysaccharide family of glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate mediate chemokine immobilization. Specifically the binding of CXCL8 (interleukin 8) to GAGs on endothelial cell surfaces is known to regulate neutrophil recruitment. Currently, it is not clear if binding of CXCL8 to GAGs leads to endothelial downstream signaling in addition to the typical CXCR1/CXCR2 (C-X-C motif chemokine receptor 1 and 2)-mediated signaling which activates neutrophils. Here we have investigated the changes in protein expression of human microvascular endothelial cells induced by CXCL8. Tumor necrosis factor alpha (TNFα) stimulation was used to mimic an inflammatory state which allowed us to identify syndecan-4 (SDC4) as the potential proteoglycan co-receptor of CXCL8 by gene array, real-time PCR and flow cytometry experiments. Enzymatic GAG depolymerization via heparinase III and chondroitinase ABC was used to emulate the effect of glycocalyx remodeling on CXCL8-induced endothelial downstream signaling. Proteomic analyses showed changes in the expression pattern of a number of endothelial proteins such as Zyxin and Caldesmon involved in cytoskeletal organization, cell adhesion and cell mobility. These results demonstrate for the first time a potential role of GAG-mediated endothelial downstream signaling in addition to the well-known CXCL8-CXCR1/CXCR2 signaling pathways in neutrophils. PMID:29207576

12. DETAIL LOOKING AT DOWNSTREAM APRON OF LOGWAY, WITH ROLLER ...

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

12. DETAIL LOOKING AT DOWNSTREAM APRON OF LOGWAY, WITH ROLLER GATE TRACK IN RIGHT FOREGROUND, POWER PENSTOCK OUTLETS (WITH DRAFT TUBE CONTROL VENTS OVER) IN LEFT BACKGROUND AND NEW YORK CANAL IN EXTREME LEFT BACKGROUND. VIEW TO NORTHWEST. - Boise Project, Boise River Diversion Dam, Across Boise River, Boise, Ada County, ID

9. SOUTHERLY VIEW OF THE ACCESS ROAD TO THE DOWNSTREAM ...

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

9. SOUTHERLY VIEW OF THE ACCESS ROAD TO THE DOWNSTREAM SIDE OF BIG DALTON DAM EXTENDING FROM THE DAM TO THE FOOTBRIDGE. VIEW FROM BIG DALTON DAM SHOWING THE TOE WEIR IN FOREGROUND AND FOOTBRIDGE IN BACKGROUND. - Big Dalton Dam, 2600 Big Dalton Canyon Road, Glendora, Los Angeles County, CA

CE-UV/VIS and CE-MS for monitoring organic impurities during the downstream processing of fermentative-produced lactic acid from second-generation renewable feedstocks.

PubMed

Laube, Hendrik; Matysik, Frank-Michael; Schmidberger, Andreas; Mehlmann, Kerstin; Toursel, Andreas; Boden, Jana

2016-01-01

During the downstream process of bio-based bulk chemicals, organic impurities, mostly residues from the fermentation process, must be separated to obtain a pure and ready-to-market chemical. In this study, capillary electrophoresis was investigated for the non-targeting downstream process monitoring of organic impurities and simultaneous quantitative detection of lactic acid during the purification process of fermentatively produced lactic acid. The downstream process incorporated 11 separation units, ranging from filtration, adsorption and ion exchange to electrodialysis and distillation, and 15 different second-generation renewable feedstocks were processed into lactic acid. The identification of organic impurities was established through spiking and the utilization of an advanced capillary electrophoresis mass spectrometry system. A total of 53 % of the organic impurities were efficiently removed via bipolar electrodialysis; however, one impurity, pyroglutamic acid, was recalcitrant to separation. It was demonstrated that the presence of pyroglutamic acid disrupts the polymerization of lactic acid into poly lactic acid. Pyroglutamic acid was present in all lactic acid solutions, independent of the type of renewable resource or the bacterium applied. Pyroglutamic acid, also known as 5-oxoproline, is a metabolite in the glutathione cycle, which is present in all living microorganisms. pyroglutamic acid is found in many proteins, and during intracellular protein metabolism, N-terminal glutamic acid and glutamine residues can spontaneously cyclize to become pyroglutamic acid. Hence, the concentration of pyroglutamic acid in the lactic acid solution can only be limited to a certain amount. The present study proved the capillary electrophoresis system to be an important tool for downstream process monitoring. The high product concentration encountered in biological production processes did not hinder the capillary electrophoresis from separating and detecting organic

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

NASA Astrophysics Data System (ADS)

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

2014-12-01

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

Targeting interleukin-6 for noninfectious uveitis

PubMed Central

Lin, Phoebe

2015-01-01

Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in the pathogenesis of many immune-mediated disorders including several types of non-infectious uveitis. These uveitic conditions include Vogt-Koyanagi-Harada syndrome, uveitis associated with Behçet disease, and sarcoidosis. This review summarizes the role of IL-6 in immunity, highlighting its effect on Th17, Th1, and plasmablast differentiation. It reviews the downstream mediators activated in the process of IL-6 binding to its receptor complex. This review also summarizes the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab. The target, dosage, potential side effects, and potential uses of these biologics are summarized in this article based on the existing literature. In summary, anti-IL-6 therapy for non-infectious uveitis shows promise in terms of efficacy and side effect profile. PMID:26392750

User experience network. Erroneous downstream occlusion alarms may disable Smiths Medical CADD-Solis infusion pumps.

PubMed

2010-10-01

Due to an issue in manufacturing, downstream occlusion (DSO) sensors in some Smiths Medical CADD-Solis infusion pumps may drift out of calibration, potentially resulting in erroneous alarms that disable the units. Hospitals experiencing the problem should return affected units to Smiths Medical for recalibration (free of charge) and should consider testing all their CADD-Solis pumps during routine maintenance to ensure that they alarm appropriately for downstream occlusions.

Rett syndrome treatment in mouse models: searching for effective targets and strategies.

PubMed

Ricceri, Laura; De Filippis, Bianca; Laviola, Giovanni

2013-05-01

Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls with a prevalence of 1 in every 10,000 births; it represents the second most common cause of intellectual disability in females. Mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) have been identified as clear etiological factors in more than 90% of classical RTT cases. Whereas the mechanisms leading to the severe, progressive and specific neurological dysfunctions when this gene is mutated still remain to be elucidated, a series of different mouse models have been generated, bearing different Mecp2 mutation. Neurobehavioural analysis in these mouse lines have been carried out and phenotyping analysis can be now utilised to preclinically evaluate the effects of potential RTT treatments. This review summarizes the different results achieved in this research field taking into account different key targets identified to ameliorate RTT phenotype in mouse models, including those not directly downstream of MeCP2 and those limited to the early phases of postnatal development. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Internal Targeting and External Control: Phototriggered Targeting in Nanomedicine.

PubMed

Arrue, Lily; Ratjen, Lars

2017-12-07

The photochemical control of structure and reactivity bears great potential for chemistry, biology, and life sciences. A key feature of photochemistry is the spatiotemporal control over secondary events. Well-established applications of photochemistry in medicine are photodynamic therapy (PDT) and photopharmacology (PP). However, although both are highly localizable through the application of light, they lack cell- and tissue-specificity. The combination of nanomaterial-based drug delivery and targeting has the potential to overcome limitations for many established therapy concepts. Even more privileged seems the merger of nanomedicine and cell-specific targeting (internal targeting) controlled by light (external control), as it can potentially be applied to many different areas of medicine and pharmaceutical research, including the aforementioned PDT and PP. In this review a survey of the interface of photochemistry, medicine and targeted drug delivery is given, especially focusing on phototriggered targeting in nanomedicine. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Water Stress in Global Transboundary River Basins: Significance of Upstream Water Use on Downstream Stress

NASA Technical Reports Server (NTRS)

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

2016-01-01

Growing population and water demand have increased pressure on water resources in various parts of the globe, including many transboundary river basins. While the impacts of upstream water use on downstream water availability have been analyzed in many of these international river basins, this has not been systematically done at the global scale using coherent and comparable datasets. In this study, we aim to assess the change in downstream water stress due to upstream water use in the world's transboundary river basins. Water stress was first calculated considering only local water use of each sub-basin based on country-basin mesh, then compared with the situation when upstream water use was subtracted from downstream water availability. Wefound that water stress was generally already high when considering only local water use, affecting 0.95-1.44 billion people or 33%-51% of the population in transboundary river basins. After accounting for upstream water use, stress level increased by at least 1 percentage-point for 30-65 sub-basins, affecting 0.29-1.13 billion people. Altogether 288 out of 298 middle-stream and downstream sub-basin areas experienced some change in stress level. Further, we assessed whether there is a link between increased water stress due to upstream water use and the number of conflictive and cooperative events in the transboundary river basins, as captured by two prominent databases. No direct relationship was found. This supports the argument that conflicts and cooperation events originate from a combination of different drivers, among which upstream-induced water stress may play a role. Our findings contribute to better understanding of upstream-downstream dynamics in water stress to help address water allocation problems.

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

PubMed Central

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

2017-01-01

Autoantibodies to the ANG II type I receptor (AT1-AA) are associated with preeclampsia (PE). We found that vitamin D supplementation reduced AT1-AA and blood pressure (MAP) in the RUPP rat model of PE. However, it was undetermined whether the decrease in AT1-AA was the mechanism whereby vitamin D lowered MAP or if it were through factors downstream of AT1-AA. Uterine artery resistance index, placental ET-1, and soluble FMS-like tyrosine kinase-1 are increased with AT1-AA-induced hypertension and are considered markers of PE in pregnant women. Therefore, we hypothesized that vitamin D would reduce PE factors during AT1-AA-induced hypertension and could lower blood pressure in a model of hypertension during pregnancy without PE features. Either ANG II (50 ng·kg−1·day) or AT1-AA (1:40) was infused from gestational day (GD) 12–19. vitamin D2 (VD2, 270 IU/day) or vitamin D3 (VD3, 15 IU/day) was administered orally from GD14–GD18. MAP (mmHg) increased in AT1-AA (121 ± 4) and ANG II (113 ± 1)-infused pregnant rats compared with normal pregnant rats (NP) (101 ± 2) but was lower in AT1-AA+VD2 (105 ± 2), AT1-AA+VD3 (109 ± 2), ANG II+VD2 (104 ± 4), and ANG II+VD3 (104 ± 3). VD2 and/or VD3 improved PE features associated with AT1-AA during pregnancy, while ANG II did not induce such features, supporting the hypothesis that AT1-AA induces PE features during pregnancy, and these are improved with vitamin D. In this study, we demonstrate that vitamin D improved many factors associated with PE and reduced blood pressure in a hypertensive model without PE features, indicating that vitamin D could be beneficial for various hypertensive disorders of pregnancy. PMID:27903510

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

PubMed

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

2017-01-01

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

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

PubMed

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

2013-11-01

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

Prostanoid receptor EP2 as a therapeutic target.

PubMed

Ganesh, Thota

2014-06-12

Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-11-08

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

Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis.

PubMed

Heidker, Rebecca M; Emerson, Mitchell R; LeVine, Steven M

2017-08-01

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc . Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g. , oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g. , ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

miR-133 is a key negative regulator of CDC42-PAK pathway in gastric cancer.

PubMed

Cheng, Zhenguo; Liu, Funan; Wang, Guanqiao; Li, Yanshu; Zhang, Hongyan; Li, Feng

2014-12-01

Cell division cycle 42 (CDC42), an important member of the Ras homolog (Rho) family, plays a key role in regulating multiple cellular processes such as cell cycle progression, migration, cell cytoskeleton organization, cell fate determination and differentiation. Among the downstream effectors of CDC42, P21-activated kinases (PAKs) obtain the most attention. Although a large body of evidence indicates that CDC42/PAKs pathway plays important role in tumor growth, invasion and metastasis, the mechanism of their negative regulation remains unclear. Here, we identified CDC42, a PAKs activating factor, was a target of miR-133. Ectopic overexpression of miRNAs not only downregulated CDC42 expression and PAKs activation, but also inhibited cancer cell proliferation and migration. We also found that miR-133 was down-regulated in 180 pairs gastric cancer tissues. miR-133 expression was negatively associated with tumor size, invasion depth and peripheral organ metastasis. Besides, dysfunction of miR-133 was an independent prognosis factor for overall survival. Our findings could provide new insights into the molecular mechanisms of gastric carcinogenesis, and may help facilitating development of CDC42/PAK-based therapies for human cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Downstream effects of ROCK signaling in cultured human corneal stromal cells: microarray analysis of gene expression.

PubMed

Harvey, Stephen A K; Anderson, Susan C; SundarRaj, Nirmala

2004-07-01

Rho-associated coiled-coil-containing protein kinase (ROCK) is a downstream target of Rho GTPase signaling and regulates the assembly of stress fibers. Previous reports indicate that Rho/ROCK signaling is involved in the regulation of several cellular processes, some of which may be cell-type specific and are probably critical to corneal stromal cell activation. The present study identified ROCK-regulated gene expression in corneal stromal cells. Corneal stromal cells derived from eyes of three different donors were cultured to yield the following designated phenotypes: baseline fibroblasts (DMEM with 10% serum), activated fibroblasts (10% serum+bFGF+heparin), and myofibroblasts (1% serum+TGF-beta 1). Cells were exposed to the ROCK inhibitor Y-27632 or vehicle for 12 hours, and transcript levels altered by ROCK inhibition were identified with oligonucleotide microarrays (GeneChips; Affymetrix, Santa Clara, CA). In these phenotypes, Y-27632 caused marked (twofold or more) increases or decreases in 14/4, 12/3, and 15/10 transcripts. In both fibroblast groups Y-27632-treatment increased expression of endothelin receptors and of parathyroid hormone-like hormone. The upregulation of alpha-smooth muscle actin in myofibroblasts was attenuated by Y-27632. Combining data from all groups identified ROCK-supported (Y-27632 inhibitable) expression of 10 transcripts, including ribonucleotide reductase M2, the cyclin B1-CDC2-CKS2 system, and four mitotic spindle-associated proteins. ROCK inhibition causes broad inhibition of DNA synthesis and mitosis and causes changes that are different between (bFGF-activated) fibroblasts and (TGF-beta 1-induced) myofibroblasts. Thus, Rho/ROCK signaling regulates both common and distinct downstream events in corneal stromal cells activated (differentiated) to fibroblast or myofibroblast phenotype.

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

48. View of unlined canal downstream from MundyLoss bridge, from ...

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

48. View of unlined canal downstream from Mundy-Loss bridge, from north side of canal looking southwest. Photo by Robin Lee Tedder, Puget Power, 1989. - Puget Sound Power & Light Company, White River Hydroelectric Project, 600 North River Avenue, Dieringer, Pierce County, WA

Acting Diverse: Target Group Orientation as Key Competence in Engineering Education

ERIC Educational Resources Information Center

Ihsen, S.; Buschmeyer, A.

2007-01-01

International companies are recognised by equity between men and women as well as between other different groups (Diversity) as an economic factor and incorporate it into their company visions. Mixed teams are set up to design target group-oriented products, for example in automotive engineering. Therefore they need employees who represent the…

Structure of Yeast OSBP-Related Protein Osh1 Reveals Key Determinants for Lipid Transport and Protein Targeting at the Nucleus-Vacuole Junction.

PubMed

Manik, Mohammad Kawsar; Yang, Huiseon; Tong, Junsen; Im, Young Jun

2017-04-04

Yeast Osh1 belongs to the oxysterol-binding protein (OSBP) family of proteins and contains multiple targeting modules optimized for lipid transport at the nucleus-vacuole junction (NVJ). The key determinants for NVJ targeting and the role of Osh1 at NVJs have remained elusive because of unknown lipid specificities. In this study, we determined the structures of the ankyrin repeat domain (ANK), and OSBP-related domain (ORD) of Osh1, in complex with Nvj1 and ergosterol, respectively. The Osh1 ANK forms a unique bi-lobed structure that recognizes a cytosolic helical segment of Nvj1. We discovered that Osh1 ORD binds ergosterol and phosphatidylinositol 4-phosphate PI(4)P in a competitive manner, suggesting counter-transport function of the two lipids. Ergosterol is bound to the hydrophobic pocket in a head-down orientation, and the structure of the PI(4)P-binding site in Osh1 is well conserved. Our results suggest that Osh1 performs non-vesicular transport of ergosterol and PI(4)P at the NVJ. Copyright © 2017 Elsevier Ltd. All rights reserved.

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 Central

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

2016-01-01

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

[Downstream migration, behavior, and distribution of fish fry in the lower reaches of the Ozernaya River (southwestern Kamchatka)].

PubMed

Pavlov, D S; Kirillova, E A; Kirillov, P I; Nezdoliĭ, V K

2015-01-01

Fry of five species of salmonids are found in the lower reaches of the Ozernaya River. The most abundant are chum salmon and pink salmon which compose the bulk of fry which migrate downstream from the river to the sea. The dates and duration of migration of particular species differed according to the specific traits of their biology. Pink salmon is characterized by a simple migration strategy: it migrated downstream in a short time after emergence from theground. Chum salmon has two strategies of downstream migration: some fry start migration soon after emergence, and others remained in the river for several weeks. Downstream migration of pink salmon occurred mainly at night in contrast to that of chum salmon, over 24 h, the part of daytime increased with growth, of the fish. Migration of pink salmon was passive. Passive migration of chum salmon changed into active-passive with growth of the fish. The ratio of fish in the inshore zone and in the current was different in the course of 24 h. The number of fish in the inshore zone decreased in the period of intensive downstream migration.

Triggers of key calcium signals during erythrocyte invasion by Plasmodium falciparum

PubMed Central

Gao, Xiaohong; Gunalan, Karthigayan; Yap, Sally Shu Lin; Preiser, Peter R.

2013-01-01

Invasion of erythrocytes by Plasmodium falciparum merozoites is a complex multi-step process mediated by specific interactions between host receptors and parasite ligands. Reticulocyte-binding protein homologues (RHs) and erythrocyte-binding-like (EBL) proteins are discharged from specialized organelles and used in early steps of invasion. Here we show that monoclonal antibodies against PfRH1 (an RH) block merozoite invasion by specifically inhibiting calcium signalling in the parasite, whereas invasion-inhibiting monoclonal antibodies targeting EBA175 (an EBL protein) have no effect on signalling. We further show that inhibition of this calcium signalling prevents EBA175 discharge and thereby formation of the junction between parasite and host cell. Our results indicate that PfRH1 has an initial sensing as well as signal transduction role that leads to the subsequent release of EBA175. They also provide new insights on how RH–host cell interactions lead to essential downstream signalling events in the parasite, suggesting new targets for malaria intervention. PMID:24280897

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

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

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

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

Immunoglobulin class switch DNA recombination: induction, targeting and beyond

PubMed Central

Xu, Zhenming; Zan, Hong; Pone, Egest J.; Mai, Thach; Casali, Paolo

2012-01-01

Class switch DNA recombination (CSR) of the immunoglobulin heavy chain (IgH) locus is central to the maturation of the antibody response and critically requires the AID cytidine deaminase. CSR entails changes of the chromatin state and transcriptional activation of the IgH locus upstream and downstream switch (S) regions that are to undergo S-S DNA recombination, induction of AID, and targeting of CSR factors to S regions by 14-3-3 adaptors and as enabled by the transcription machinery and histone modifications. In this Review, we focus on recent advances in CSR induction and targeting. We also outline an integrated model of the assembly of macromolecular complexes that transduce critical epigenetic information to enzymatic effectors of the CSR machinery. PMID:22728528

VIEW OF FOSSIL CREEK DIVERSION DAM FROM DOWNSTREAM (INCLUDES 1950s ...

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

VIEW OF FOSSIL CREEK DIVERSION DAM FROM DOWNSTREAM (INCLUDES 1950s AUTOMATIC/REMOTE CONTROL SLUICE GATE IN UPPER CENTER OF DAM, NORTH SIDE). LOOKING NORTH-NORTHWEST - Childs-Irving Hydroelectric Project, Fossil Creek Diversion Dam, Forest Service Road 708/502, Camp Verde, Yavapai County, AZ

40 CFR 80.219 - Designation and downstream requirements for GPA gasoline.

Code of Federal Regulations, 2011 CFR

2011-07-01

... requirements for GPA gasoline. 80.219 Section 80.219 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Gasoline Sulfur Geographic Phase-in Program § 80.219 Designation and downstream requirements for GPA gasoline. The requirements and...

40 CFR 80.219 - Designation and downstream requirements for GPA gasoline.

Code of Federal Regulations, 2010 CFR

2010-07-01

... requirements for GPA gasoline. 80.219 Section 80.219 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Gasoline Sulfur Geographic Phase-in Program § 80.219 Designation and downstream requirements for GPA gasoline. The requirements and...

40 CFR 80.219 - Designation and downstream requirements for GPA gasoline.

Code of Federal Regulations, 2014 CFR

2014-07-01

... requirements for GPA gasoline. 80.219 Section 80.219 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Gasoline Sulfur Geographic Phase-in Program § 80.219 Designation and downstream requirements for GPA gasoline. The requirements and...

40 CFR 80.219 - Designation and downstream requirements for GPA gasoline.

Code of Federal Regulations, 2012 CFR

2012-07-01

... requirements for GPA gasoline. 80.219 Section 80.219 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Gasoline Sulfur Geographic Phase-in Program § 80.219 Designation and downstream requirements for GPA gasoline. The requirements and...

40 CFR 80.219 - Designation and downstream requirements for GPA gasoline.

Code of Federal Regulations, 2013 CFR

2013-07-01

... requirements for GPA gasoline. 80.219 Section 80.219 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Gasoline Sulfur Geographic Phase-in Program § 80.219 Designation and downstream requirements for GPA gasoline. The requirements and...

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

PubMed

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

2016-11-15

Climate change is expected to influence infection risks while bathing downstream of sewage emissions from combined sewage overflows (CSOs) or waste water treatment plants (WWTPs) due to changes in pathogen influx, rising temperatures and changing flow rates of the receiving waters. In this study, climate change impacts on the surface water concentrations of Campylobacter, Cryptosporidium and norovirus originating from sewage were modelled. Quantitative microbial risk assessment (QMRA) was used to assess changes in risks of infection. In general, infection risks downstream of WWTPs are higher than downstream CSOs. Even though model outputs show an increase in CSO influxes, in combination with changes in pathogen survival, dilution within the sewage system and bathing behaviour, the effects on the infection risks are limited. However, a decrease in dilution capacity of surface waters could have significant impact on the infection risks of relatively stable pathogens like Cryptosporidium and norovirus. Overall, average risks are found to be higher downstream WWTPs compared to CSOs. Especially with regard to decreased flow rates, adaptation measures on treatment at WWTPs may be more beneficial for human health than decreasing CSO events. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Brucella TIR-like protein TcpB/Btp1 specifically targets the host adaptor protein MAL/TIRAP to promote infection.

PubMed

Li, Wenna; Ke, Yuehua; Wang, Yufei; Yang, Mingjuan; Gao, Junguang; Zhan, Shaoxia; Xinying, Du; Huang, Liuyu; Li, Wenfeng; Chen, Zeliang; Li, Juan

2016-08-26

Brucella spp. are known to avoid host immune recognition and weaken the immune response to infection. Brucella like accomplish this by employing two clever strategies, called the stealth strategy and hijacking strategy. The TIR domain-containing protein (TcpB/Btp1) of Brucella melitensis is thought to be involved in inhibiting host NF-κB activation by binding to adaptors downstream of Toll-like receptors. However, of the five TIR domain-containing adaptors conserved in mammals, whether MyD88 or MAL, even other three adaptors, are specifically targeted by TcpB has not been identified. Here, we confirmed the effect of TcpB on B.melitensis virulence in mice and found that TcpB selectively targets MAL. By using siRNA against MAL, we found that TcpB from B.melitensis is involved in intracellular survival and that MAL affects intracellular replication of B.melitensis. Our results confirm that TcpB specifically targets MAL/TIRAP to disrupt downstream signaling pathways and promote intra-host survival of Brucella spp. Copyright © 2016 Elsevier Inc. All rights reserved.

Initiated chemical vapor deposition polymers for high peak-power laser targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baxamusa, Salmaan H.; Lepro, Xavier; Lee, Tom

2016-12-05

Here, we report two examples of initiated chemical vapor deposition (iCVD) polymers being developed for use in laser targets for high peak-power laser systems. First, we show that iCVD poly(divinylbenzene) is more photo-oxidatively stable than the plasma polymers currently used in laser targets. Thick layers (10–12 μm) of this highly crosslinked polymer can be deposited with near-zero intrinsic film stress. Second, we show that iCVD epoxy polymers can be crosslinked after deposition to form thin adhesive layers for assembling precision laser targets. The bondlines can be made as thin as ~ 1 μm, approximately a factor of 2 thinner thanmore » achievable using viscous resin-based adhesives. These bonds can withstand downstream coining and stamping processes.« less

Experimental Measurement-Device-Independent Quantum Key Distribution

NASA Astrophysics Data System (ADS)

Liu, Yang; Chen, Teng-Yun; Wang, Liu-Jun; Liang, Hao; Shentu, Guo-Liang; Wang, Jian; Cui, Ke; Yin, Hua-Lei; Liu, Nai-Le; Li, Li; Ma, Xiongfeng; Pelc, Jason S.; Fejer, M. M.; Peng, Cheng-Zhi; Zhang, Qiang; Pan, Jian-Wei

2013-09-01

Quantum key distribution is proven to offer unconditional security in communication between two remote users with ideal source and detection. Unfortunately, ideal devices never exist in practice and device imperfections have become the targets of various attacks. By developing up-conversion single-photon detectors with high efficiency and low noise, we faithfully demonstrate the measurement-device-independent quantum-key-distribution protocol, which is immune to all hacking strategies on detection. Meanwhile, we employ the decoy-state method to defend attacks on a nonideal source. By assuming a trusted source scenario, our practical system, which generates more than a 25 kbit secure key over a 50 km fiber link, serves as a stepping stone in the quest for unconditionally secure communications with realistic devices.

Experimental measurement-device-independent quantum key distribution.

PubMed

Liu, Yang; Chen, Teng-Yun; Wang, Liu-Jun; Liang, Hao; Shentu, Guo-Liang; Wang, Jian; Cui, Ke; Yin, Hua-Lei; Liu, Nai-Le; Li, Li; Ma, Xiongfeng; Pelc, Jason S; Fejer, M M; Peng, Cheng-Zhi; Zhang, Qiang; Pan, Jian-Wei

2013-09-27

Quantum key distribution is proven to offer unconditional security in communication between two remote users with ideal source and detection. Unfortunately, ideal devices never exist in practice and device imperfections have become the targets of various attacks. By developing up-conversion single-photon detectors with high efficiency and low noise, we faithfully demonstrate the measurement-device-independent quantum-key-distribution protocol, which is immune to all hacking strategies on detection. Meanwhile, we employ the decoy-state method to defend attacks on a nonideal source. By assuming a trusted source scenario, our practical system, which generates more than a 25 kbit secure key over a 50 km fiber link, serves as a stepping stone in the quest for unconditionally secure communications with realistic devices.

Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR).

PubMed

Xiao, Kunhong; Sun, Jinpeng; Kim, Jihee; Rajagopal, Sudarshan; Zhai, Bo; Villén, Judit; Haas, Wilhelm; Kovacs, Jeffrey J; Shukla, Arun K; Hara, Makoto R; Hernandez, Marylens; Lachmann, Alexander; Zhao, Shan; Lin, Yuan; Cheng, Yishan; Mizuno, Kensaku; Ma'ayan, Avi; Gygi, Steven P; Lefkowitz, Robert J

2010-08-24

beta-Arrestin-mediated signaling downstream of seven transmembrane receptors (7TMRs) is a relatively new paradigm for signaling by these receptors. We examined changes in protein phosphorylation occurring when HEK293 cells expressing the angiotensin II type 1A receptor (AT1aR) were stimulated with the beta-arrestin-biased ligand Sar(1), Ile(4), Ile(8)-angiotensin (SII), a ligand previously found to signal through beta-arrestin-dependent, G protein-independent mechanisms. Using a phospho-antibody array containing 46 antibodies against signaling molecules, we found that phosphorylation of 35 proteins increased upon SII stimulation. These SII-mediated phosphorylation events were abrogated after depletion of beta-arrestin 2 through siRNA-mediated knockdown. We also performed an MS-based quantitative phosphoproteome analysis after SII stimulation using a strategy of stable isotope labeling of amino acids in cell culture (SILAC). We identified 1,555 phosphoproteins (4,552 unique phosphopeptides), of which 171 proteins (222 phosphopeptides) showed increased phosphorylation, and 53 (66 phosphopeptides) showed decreased phosphorylation upon SII stimulation of the AT1aR. This study identified 38 protein kinases and three phosphatases whose phosphorylation status changed upon SII treatment. Using computational approaches, we performed system-based analyses examining the beta-arrestin-mediated phosphoproteome including construction of a kinase-substrate network for beta-arrestin-mediated AT1aR signaling. Our analysis demonstrates that beta-arrestin-dependent signaling processes are more diverse than previously appreciated. Notably, our analysis identifies an AT1aR-mediated cytoskeletal reorganization network whereby beta-arrestin regulates phosphorylation of several key proteins, including cofilin and slingshot. This study provides a system-based view of beta-arrestin-mediated phosphorylation events downstream of a 7TMR and opens avenues for research in a rapidly evolving area

Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells.

PubMed

Ning, Shang-lei; Zheng, Wen-shuai; Su, Jing; Liang, Nan; Li, Hui; Zhang, Dao-lai; Liu, Chun-hua; Dong, Jun-hong; Zhang, Zheng-kui; Cui, Min; Hu, Qiao-Xia; Chen, Chao-chao; Liu, Chang-hong; Wang, Chuan; Pang, Qi; Chen, Yu-xin; Yu, Xiao; Sun, Jin-peng

2015-11-01

Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. Apoptosis in pancreatic beta cell apoptosis was evaluated using Hoechst-33342 staining, TUNEL assays and Annexin-V-FITC/PI staining. Insulin secretion and second messenger production were monitored using ELISAs. Protein and phospho-protein levels were determined by Western blotting. A glucose tolerance test was carried out to examine the functions of CCK-8s in streptozotocin-induced diabetic mice. The sulfated carboxy-terminal octapeptide CCK26-33 amide (CCK-8s) activated CCK1 receptors and induced accumulation of both IP3 and cAMP. Whereas Gq -PLC-IP3 signalling was required for the CCK-8s-induced insulin secretion under low-glucose conditions, Gs -PKA/Epac signalling contributed more strongly to the CCK-8s-mediated insulin secretion in high-glucose conditions. CCK-8s also promoted formation of the CCK1 receptor/β-arrestin-1 complex in pancreatic beta cells. Using β-arrestin-1 knockout mice, we demonstrated that β-arrestin-1 is a key mediator of both CCK-8s-mediated insulin secretion and of its the protective effect against apoptosis in pancreatic beta cells. The anti-apoptotic effects of β-arrestin-1 occurred through cytoplasmic late-phase ERK activation, which activates the 90-kDa ribosomal S6 kinase-phospho-Bcl-2-family protein pathway. Knowledge of different CCK1 receptor-activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK1 receptor ligands for the development of new anti-diabetic drugs. © 2015 The British Pharmacological Society.

Groundwater-Surface Water Interactions and Downstream Transport of Water, Heat, and Solutes in a Hydropeaked River

NASA Astrophysics Data System (ADS)

Ferencz, S. B.; Cardenas, M. B.; Neilson, B. T.; Watson, J.

2017-12-01

A majority of the world's largest river systems are regulated by dams. In addition to being used for water resources management and flood prevention, many large dams are also used for hydroelectric power generation. In the United States, dams account for 7% of domestic electricity, and hydropower accounts for 16% of worldwide electricity production. To help meet electricity demand during peak usage times, hydropower utilities often increase their releases of water during high demand periods. This practice, termed hydropeaking, can cause large transient flow regimes downstream of hydroelectric dams. These transient flow increases can result in order of magnitude daily fluctuations in discharge, and the released water can have different thermal and chemical properties than ambient river water. As hydropeaking releases travel downstream, the temporary rise in stage and increase in discharge can enhance surface water-groundwater (SW-GW) exchange between the river and its alluvial aquifer. This dam-induced SW-GW exchange, combined with hydrodynamic attenuation and heat exchange processes, result in complex responses downstream. The dam-regulated Lower Colorado River downstream of Austin, TX was used as a natural laboratory to observe SW-GW interactions and downstream transport of water, heat, and solutes under hydropeaking conditions. To characterize SW-GW interactions, well transects were installed in the banks of the river to observe exchanges between the river and alluvial aquifer. The well transects were installed at three different distances from the dam (15km, 35km, and 80km). At each well transect conductivity, temperature, and pressure sensors were deployed in the monitoring wells and in the channel. Additional conductivity and temperature sensors were deployed along the study reach to provide a more detailed record of heat and solute transport during hydropeaking releases. The field data spans over two months of daily dam releases that were punctuated by two

A downstream voyage with mercury

USGS Publications Warehouse

Heinz, Gary

2016-01-01

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

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

Human sperm liver receptor homolog-1 (LRH-1) acts as a downstream target of the estrogen signaling pathway

PubMed Central

Montanaro, Daniela; Santoro, Marta; Carpino, Amalia; Perrotta, Ida; De Amicis, Francesca; Sirianni, Rosa; Rago, Vittoria; Gervasi, Serena; Aquila, Saveria

2015-01-01

In the last decade, the study of human sperm anatomy, at molecular level, has revealed the presence of several nuclear protein receptors. In this work, we examined the expression profile and the ultrastructural localization of liver receptor homolog-1 (LRH-1) in human spermatozoa. We evidenced the presence of the receptor by Western blotting and real time-RT-PCR. Furthermore, we used immunogold electron microscopy to investigate the sperm anatomical regions containing LRH-1. The receptor was mainly located in the sperm head, whereas its expression was reduced in the neck and across the tail. Interestingly, we observed the presence of LRH-1 in different stages of testicular germ cell development by immunohistochemistry. In somatic cells, it has been suggested that the LRH-1 pathway is tightly linked with estrogen signaling and the important role of estradiol has been widely studied in sperm cells. To assess the significance of LRH-1 in male gametes and to deepen understanding of the role of estrogens in these cells, we investigated important sperm features such as motility, survival and capacitation. Spermatozoa were treated with 10 nm estradiol and the inhibition of LRH-1 reversed the estradiol stimulatory action. From our data, we discovered that human spermatozoa can be considered a new site of expression for LRH-1, evidencing its role in sperm motility, survival and cholesterol efflux. Furthermore, we may presume that in spermatozoa the LRH-1 effects are closely integrated with the estrogen signaling, supporting LRH-1 as a downstream effector of the estradiol pathway on some sperm functions. PMID:26241668

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

EVI2B is a C/EBPα target gene required for granulocytic differentiation and functionality of hematopoietic progenitors.

PubMed

Zjablovskaja, Polina; Kardosova, Miroslava; Danek, Petr; Angelisova, Pavla; Benoukraf, Touati; Wurm, Alexander A; Kalina, Tomas; Sian, Stephanie; Balastik, Martin; Delwel, Ruud; Brdicka, Tomas; Tenen, Daniel G; Behre, Gerhard; Fiore, Fréderic; Malissen, Bernard; Horejsi, Vaclav; Alberich-Jorda, Meritxell

2017-04-01

Development of hematopoietic populations through the process of differentiation is critical for proper hematopoiesis. The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is a master regulator of myeloid differentiation, and the identification of C/EBPα target genes is key to understand this process. Here we identified the Ecotropic Viral Integration Site 2B (EVI2B) gene as a direct target of C/EBPα. We showed that the product of the gene, the transmembrane glycoprotein EVI2B (CD361), is abundantly expressed on the surface of primary hematopoietic cells, the highest levels of expression being reached in mature granulocytes. Using shRNA-mediated downregulation of EVI2B in human and murine cell lines and in primary hematopoietic stem and progenitor cells, we demonstrated impaired myeloid lineage development and altered progenitor functions in EVI2B-silenced cells. We showed that the compromised progenitor functionality in Evi2b-depleted cells can be in part explained by deregulation of cell proliferation and apoptosis. In addition, we generated an Evi2b knockout murine model and demonstrated altered properties of hematopoietic progenitors, as well as impaired G-CSF dependent myeloid colony formation in the knockout cells. Remarkably, we found that EVI2B is significantly downregulated in human acute myeloid leukemia samples characterized by defects in CEBPA. Altogether, our data demonstrate that EVI2B is a downstream target of C/EBPα, which regulates myeloid differentiation and functionality of hematopoietic progenitors.

Observational evidence of the downstream impact on tropical rainfall from stratospheric Kelvin waves

NASA Astrophysics Data System (ADS)

Zhang, Lei; Karnauskas, Kristopher B.; Weiss, Jeffrey B.; Polvani, Lorenzo M.

2017-08-01

Analysis of one continuous decade of daily, high-vertical resolution sounding data from five proximate islands in the western equatorial Pacific region reveals eastward and downward propagating Kelvin waves in the tropical stratosphere, with a zonal wave number one structure and a period of 15 days. By defining an initiation index, we find that these waves are primarily generated over the western Pacific warm pool and South America-tropical Atlantic sector, consistent with regions of frequent deep convection. The zonal phase speed of the stratospheric Kelvin waves (SKWs) is relatively slow ( 10 m s-1) over the initiation region due to coupling with deep convection, and becomes much faster ( 30-40 m s-1) once decoupled from the downstream troposphere. SKWs have significant impacts on downstream tropical rainfall through modulation of tropopause height. The cold phase of SKWs at tropopause leads to higher tropopause heights and more convection in tropics—with opposite impacts associated with the warm phase. Downstream tropical precipitation anomalies associated with these SKWs also propagate eastward with the same speed and zonal scale as observed SKWs. Interannual variability of the amplitude of the SKWs is shown to be associated with the Quasi-Biennial oscillation (QBO); implications for predictability are discussed.

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

From Process Development to Manufacturing: Lab-Intensive Courses in Downstream Bioprocessing

ERIC Educational Resources Information Center

Gilleskie, Gary L.; Reeves, Baley A.

2014-01-01

Most chemical engineering graduates work in industry, a fact that underscores the need for courses to provide experiences that prepare them for industry. The Biomanufacturing Training and Education Center (BTEC) at North Carolina State University has addressed this need by developing and delivering a comprehensive downstream bioprocessing program…

An experimental study of turbine vane heat transfer with leading edge and downstream film cooling

NASA Astrophysics Data System (ADS)

Nirmalan, V.; Hylton, L. D.

1989-06-01

This paper presents the effects of downstream film cooling, with and without leading edge showerhead film cooling, on turbine-vane external heat transfer. Steady-state experimental measurements were made in a three-vane linear two-dimensional cascade. The principal independent parameters were maintained over ranges consistent with actual engine conditions. The test matrix was structured to provide an assessment of the independent influence of parameters of interest, namely, exit Mach number, exit Reynolds number, coolant-to-gas temperature ratio, and coolant-to-gas pressure ratio. The data obtained indicate that considerable cooling benefits can be achieved by utilizing downstream film cooling. The downstream film cooling process was shown to be a complex interaction of two competing mechanisms. The thermal dilution effect, associated with the injection of relatively cold fluid, results in a decrease in the heat transfer to the airfoil. Conversely, the turbulence augmentation, produced by the injection process, results in increased heat transfer to the airfoil.

An experimental study of turbine vane heat transfer with leading edge and downstream film cooling

NASA Technical Reports Server (NTRS)

Nirmalan, V.; Hylton, L. D.

1989-01-01

This paper presents the effects of downstream film cooling, with and without leading edge showerhead film cooling, on turbine-vane external heat transfer. Steady-state experimental measurements were made in a three-vane linear two-dimensional cascade. The principal independent parameters were maintained over ranges consistent with actual engine conditions. The test matrix was structured to provide an assessment of the independent influence of parameters of interest, namely, exit Mach number, exit Reynolds number, coolant-to-gas temperature ratio, and coolant-to-gas pressure ratio. The data obtained indicate that considerable cooling benefits can be achieved by utilizing downstream film cooling. The downstream film cooling process was shown to be a complex interaction of two competing mechanisms. The thermal dilution effect, associated with the injection of relatively cold fluid, results in a decrease in the heat transfer to the airfoil. Conversely, the turbulence augmentation, produced by the injection process, results in increased heat transfer to the airfoil.

The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation.

PubMed

Meredith, Leslie J; Wang, Chiung-Min; Nascimento, Leticia; Liu, Runhua; Wang, Lizhong; Yang, Wei-Hsiung

2016-02-01

Transcription factor forkhead box protein P2 (FOXP2) plays an essential role in the development of language and speech. However, the transcriptional activity of FOXP2 regulated by the post-translational modifications remains unknown. Here, we demonstrated that FOXP2 is clearly defined as a SUMO target protein at the cellular levels as FOXP2 is covalently modified by both SUMO1 and SUMO3. Furthermore, SUMOylation of FOXP2 was significantly decreased by SENP2 (a specific SUMOylation protease). We further showed that FOXP2 is selectively SUMOylated in vivo on a phylogenetically conserved lysine 674 but the SUMOylation does not alter subcellular localization and stability of FOXP2. Interestingly, we observed that human etiological FOXP2 R553H mutation robustly reduces its SUMOylation potential as compared to wild-type FOXP2. In addition, the acidic residues downstream the core SUMO motif on FOXP2 are required for its full SUMOylation capacity. Finally, our functional analysis using reporter gene assays showed that SUMOylation may modulate transcriptional activity of FOXP2 in regulating downstream target genes (DISC1, SRPX2, and MiR200c). Altogether, we provide the first evidence that FOXP2 is a substrate for SUMOylation and SUMOylation of FOXP2 plays a functional role in regulating its transcriptional activity. © 2015 Wiley Periodicals, Inc.

The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation

PubMed Central

Meredith, Leslie J.; Wang, Chiung-Min; Nascimento, Leticia; Liu, Runhua; Wang, Lizhong; Yang, Wei-Hsiung

2017-01-01

Transcription factor forkhead box protein P2 (FOXP2) plays an essential role in the development of language and speech. However, the transcriptional activity of FOXP2 regulated by the post-translational modifications remains unknown. Here we demonstrated that FOXP2 is clearly defined as a SUMO target protein at the cellular levels as FOXP2 is covalently modified by both SUMO1 and SUMO3. Furthermore, SUMOylation of FOXP2 was significantly decreased by SENP2 (a specific SUMOylation protease). We further showed that FOXP2 is selectively SUMOylated in vivo on a phylogenetically conserved lysine 674 but the SUMOylation does not alter subcellular localization and stability of FOXP2. Interestingly, we observed that human etiological FOXP2 R553H mutation robustly reduces its SUMOylation potential as compared to wild-type FOXP2. In addition, the acidic residues downstream the core SUMO motif on FOXP2 are required for its full SUMOylation capacity. Finally, our functional analysis using reporter gene assays showed that SUMOylation may modulate transcriptional activity of FOXP2 in regulating downstream target genes (DISC1, SRPX2 and MiR200c). Altogether, we provide the first evidence that FOXP2 is a substrate for SUMOylation and SUMOylation of FOXP2 plays a functional role in regulating its transcriptional activity. PMID:26212494

A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity.

PubMed

Dasen, Jeremy S; Tice, Bonnie C; Brenner-Morton, Susan; Jessell, Thomas M

2005-11-04

Spinal motor neurons acquire specialized "pool" identities that determine their ability to form selective connections with target muscles in the limb, but the molecular basis of this striking example of neuronal specificity has remained unclear. We show here that a Hox transcriptional regulatory network specifies motor neuron pool identity and connectivity. Two interdependent sets of Hox regulatory interactions operate within motor neurons, one assigning rostrocaudal motor pool position and a second directing motor pool diversity at a single segmental level. This Hox regulatory network directs the downstream transcriptional identity of motor neuron pools and defines the pattern of target-muscle connectivity.

A Key Evolutionary Mutation Enhances DNA Binding of the FOXP2 Forkhead Domain.

PubMed

Morris, Gavin; Fanucchi, Sylvia

2016-04-05

Forkhead box (FOX) transcription factors share a conserved forkhead DNA binding domain (FHD) and are key role players in the development of many eukaryotic species. Their involvement in various congenital disorders and cancers makes them clinically relevant targets for novel therapeutic strategies. Among them, the FOXP subfamily of multidomain transcriptional repressors is unique in its ability to form DNA binding homo and heterodimers. The truncated FOXP2 FHD, in the absence of the leucine zipper, exists in equilibrium between monomeric and domain-swapped dimeric states in vitro. As a consequence, determining the DNA binding properties of the FOXP2 FHD becomes inherently difficult. In this work, two FOXP2 FHD hinge loop mutants have been generated to successfully prevent both the formation (A539P) and the dissociation (F541C) of the homodimers. This allows for the separation of the two species for downstream DNA binding studies. Comparison of DNA binding of the different species using electrophoretic mobility shift assay, fluorescence anisotropy and isothermal titration calorimetry indicates that the wild-type FOXP2 FHD binds DNA as a monomer. However, comparison of the DNA-binding energetics of the monomer and wild-type FHD, reveals that there is a difference in the mechanism of binding between the two species. We conclude that the naturally occurring reverse mutation (P539A) seen in the FOXP subfamily increases DNA binding affinity and may increase the potential for nonspecific binding compared to other FOX family members.

PIV measurements and flow characteristics downstream of mangrove root models

NASA Astrophysics Data System (ADS)

Kazemi, Amirkhosro; Curet, Oscar

2016-11-01

Mangrove forests attracted attentions as a solution to protect coastal areas exposed to sea-level rising, frequent storms, and tsunamis. Mangrove forests found in tide-dominated flow regions are characterized by their massive and complex root systems, which play a prominent role in the structure of tidal flow currents. To understand the role of mangrove roots in flow structure, we modeled mangrove roots with rigid and flexible arrays of cylinders with different spacing between them as well as different configurations. In this work, we investigate the fluid dynamics downstream of the models using a 2-D time-resolved particle image velocimetry (PIV) and flow visualization. We carried out experiments for four different Reynolds number based on cylinder diameters ranges from 2200 to 12000. We present time-averaged and time-resolved flow parameters including velocity distribution, vorticity, streamline, Reynolds shear stress and turbulent kinetic energy. The results show that the flow structure has different vortex shedding downstream of the cylinders due to interactions of shear layers separating from cylinders surface. The spectral analysis of the measured velocity data is also performed to obtain Strouhal number of the unsteady flow in the cylinder wake.

Evidence for cumulative temperature as an initiating and terminating factor in downstream migratory behavior of Atlantic salmon (Salmo salar) smolts

USGS Publications Warehouse

Zydlewski, G.B.; Haro, A.; McCormick, S.D.

2005-01-01

Temperature control of Atlantic salmon (Salmo salar) smolt migration was tested using a novel technique allowing nearly continuous monitoring of behavior with complete control over environmental conditions. Parr and presmolts were implanted with passive integrated transponder tags, placed in simulated streams, and monitored for upstream and downstream movements. Beginning 18 April, temperature was increased 1??C every third day (advanced), fourth day (ambient), and tenth day (delayed). Smolt downstream movements were initially low, peaked in mid-May, and subsequently declined under all conditions. Parr downstream movements were significantly lower than those of smolts in all treatments (0.8 ?? 0.5 movement??day-1 versus 26.5 ?? 4.5 movements??day-1, mean ?? SE) and showed no increase. At delayed temperatures, smolts sustained downstream movements through July; those under ambient and advanced conditions ceased activity by mid-June. Initiation and termination of downstream movements occurred at significantly different temperatures but at the same number of degree-days in all treatments. Physiological changes associated with smolting (gill Na+,K +-ATPase activity and plasma thyroxine) were coincident with behavioral changes. This is the first evidence of a behavioral component to the smolt window. We found that temperature experience over time is more relevant to initiation and termination of downstream movement than a temperature threshold. ?? 2005 NRC Canada.

Effect of Pulsed Plasma Jets on the Recovering Boundary Layer Downstream of a Reflected Shock Interaction

NASA Astrophysics Data System (ADS)

Greene, Benton; Clemens, Noel; Magari, Patrick; Micka, Daniel; Ueckermann, Mattheus

2015-11-01

Shock-induced turbulent boundary layer separation can have many detrimental effects in supersonic inlets including flow distortion and instability, structural fatigue, poor pressure recovery, and unstart. The current study investigates the effect of pulsed plasma jets on the recovering boundary layer downstream of a reflected shock wave-boundary layer interaction. The effects of pitch and skew angle of the jet as well as the heating parameter and discharge time scale are tested using several pulsing frequencies. In addition, the effect of the plasma jets on the undisturbed boundary layer at 6 mm and 11 mm downstream of the jets is measured. A pitot-static pressure probe is used to measure the velocity profile of the boundary layer 35 mm downstream of the plasma jets, and the degree of boundary layer distortion is compared between the different models and run conditions. Additionally, the effect of each actuator configuration on the shape of the mean separated region is investigated using surface oil flow visualization. Previous studies with lower energy showed a weak effect on the downstream boundary layer. The current investigation will attempt to increase this effect using a higher-energy discharge. Funded by AFRL through and SBIR in collaboration with Creare, LLC.

Kappa-Electrons Downstream of the Solar Wind Termination Shock

NASA Astrophysics Data System (ADS)

Fahr, H. J.

2017-12-01

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

Evidence-based identification of key beliefs explaining adult male circumcision motivation in Zimbabwe: targets for behavior change messaging.

PubMed

Montaño, Daniel E; Kasprzyk, Danuta; Hamilton, Deven T; Tshimanga, Mufuta; Gorn, Gerald

2014-05-01

Male circumcision (MC) reduces HIV acquisition among men, leading WHO/UNAIDS to recommend a goal to circumcise 80 % of men in high HIV prevalence countries. Significant investment to increase MC capacity in priority countries was made, yet only 5 % of the goal has been achieved in Zimbabwe. The integrated behavioral model (IBM) was used as a framework to investigate the factors affecting MC motivation among men in Zimbabwe. A survey instrument was designed based on elicitation study results, and administered to a representative household-based sample of 1,201 men aged 18-30 from two urban and two rural areas in Zimbabwe. Multiple regression analysis found all five IBM constructs significantly explained MC Intention. Nearly all beliefs underlying the IBM constructs were significantly correlated with MC Intention. Stepwise regression analysis of beliefs underlying each construct respectively found that 13 behavioral beliefs, 5 normative beliefs, 4 descriptive norm beliefs, 6 efficacy beliefs, and 10 control beliefs were significant in explaining MC Intention. A final stepwise regression of the five sets of significant IBM construct beliefs identified 14 key beliefs that best explain Intention. Similar analyses were carried out with subgroups of men by urban-rural and age. Different sets of behavioral, normative, efficacy, and control beliefs were significant for each sub-group, suggesting communication messages need to be targeted to be most effective for sub-groups. Implications for the design of effective MC demand creation messages are discussed. This study demonstrates the application of theory-driven research to identify evidence-based targets for intervention messages to increase men's motivation to get circumcised and thereby improve demand for male circumcision.

The Effects of Dams on Downstream Channel Characteristics in Pennsylvania and Maryland: Assessing the Potential Consequences of Dam Removal

NASA Astrophysics Data System (ADS)

Skalak, K. J.; Pizzuto, J. E.; Jenkins, P.

2003-12-01

The potential downstream effects of dam removal were assessed on fifteen sites of varying dam size and characteristics in Pennsylvania and Maryland. The dams ranged in size from a 30 cm high fish weir to a water supply dam 57 m high. Stream order ranged from 1 to 4. The dams are located in watersheds with varying degrees of human disturbance and urbanization. The dams are also operated differently, with significant consequences for hydraulic residence time and downstream flow variability. Most streams were alluvial, but 6 of the reaches were clearly bedrock channels. We hypothesize that the channel upstream, which is unaffected by the dam, will provide an accurate model for the channel downstream of the dam long after dam removal. Therefore, reaches upstream and downstream of the dam were compared to determine the effects of the dam as well as the condition of the stream that will ultimately develop decades after dam removal. Surprisingly, the dams had no consistent influence on channel morphology. However, the percentage of sand is significantly lower downstream than upstream: the mean % sand downstream is 11.47%, while the mean % sand upstream is 21.39%. The coarser fractions of the bed, as represented by the 84th percentile grain diameter, are unaffected by the presence of the dam. These results imply that decades after dam removal, the percentage of sand on the bed will increase, but the coarse fraction of the bed will remain relatively unchanged.

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

PubMed

Hayes, Maria; Tiwari, Brijesh K

2015-09-17

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

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.

The Impact of Impoundment on Mercury Bioaccumulation in Fish Downstream from a Newly Constructed Reservoir, Wujiang River, Southwest China.

PubMed

Li, Sixin; Zhou, Lianfeng; Chang, Jianbo; Yang, Zhi; Hu, Juxiang; Hongjun, Wang

2017-11-01

Mercury concentrations in fish were investigated downstream from a newly impounded subtropical reservoir in August 2008. After 6-7 months of reservoir impoundment, mean mercury concentration in fish from downstream is significantly increased by 1.9 times. Not only carnivorous fish but also benthic fish had significantly higher total mercury concentrations than others. No significant correlation was found between total mercury concentrations and body length or weight of 13 fish species. Compared with the pre-impoundment, total mercury in fish from downstream is significantly increased by reservoir impoundment, but the increased rate is lower than those in subarctic and temperate areas. Fish samples surpassed the Chinese hygienic standard for tolerances of mercury in foods increased by 4.3%. More attention should be given to fish mercury levels from downstream sites to prevent possible adverse effects on the health of local people.

Targeting Extracellular DNA to Deliver IGF-1 to the Injured Heart

NASA Astrophysics Data System (ADS)

Khan, Raffay S.; Martinez, Mario D.; Sy, Jay C.; Pendergrass, Karl D.; Che, Pao-Lin; Brown, Milton E.; Cabigas, E. Bernadette; Dasari, Madhuri; Murthy, Niren; Davis, Michael E.

2014-03-01

There is a great need for the development of therapeutic strategies that can target biomolecules to damaged myocardium. Necrosis of myocardium during a myocardial infarction (MI) is characterized by extracellular release of DNA, which can serve as a potential target for ischemic tissue. Hoechst, a histological stain that binds to double-stranded DNA can be conjugated to a variety of molecules. Insulin-like growth factor-1 (IGF-1), a small protein/polypeptide with a short circulating-half life is cardioprotective following MI but its clinical use is limited by poor delivery, as intra-myocardial injections have poor retention and chronic systemic presence has adverse side effects. Here, we present a novel delivery vehicle for IGF-1, via its conjugation to Hoechst for targeting infarcted tissue. Using a mouse model of ischemia-reperfusion, we demonstrate that intravenous delivery of Hoechst-IGF-1 results in activation of Akt, a downstream target of IGF-1 and protects from cardiac fibrosis and dysfunction following MI.

Mercury Handling for the Target System for a Muon Collider

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graves, Van B; Mcdonald, K; Kirk, H.

2012-01-01

The baseline target concept for a Muon Collider or Neutrino Factory is a free-stream mercury jet being impacted by an 8-GeV proton beam. The target is located within a 20-T magnetic field, which captures the generated pions that are conducted to a downstream decay channel. Both the mercury and the proton beam are introduced at slight downward angles to the magnetic axis. A pool of mercury serves as a receiving reservoir for the mercury and a dump for the unexpended proton beam. The impact energy of the remaining beam and jet are substantial, and it is required that splashes andmore » waves be controlled in order to minimize the potential for interference of pion production at the target. Design issues discussed in this paper include the nozzle, splash mitigation in the mercury pool, the mercury containment vessel, and the mercury recirculation system.« less

IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma

PubMed Central

2013-01-01

Background High-grade osteosarcoma is an aggressive tumor most often developing in the long bones of adolescents, with a second peak in the 5th decade of life. Better knowledge on cellular signaling in this tumor may identify new possibilities for targeted treatment. Methods We performed gene set analysis on previously published genome-wide gene expression data of osteosarcoma cell lines (n=19) and pretreatment biopsies (n=84). We characterized overexpression of the insulin-like growth factor receptor (IGF1R) signaling pathways in human osteosarcoma as compared with osteoblasts and with the hypothesized progenitor cells of osteosarcoma – mesenchymal stem cells. This pathway plays a key role in the growth and development of bone. Since most profound differences in mRNA expression were found at and upstream of the receptor of this pathway, we set out to inhibit IR/IGF1R using OSI-906, a dual inhibitor for IR/IGF1R, on four osteosarcoma cell lines. Inhibitory effects of this drug were measured by Western blotting and cell proliferation assays. Results OSI-906 had a strong inhibitory effect on proliferation of 3 of 4 osteosarcoma cell lines, with IC50s below 100 nM at 72 hrs of treatment. Phosphorylation of IRS-1, a direct downstream target of IGF1R signaling, was inhibited in the responsive osteosarcoma cell lines. Conclusions This study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma. PMID:23688189

Timing and Targeting of Treatment in Left Ventricular Hypertrophy.

PubMed

Nam, Deokhwa; Reineke, Erin L

2017-01-01

In most clinical cases, left ventricular hypertrophy (LVH) occurs over time from persistent cardiac stress. At the molecular level, this results in both transient and long-term changes to metabolic, sarcomeric, ion handling, and stress signaling pathways. Although this is initially an adaptive change, the mechanisms underlying LVH eventually lead to maladaptive changes including fibrosis, decreased cardiac function, and failure. Understanding the regulators of long-term changes, which are largely driven by transcriptional remodeling, is a crucial step in identifying novel therapeutic targets for preventing the downstream negative effects of LVH and treatments that could reverse or prevent it. The development of effective therapeutics, however, will require a critical understanding of what to target, how to modify important pathways, and how to identify the stage of pathology in which a specific treatment should be used.

Morphology analysis in middle-downstream area of Progo River due to the debris flow

NASA Astrophysics Data System (ADS)

Fitriadin, Ahmad Azmi; Ikhsan, Jaza'ul; Harsanto, Puji

2017-06-01

One of the problems that occur in Progo River is the formation of sediment in the downstream section. The sediment material in the upstream becomes the source of sediment at the downstream area. Excess sediment supply from the upstream causes morphological changes in a relatively short time. The morphological changes in riverbed will affect hydraulics conditions. Hydraulic has an important role in the process of aggradation and degradation in the riverbed. Furthermore, the process of erosion and sedimentation will affect the stability of the construction in the water. In Progo River, there are some buildings of infrastructure such as revetment, bridge, irrigation intake, groundsill, and weir. Based on the results of a numerical model of the hydraulic analysis system, there was approximately 87,000,000 m3 of sediment on Progo River in 2015. In fact, aggradation and degradation occurred very intensively in the middle-downstream area of Progo River. Sediment movement simulation also showed that the sediment supply of lava could prevent excessive bed degradation. Nevertheless, the absence of sediment supply will lead to bed degradation process. It indicates that the management of the sediment supply in the upstream area must be managed properly.

Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Calcium Binding Properties and Allosteric Regulation of Downstream Regulatory Element Antagonist Modulator (DREAM).

PubMed

Zhang, Jun; Li, Jing; Craig, Theodore A; Kumar, Rajiv; Gross, Michael L

2017-07-18

Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca 2+ -binding protein that also binds to a specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca 2+ but detaches from DRE under Ca 2+ stimulation, allowing gene expression. The Ca 2+ binding properties of DREAM and the consequences of the binding on protein structure are key to understanding the function of DREAM. Here we describe the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis to investigate the Ca 2+ binding properties and the subsequent conformational changes of full-length DREAM. We demonstrate that all EF-hands undergo large conformation changes upon calcium binding even though the EF-1 hand is not capable of binding to Ca 2+ . Moreover, EF-2 is a lower-affinity site compared to EF-3 and -4 hands. Comparison of HDX profiles between wild-type DREAM and two EF-1 mutated constructs illustrates that the conformational changes in the EF-1 hand are induced by long-range structural interactions. HDX analyses also reveal a conformational change in an N-terminal leucine-charged residue-rich domain (LCD) remote from Ca 2+ -binding EF-hands. This LCD domain is responsible for the direct interaction between DREAM and cAMP response element-binding protein (CREB) and regulates the recruitment of the co-activator, CREB-binding protein. These long-range interactions strongly suggest how conformational changes transmit the Ca 2+ signal to CREB-mediated gene transcription.

The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Kyung-Chang; School of Life Science and Biotechnology, Korea University, Seoul; Kim, Hyeon Guk

2011-01-14

Research highlights: {yields} CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. {yields} CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. {yields} HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. {yields} H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. {yields} HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also asmore » the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56{sup Lck}, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56{sup Lck}, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new

Key Stage 3 Pupils' Views about Reading

ERIC Educational Resources Information Center

Atkinson, Cathy

2006-01-01

Recent developments in literacy teaching have tended to target the needs of primary, rather than high school pupils and focus on technical, rather than affective aspects of reading. This paper describes a questionnaire-based study undertaken to identify perceptions and views held by Key Stage 3 readers of different ages, genders and abilities.…

European downstream oil industry safety performance : statistical summary of reported incidents, 1998

DOT National Transportation Integrated Search

1999-07-01

This report is the fifth by CONCAWE reviewing the safety performance of the downstream oil industry in Europe. The area of coverage is primarily the EU, EEA and Hungary, but for some companies the data for other European countries such as Poland, Cze...

European downstream oil industry safety performance : statistical summary of reported incidents, 1996

DOT National Transportation Integrated Search

1997-12-01

This report is the third by CONCAWE reviewing the safety performance of the downstream oil industry in Western Europe. It includes the results of 28 companies which together represent over 90% of the oil refining capacity in Europe. It is therefore a...

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

PubMed Central

Hayes, Maria; Tiwari, Brijesh K.

2015-01-01

Bioactive peptides and carbohydrates are sourced from a myriad of plant, animal and insects and have huge potential for use as food ingredients and pharmaceuticals. However, downstream processing bottlenecks hinder the potential use of these natural bioactive compounds and add cost to production processes. This review discusses the health benefits and bioactivities associated with peptides and carbohydrates of natural origin and downstream processing methodologies and novel processes which may be used to overcome these. PMID:26393573

T-REX on-demand redox targeting in live cells.

PubMed

Parvez, Saba; Long, Marcus J C; Lin, Hong-Yu; Zhao, Yi; Haegele, Joseph A; Pham, Vanha N; Lee, Dustin K; Aye, Yimon

2016-12-01

This protocol describes targetable reactive electrophiles and oxidants (T-REX)-a live-cell-based tool designed to (i) interrogate the consequences of specific and time-resolved redox events, and (ii) screen for bona fide redox-sensor targets. A small-molecule toolset comprising photocaged precursors to specific reactive redox signals is constructed such that these inert precursors specifically and irreversibly tag any HaloTag-fused protein of interest (POI) in mammalian and Escherichia coli cells. Syntheses of the alkyne-functionalized endogenous reactive signal 4-hydroxynonenal (HNE(alkyne)) and the HaloTag-targetable photocaged precursor to HNE(alkyne) (also known as Ht-PreHNE or HtPHA) are described. Low-energy light prompts photo-uncaging (t 1/2 <1-2 min) and target-specific modification. The targeted modification of the POI enables precisely timed and spatially controlled redox events with no off-target modification. Two independent pathways are described, along with a simple setup to functionally validate known targets or discover novel sensors. T-REX sidesteps mixed responses caused by uncontrolled whole-cell swamping with reactive signals. Modification and downstream response can be analyzed by in-gel fluorescence, proteomics, qRT-PCR, immunofluorescence, fluorescence resonance energy transfer (FRET)-based and dual-luciferase reporters, or flow cytometry assays. T-REX targeting takes 4 h from initial probe treatment. Analysis of targeted redox responses takes an additional 4-24 h, depending on the nature of the pathway and the type of readouts used.

T-REX on-demand redox targeting in live cells

PubMed Central

Parvez, Saba; Long, Marcus J C; Lin, Hong-Yu; Zhao, Yi; Haegele, Joseph A; Pham, Vanha N; Lee, Dustin K; Aye, Yimon

2017-01-01

This protocol describes targetable reactive electrophiles and oxidants (T-REX)—a live-cell-based tool designed to (i) interrogate the consequences of specific and time-resolved redox events, and (ii) screen for bona fide redox-sensor targets. A small-molecule toolset comprising photocaged precursors to specific reactive redox signals is constructed such that these inert precursors specifically and irreversibly tag any HaloTag-fused protein of interest (POI) in mammalian and Escherichia coli cells. Syntheses of the alkyne-functionalized endogenous reactive signal 4-hydroxynonenal (HNE (alkyne)) and the HaloTag-targetable photocaged precursor to HNE (alkyne) (also known as Ht-PreHNE or HtPHA) are described. Low-energy light prompts photo-uncaging (t1/2 <1–2 min) and target-specific modification. The targeted modification of the POI enables precisely timed and spatially controlled redox events with no off-target modification. Two independent pathways are described, along with a simple setup to functionally validate known targets or discover novel sensors. T-REX sidesteps mixed responses caused by uncontrolled whole-cell swamping with reactive signals. Modification and downstream response can be analyzed by in-gel fluorescence, proteomics, qRT-PCR, immunofluorescence, fluorescence resonance energy transfer (FRET)-based and dual-luciferase reporters, or flow cytometry assays. T-REX targeting takes 4 h from initial probe treatment. Analysis of targeted redox responses takes an additional 4–24 h, depending on the nature of the pathway and the type of readouts used. PMID:27809314

The effect of catalyst length and downstream reactor distance on catalytic combustor performance

NASA Technical Reports Server (NTRS)

Anderson, D.

1980-01-01

A study was made to determine the effects on catalytic combustor performance which resulted from independently varying the length of a catalytic reactor and the length available for gas-phase reactions downstream of the catalyst. Monolithic combustion catalysts from three manufacturers were tested in a combustion test rig with no. 2 diesel fuel. Catalytic reactor lengths of 2.5 and 5.4 cm, and downstream gas-phase reaction distances of 7.3, 12.4, 17.5, and 22.5 cm were evaluated. Measurements of carbon monoxide, unburned hydrocarbons, nitrogen oxides, and pressure drop were made. The catalytic-reactor pressure drop was less than 1 percent of the upstream total pressure for all test configurations and test conditions. Nitrogen oxides and unburned hydrocarbons emissions were less than 0.25 g NO2/kg fuel and 0.6 g HC/kg fuel, respectively. The minimum operating temperature (defined as the adiabatic combustion temperature required to obtain carbon monoxide emissions below a reference level of 13.6 g CO/kg fuel) ranged from 1230 K to 1500 K for the various conditions and configurations tested. The minimum operating temperature decreased with increasing total (catalytic-reactor-plus-downstream-gas-phase-reactor-zone) residence time but was independent of the relative times spent in each region when the catalytic-reactor residence time was greater than or equal to 1.4 ms.

Experimental tsunami deposits: Linking hydrodynamics to sediment entrainment, advection lengths and downstream fining

NASA Astrophysics Data System (ADS)

Johnson, Joel P. L.; Delbecq, Katie; Kim, Wonsuck; Mohrig, David

2016-01-01

A goal of paleotsunami research is to quantitatively reconstruct wave hydraulics from sediment deposits in order to better understand coastal hazards. Simple models have been proposed to predict wave heights and velocities, based largely on deposit grain size distributions (GSDs). Although seemingly consistent with some recent tsunamis, little independent data exist to test these equations. We conducted laboratory experiments to evaluate inversion assumptions and uncertainties. A computer-controlled lift gate instantaneously released 6.5 m3 of water into a 32 m flume with shallow ponded water, creating a hydraulic bore that transported sand from an upstream source dune. Differences in initial GSDs and ponded water depths influenced entrainment, transport, and deposition. While the source dune sand was fully suspendable based on size alone, experimental tsunamis produced deposits dominated by bed load sand transport in the upstream 1/3 of the flume and suspension-dominated transport downstream. The suspension deposits exhibited downstream fining and thinning. At 95% confidence, a published advection-settling model predicts time-averaged flow depths to approximately a factor of two, and time-averaged downstream flow velocities to within a factor of 1.5. Finally, reasonable scaling is found between flume and field cases by comparing flow depths, inundation distances, Froude numbers, Rouse numbers and grain size trends in suspension-dominated tsunami deposits, justifying laboratory study of sediment transport and deposition by tsunamis.

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

PubMed

Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

2017-11-01

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Habitat quality and recruitment success of cui-ui in the Truckee River downstream of Marble Bluff Dam, Pyramid Lake, Nevada

USGS Publications Warehouse

Scoppettone, G. Gary; Rissler, Peter H.; Salgado, J. Antonio; Harry, Beverly

2013-01-01

We compared cui-ui (Chasmistes cujus) recruitment from two reaches of the Truckee River with histories of severe erosional downcutting caused by a decline in Pyramid Lake surface elevation. In 1975, Marble Bluff Dam (MBD) was constructed 5 kilometers upstream of the extant mouth of the Truckee River to stabilize the upstream reach of the river; the downstream reach of the river remained unstable and consequently unsuitable for cui-ui recruitment. By the early 2000s, there was a decrease in the Truckee River’s slope from MBD to Pyramid Lake after a series of wet years in the 1990s. This was followed by changes in river morphology and erosion abatement. These changes led to the question as to cui-ui recruitment potential in the Truckee River downstream of MBD. In 2012, more than 7,000 cui-ui spawners were passed upstream of MBD, although an indeterminate number of cui-ui spawned downstream of MBD. In this study, we compared cui-ui recruitment upstream and downstream of MBD during a Truckee River low-flow year (2012). Cui-ui larvae emigration to Pyramid Lake began earlier and ended later downstream of MBD. A greater number of cui-ui larvae was produced downstream of MBD than upstream. This also was true for native Tahoe sucker (Catostomus tahoensis) and Lahontan redside (Richardsonius egregius). The improved Truckee River stability downstream of MBD and concomitant cui-ui recruitment success is attributed to a rise in Pyramid Lake's surface elevation. A decline in lake elevation may lead to a shift in stream morphology and substrate composition to the detriment of cui-ui reproductive success as well as the reproductive success of other native fishes.

Pattern of downstream eddies in stratocumulus clouds over Pacific Ocean

NASA Image and Video Library

1973-08-01

SL3-121-2371 (July-September 1973) --- A pattern of downstream eddies in the stratocumulus clouds over the Pacific Ocean west of Baja California, as photographed by the crewmen of the second Skylab manned mission (Skylab 3) from the space station cluster in Earth orbit. The clouds, produced by the cold California current running to the south and southwest, are prevented from rising by warm air above them. Photo credit: NASA

Matrix metalloproteinase proteomics: substrates, targets, and therapy.

PubMed

Morrison, Charlotte J; Butler, Georgina S; Rodríguez, David; Overall, Christopher M

2009-10-01

Proteomics encompasses powerful techniques termed 'degradomics' for unbiased high-throughput protease substrate discovery screens that have been applied to an important family of extracellular proteases, the matrix metalloproteinases (MMPs). Together with the data generated from genetic deletion and transgenic mouse models and genomic profiling, these screens can uncover the diverse range of MMP functions, reveal which MMPs and MMP-mediated pathways exacerbate pathology, and which are involved in protection and the resolution of disease. This information can be used to identify and validate candidate drug targets and antitargets, and is critical for the development of new inhibitors of MMP function. Such inhibitors may target either the MMP directly in a specific manner or pathways upstream and downstream of MMP activity that are mediating deleterious effects in disease. Since MMPs do not operate alone but are part of the 'protease web', it is necessary to use system-wide approaches to understand MMP proteolysis in vivo, to discover new biological roles and their potential for therapeutic modification.

Caspar Creek experimental watersheds: cumulative effects of forest practices on downstream resources

Treesearch

Anne M. Rosenthal; Thomas E. Featured: Lisle

2005-01-01

Research at Caspar Creek provides information that helps forest managers assess and predict the environmental effects of forest practices and natural disturbances on downstream resources. Monitoring long-term effects and adapting practices can help protect and restore water quality and fish habitat in Northern California.

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

Code of Federal Regulations, 2014 CFR

2014-07-01

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

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

Code of Federal Regulations, 2010 CFR

2010-07-01

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

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

Code of Federal Regulations, 2013 CFR

2013-07-01

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

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

Code of Federal Regulations, 2012 CFR

2012-07-01

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

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

Code of Federal Regulations, 2011 CFR

2011-07-01

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

Semi-empirical analysis of liquid fuel distribution downstream of a plain orifice injector under cross-stream air flow

NASA Astrophysics Data System (ADS)

Cao, M.-H.; Jiang, H.-K.; Chin, J.-S.

1982-04-01

An improved flat-fan spray model is used for the semi-empirical analysis of liquid fuel distribution downstream of a plain orifice injector under cross-stream air flow. The model assumes that, due to the aerodynamic force of the high-velocity cross air flow, the injected fuel immediately forms a flat-fan liquid sheet perpendicular to the cross flow. Once the droplets have been formed, the trajectories of individual droplets determine fuel distribution downstream. Comparison with test data shows that the proposed model accurately predicts liquid fuel distribution at any point downstream of a plain orifice injector under high-velocity, low-temperature uniform cross-stream air flow over a wide range of conditions.

The Mediator Complex MED15 Subunit Mediates Activation of Downstream Lipid-Related Genes by the WRINKLED1 Transcription Factor.

PubMed

Kim, Mi Jung; Jang, In-Cheol; Chua, Nam-Hai

2016-07-01

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. © 2016 American Society of Plant Biologists. All Rights Reserved.

Targeting inflammation in pancreatic cancer: Clinical translation

PubMed Central

Steele, Colin William; Kaur Gill, Nina Angharad; Jamieson, Nigel Balfour; Carter, Christopher Ross

2016-01-01

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma. PMID:27096033

Competing targets of microRNA-608 affect anxiety and hypertension

PubMed Central

Hanin, Geula; Shenhar-Tsarfaty, Shani; Yayon, Nadav; Hoe, Yau Yin; Bennett, Estelle R.; Sklan, Ella H.; Rao, Dabeeru. C.; Rankinen, Tuomo; Bouchard, Claude; Geifman-Shochat, Susana; Shifman, Sagiv; Greenberg, David S.; Soreq, Hermona

2014-01-01

MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA–target interaction can simultaneously affect multiple other miRNA–target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3′-untranslated region (3′UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways. PMID:24722204

Targeted tandem duplication of a large chromosomal segment in Aspergillus oryzae.

PubMed

Takahashi, Tadashi; Sato, Atsushi; Ogawa, Masahiro; Hanya, Yoshiki; Oguma, Tetsuya

2014-08-01

We describe here the first successful construction of a targeted tandem duplication of a large chromosomal segment in Aspergillus oryzae. The targeted tandem chromosomal duplication was achieved by using strains that had a 5'-deleted pyrG upstream of the region targeted for tandem chromosomal duplication and a 3'-deleted pyrG downstream of the target region. Consequently,strains bearing a 210-kb targeted tandem chromosomal duplication near the centromeric region of chromosome 8 and strains bearing a targeted tandem chromosomal duplication of a 700-kb region of chromosome 2 were successfully constructed. The strains bearing the tandem chromosomal duplication were efficiently obtained from the regenerated protoplast of the parental strains. However, the generation of the chromosomal duplication did not depend on the introduction of double-stranded breaks(DSBs) by I-SceI. The chromosomal duplications of these strains were stably maintained after five generations of culture under nonselective conditions. The strains bearing the tandem chromosomal duplication in the 700-kb region of chromosome 2 showed highly increased protease activity in solid-state culture, indicating that the duplication of large chromosomal segments could be a useful new breeding technology and gene analysis method.

Targeted repression of AXIN2 and MYC gene expression using designer TALEs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rennoll, Sherri A.; Scott, Samantha A.; Yochum, Gregory S., E-mail: gsy3@psu.edu

Highlights: • We designed TALE–SID fusion proteins to target AXIN2 and MYC. • TALE–SIDs bound the chromosomal AXIN2 and MYC genes and repressed their expression. • TALE–SIDs repress β-catenin{sup S45F}-dependent AXIN2 and MYC transcription. - Abstract: Designer TALEs (dTALEs) are chimeric transcription factors that can be engineered to regulate gene expression in mammalian cells. Whether dTALEs can block gene transcription downstream of signal transduction cascades, however, has yet to be fully explored. Here we tested whether dTALEs can be used to target genes whose expression is controlled by Wnt/β-catenin signaling. TALE DNA binding domains were engineered to recognize sequences adjacentmore » to Wnt responsive enhancer elements (WREs) that control expression of axis inhibition protein 2 (AXIN2) and c-MYC (MYC). These custom DNA binding domains were linked to the mSin3A interaction domain (SID) to generate TALE–SID chimeric repressors. The TALE–SIDs repressed luciferase reporter activity, bound their genomic target sites, and repressed AXIN2 and MYC expression in HEK293 cells. We generated a novel HEK293 cell line to determine whether the TALE–SIDs could function downstream of oncogenic Wnt/β-catenin signaling. Treating these cells with doxycycline and tamoxifen stimulates nuclear accumulation of a stabilized form of β-catenin found in a subset of colorectal cancers. The TALE–SIDs repressed AXIN2 and MYC expression in these cells, which suggests that dTALEs could offer an effective therapeutic strategy for the treatment of colorectal cancer.« less

Enhancing emotional-based target prediction

NASA Astrophysics Data System (ADS)

Gosnell, Michael; Woodley, Robert

2008-04-01

This work extends existing agent-based target movement prediction to include key ideas of behavioral inertia, steady states, and catastrophic change from existing psychological, sociological, and mathematical work. Existing target prediction work inherently assumes a single steady state for target behavior, and attempts to classify behavior based on a single emotional state set. The enhanced, emotional-based target prediction maintains up to three distinct steady states, or typical behaviors, based on a target's operating conditions and observed behaviors. Each steady state has an associated behavioral inertia, similar to the standard deviation of behaviors within that state. The enhanced prediction framework also allows steady state transitions through catastrophic change and individual steady states could be used in an offline analysis with additional modeling efforts to better predict anticipated target reactions.

Profiling the role of mammalian target of rapamycin in the vascular smooth muscle metabolome in pulmonary arterial hypertension

PubMed Central

Kudryashova, Tatiana V.; Goncharov, Dmitry A.; Pena, Andressa; Ihida-Stansbury, Kaori; DeLisser, Horace; Kawut, Steven M.

2015-01-01

Abstract Increased proliferation and resistance to apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs), coupled with metabolic reprogramming, are key components of pulmonary vascular remodeling, a major and currently irreversible pathophysiological feature of pulmonary arterial hypertension (PAH). We recently reported that activation of mammalian target of rapamycin (mTOR) plays a key role in increased energy generation and maintenance of the proliferative, apoptosis-resistant PAVSMC phenotype in human PAH, but the downstream effects of mTOR activation on PAH PAVSMC metabolism are not clear. Using liquid and gas chromatography–based mass spectrometry, we performed pilot metabolomic profiling of human microvascular PAVSMCs from idiopathic-PAH subjects before and after treatment with the selective adenosine triphosphate–competitive mTOR inhibitor PP242 and from nondiseased lungs. We have shown that PAH PAVSMCs have a distinct metabolomic signature of altered metabolites—components of fatty acid synthesis, deficiency of sugars, amino sugars, and nucleotide sugars—intermediates of protein and lipid glycosylation, and downregulation of key biochemicals involved in glutathione and nicotinamide adenine dinucleotide (NAD) metabolism. We also report that mTOR inhibition attenuated or reversed the majority of the PAH-specific abnormalities in lipogenesis, glycosylation, glutathione, and NAD metabolism without affecting altered polyunsaturated fatty acid metabolism. Collectively, our data demonstrate a critical role of mTOR in major PAH PAVSMC metabolic abnormalities and suggest the existence of de novo lipid synthesis in PAVSMCs in human PAH that may represent a new, important component of disease pathogenesis worthy of future investigation. PMID:26697174

Elastic and inelastic scattering of 134Xe beams on C2D4 targets measured with GODDESS

NASA Astrophysics Data System (ADS)

Sims, Harrison; Cizewski, Jolie; Lapailleur, Alex; Garland, Heather; Xination, Dai; Pain, Steven; Hall, Matthew; Goddess Collaboration

2017-09-01

The GODDESS (Gammasphere-ORRUBA: Dual Detector for Experimental Structure Studies) coupling of the ORRUBA charged-particle array with Gammasphere is designed to enable high-resolution particle-gamma measurements in inverse kinematics with radioactive beams. The high resolution and coverage of GODDESS allows for multiple reaction channels to be studied simultaneously. For the stable-beam commissioning of GODDESS, the 134Xe(d,p γ)135Xe reaction was measured using a beam of 134Xe at 8 MeV/A, delivered by the ATLAS facility at Argonne National Laboratory. The beam impinged on an 800 μg/cm2 C2D4 target, and charged particles were detected in the GODDESS silicon array between 15 and 165 degrees. Coincident gamma rays were measured with Gammasphere, with 10 % efficiency at 1.3 MeV. In the detectors downstream of the target, elastically- and inelastically-scattered target ions (deuterium and carbon) were detected, populating the ground and low-lying excited states in 134Xe. An overview of GODDESS will be presented, along with the analysis of the downstream data, including the differential scattering cross sections and population of collective states in 134Xe. Work supported in part by the U.S. D.O.E. and National Science Foundation.

A coupled modelling effort to study the fate of contaminated sediments downstream of the Coles Hill deposit, Virginia, USA

NASA Astrophysics Data System (ADS)

Castro-Bolinaga, C. F.; Zavaleta, E. R.; Diplas, P.

2015-03-01

This paper presents the preliminary results of a coupled modelling effort to study the fate of tailings (radioactive waste-by product) downstream of the Coles Hill uranium deposit located in Virginia, USA. The implementation of the overall modelling process includes a one-dimensional hydraulic model to qualitatively characterize the sediment transport process under severe flooding conditions downstream of the potential mining site, a two-dimensional ANSYS Fluent model to simulate the release of tailings from a containment cell located partially above the local ground surface into the nearby streams, and a one-dimensional finite-volume sediment transport model to examine the propagation of a tailings sediment pulse in the river network located downstream. The findings of this investigation aim to assist in estimating the potential impacts that tailings would have if they were transported into rivers and reservoirs located downstream of the Coles Hill deposit that serve as municipal drinking water supplies.

Headwater effects on downstream waters: Legal perspectives, science needs, and assessment approaches

EPA Science Inventory

Headwater streams make up at least 53% of total stream length in the US. Although these systems are of interest for their own sake, there has recently been significant focus on how headwater streams contribute to downstream waters. This has resulted in part from recent legal op...

Vesicle Docking Is a Key Target of Local PI(4,5)P2 Metabolism in the Secretory Pathway of INS-1 Cells.

PubMed

Ji, Chen; Fan, Fan; Lou, Xuelin

2017-08-08

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) signaling is transient and spatially confined in live cells. How this pattern of signaling regulates transmitter release and hormone secretion has not been addressed. We devised an optogenetic approach to control PI(4,5)P 2 levels in time and space in insulin-secreting cells. Combining this approach with total internal reflection fluorescence microscopy, we examined individual vesicle-trafficking steps. Unlike long-term PI(4,5)P 2 perturbations, rapid and cell-wide PI(4,5)P 2 reduction in the plasma membrane (PM) strongly inhibits secretion and intracellular Ca 2+ concentration ([Ca 2+ ] i ) responses, but not sytaxin1a clustering. Interestingly, local PI(4,5)P 2 reduction selectively at vesicle docking sites causes remarkable vesicle undocking from the PM without affecting [Ca 2+ ] i . These results highlight a key role of local PI(4,5)P 2 in vesicle tethering and docking, coordinated with its role in priming and fusion. Thus, different spatiotemporal PI(4,5)P 2 signaling regulates distinct steps of vesicle trafficking, and vesicle docking may be a key target of local PI(4,5)P 2 signaling in vivo. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Mirroring of fast solar flare electrons on a downstream corotating interaction region

NASA Technical Reports Server (NTRS)

Anderson, K. A.; Sommers, J.; Lin, R. P.; Pick, M.; Chaizy, P.; Murphy, N.; Smith, E. J.; Phillips, J. L.

1995-01-01

We discuss an example of confinement of fast solar electrons by a discrete solar wind-interplanetary magnetic field structure on February 22, 1991. The structure is about 190,000 km in width and is clearly defined by changes in the direction of the magnetic field at the Ulysses spacecraft. This structure carries electrons moving toward the Sun as well as away from the Sun. A loss cone in the angular distribution of the fast electrons shows that mirroring, presumably magnetic, takes place downstream from the spacecraft. Following passage of this narrow structure, the return flux vanishes for 21 min after which time the mirroring resumes and persists for several hours. We identify the enhanced magnetic field region lying downstream from the Ulysses spacecraft that is responsible for the mirroring to be a corotating stream interaction region. Backstreaming suprathermal electron measurements by the Los Alamos National Laboratory plasma experiment on the Ulysses spacecraft support this interpretation.

Sluiceway Operations for Adult Steelhead Downstream Passage at The Dalles Dam, Columbia River, USA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khan, Fenton; Royer, Ida M.; Johnson, Gary E.

2013-10-01

This study evaluated adult steelhead (Oncorhynchus mykiss; fallbacks and kelts) downstream passage at The Dalles Dam in the Columbia River, USA, during the late fall, winter, and early spring months between 2008 and 2011. The purpose of the study was to determine the efficacy of operating the dam’s ice-and-trash sluiceway during non-spill months to provide a relatively safe, non-turbine, surface outlet for overwintering steelhead fallbacks and downstream migrating steelhead kelts. We applied the fixed-location hydroacoustic technique to estimate fish passage rates at the sluiceway and turbines of the dam. The spillway was closed during our sampling periods, which generally occurredmore » in late fall, winter, and early spring. The sluiceway was highly used by adult steelhead (91–99% of total fish sampled passing the dam) during all sampling periods. Turbine passage was low when the sluiceway was not operated. This implies that lack of a sluiceway route did not result in increased turbine passage. However, when the sluiceway was open, adult steelhead used it to pass through the dam. The sluiceway may be operated during late fall, winter, and early spring to provide an optimal, non-turbine route for adult steelhead (fallbacks and kelts) downstream passage at The Dalles Dam.« less

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

Enantioselective Effects of Chiral Pesticides on their Primary Targets and Secondary Targets.

PubMed

Yang, Ye; Zhang, Jianyun; Yao, Yijun

2017-01-01

Enantioselectivity has been well recognized in the environmental fate and effects of chiral pesticides. Enantiospecific action of the optical enantiomers on the biological molecules establishes the mechanistic basis for the enantioselective toxicity of chiral pesticides to both target and non-target organisms. We undertook a structured search of bibliographic databases for research literature concerning the enantioselective effects of chiral pesticides, including insecticides, herbicides and fungicides, on biomolecules in various species by using some key words. The results of the relevant literatures were reviewed in the text and summarized in tables. Pesticides generally exert their activity on the target organisms via disrupting the primary target biomolecules. In non-target species, effects of pesticides on the secondary targets distinguished from the primary ones make great contribution to their toxicity. Recent investigations have provided convincing evidence of enantioselective toxicity of chiral pesticides to both target and non-target species which is recognized to result from their enantiospecific action on the primary or secondary targets in organisms. This review confirms that chiral pesticides have enantiospecific effects on both primary and secondary target biomolecules in organisms. Future studies regarding toxicological effects of chiral pesticides should focus on the relationship between the enantiomeric difference in the compound-biomolecules interaction and the enantioselectivity in their toxicity.

Control of jasmonate biosynthesis and senescence by miR319 targets.

PubMed

Schommer, Carla; Palatnik, Javier F; Aggarwal, Pooja; Chételat, Aurore; Cubas, Pilar; Farmer, Edward E; Nath, Utpal; Weigel, Detlef

2008-09-23

Considerable progress has been made in identifying the targets of plant microRNAs, many of which regulate the stability or translation of mRNAs that encode transcription factors involved in development. In most cases, it is unknown, however, which immediate transcriptional targets mediate downstream effects of the microRNA-regulated transcription factors. We identified a new process controlled by the miR319-regulated clade of TCP (TEOSINTE BRANCHED/CYCLOIDEA/PCF) transcription factor genes. In contrast to other miRNA targets, several of which modulate hormone responses, TCPs control biosynthesis of the hormone jasmonic acid. Furthermore, we demonstrate a previously unrecognized effect of TCPs on leaf senescence, a process in which jasmonic acid has been proposed to be a critical regulator. We propose that miR319-controlled TCP transcription factors coordinate two sequential processes in leaf development: leaf growth, which they negatively regulate, and leaf senescence, which they positively regulate.

Targeting human breast cancer cells by an oncolytic adenovirus using microRNA-targeting strategy.

PubMed

Shayestehpour, Mohammad; Moghim, Sharareh; Salimi, Vahid; Jalilvand, Somayeh; Yavarian, Jila; Romani, Bizhan; Mokhtari-Azad, Talat

2017-08-15

MicroRNA-targeting strategy is a promising approach that enables oncolytic viruses to replicate in tumor cells but not in normal cells. In this study, we targeted adenoviral replication toward breast cancer cells by inserting ten complementary binding sites for miR-145-5p downstream of E1A gene. In addition, we evaluated the effect of increasing miR-145 binding sites on inhibition of virus replication. Ad5-control and adenoviruses carrying five or ten copies of miR145-5p target sites (Ad5-5miR145T, Ad5-10miR145T) were generated and inoculated into MDA-MB-453, BT-20, MCF-7 breast cancer cell lines and human mammary epithelial cells (HMEpC). Titer of Ad5-10miR145T in HMEpC was significantly lower than Ad5-control titer. Difference between the titer of these two viruses at 12, 24, 36, and 48h after infection was 1.25, 2.96, 3.06, and 3.77 log TCID 50 . No significant difference was observed between the titer of both adenoviruses in MDA-MB-453, BT-20 and MCF-7 cells. The infectious titer of adenovirus containing 10 miR-145 binding sites in HMEpC cells at 24, 36, and 48h post-infection was 1.7, 2.08, and 4-fold, respectively, lower than the titer of adenovirus carrying 5 miR-145 targets. Our results suggest that miR-145-targeting strategy provides selectivity for adenovirus replication in breast cancer cells. Increasing the number of miRNA binding sites within the adenoviral genome confers more selectivity for viral replication in cancer cells. Copyright © 2017. Published by Elsevier B.V.

Key Competencies: Drug and Alcohol Education. Secondary Schools.

ERIC Educational Resources Information Center

Philadelphia School District, PA.

This guide, designed for use with secondary school students, attempts to prevent drug and alcohol abuse among students. The Key Competencies program targets several characteristics which have been identified in addicted children: poor self image, improper sense of values, and lack of identity. For grades seven through nine, strategies are…

Key papers in prostate cancer.

PubMed

Rodney, Simon; Shah, Taimur Tariq; Patel, Hitendra R H; Arya, Manit

2014-11-01

Prostate cancer is the most common cancer and second leading cause of death in men. The evidence base for the diagnosis and treatment of prostate cancer is continually changing. We aim to review and discuss past and contemporary papers on these topics to provoke debate and highlight key dilemmas faced by the urological community. We review key papers on prostate-specific antigen screening, radical prostatectomy versus surveillance strategies, targeted therapies, timing of radiotherapy and alternative anti-androgen therapeutics. Previously, the majority of patients, irrespective of risk, underwent radical open surgical procedures associated with considerable morbidity and mortality. Evidence is emerging that not all prostate cancers are alike and that low-grade disease can be safely managed by surveillance strategies and localized treatment to the prostate. The question remains as to how to accurately stage the disease and ultimately choose which treatment pathway to follow.

Model Insensitive and Calibration Independent Method for Determination of the Downstream Neutral Hydrogen Density Through Ly-alpha Glow Observations

NASA Technical Reports Server (NTRS)

Gangopadhyay, P.; Judge, D. L.

1996-01-01

Our knowledge of the various heliospheric phenomena (location of the solar wind termination shock, heliopause configuration and very local interstellar medium parameters) is limited by uncertainties in the available heliospheric plasma models and by calibration uncertainties in the observing instruments. There is, thus, a strong motivation to develop model insensitive and calibration independent methods to reduce the uncertainties in the relevant heliospheric parameters. We have developed such a method to constrain the downstream neutral hydrogen density inside the heliospheric tail. In our approach we have taken advantage of the relative insensitivity of the downstream neutral hydrogen density profile to the specific plasma model adopted. We have also used the fact that the presence of an asymmetric neutral hydrogen cavity surrounding the sun, characteristic of all neutral densities models, results in a higher multiple scattering contribution to the observed glow in the downstream region than in the upstream region. This allows us to approximate the actual density profile with one which is spatially uniform for the purpose of calculating the downstream backscattered glow. Using different spatially constant density profiles, radiative transfer calculations are performed, and the radial dependence of the predicted glow is compared with the observed I/R dependence of Pioneer 10 UV data. Such a comparison bounds the large distance heliospheric neutral hydrogen density in the downstream direction to a value between 0.05 and 0.1/cc.

Has dyke development in the Vietnamese Mekong Delta shifted flood hazard downstream?

NASA Astrophysics Data System (ADS)

Van Khanh Triet, Nguyen; Viet Dung, Nguyen; Fujii, Hideto; Kummu, Matti; Merz, Bruno; Apel, Heiko

2017-08-01

In the Vietnamese part of the Mekong Delta (VMD) the areas with three rice crops per year have been expanded rapidly during the last 15 years. Paddy-rice cultivation during the flood season has been made possible by implementing high-dyke flood defenses and flood control structures. However, there are widespread claims that the high-dyke system has increased water levels in downstream areas. Our study aims at resolving this issue by attributing observed changes in flood characteristics to high-dyke construction and other possible causes. Maximum water levels and duration above the flood alarm level are analysed for gradual trends and step changes at different discharge gauges. Strong and robust increasing trends of peak water levels and duration downstream of the high-dyke areas are found with a step change in 2000/2001, i.e. immediately after the disastrous flood which initiated the high-dyke development. These changes are in contrast to the negative trends detected at stations upstream of the high-dyke areas. This spatially different behaviour of changes in flood characteristics seems to support the public claims. To separate the impact of the high-dyke development from the impact of the other drivers - i.e. changes in the flood hydrograph entering the Mekong Delta, and changes in the tidal dynamics - hydraulic model simulations of the two recent large flood events in 2000 and 2011 are performed. The hydraulic model is run for a set of scenarios whereas the different drivers are interchanged. The simulations reveal that for the central VMD an increase of 9-13 cm in flood peak and 15 days in duration can be attributed to high-dyke development. However, for this area the tidal dynamics have an even larger effect in the range of 19-32 cm. However, the relative contributions of the three drivers of change vary in space across the delta. In summary, our study confirms the claims that the high-dyke development has raised the flood hazard downstream. However, it is not

Wash-away of contaminant downstream of a backward-facing step over a range of Schmidt number

NASA Astrophysics Data System (ADS)

Min, Hannah; Fischer, Paul F.; Pearlstein, Arne J.

2017-11-01

We report computations of two-dimensional unsteady convective mass transfer in flow over a backward-facing step, in which a contaminant initially present downstream of the step is ``washed away''. Results are presented for a range of Schmidt numbers, showing how the recirculation region downstream of the step not only serves to retain contaminant near the step, but also transports contaminant upstream towards the step. The results for the highest Schmidt number considered (2650) are relevant to wash-away of low-molecular weight species in liquids, for which some implications are discussed.

siRNAs targeted to certain polyadenylation sites promote specific, RISC-independent degradation of messenger RNAs.

PubMed

Vickers, Timothy A; Crooke, Stanley T

2012-07-01

While most siRNAs induce sequence-specific target mRNA cleavage and degradation in a process mediated by Ago2/RNA-induced silencing complex (RISC), certain siRNAs have also been demonstrated to direct target RNA reduction through deadenylation and subsequent degradation of target transcripts in a process which involves Ago1/RISC and P-bodies. In the current study, we present data suggesting that a third class of siRNA exist, which are capable of promoting target RNA reduction that is independent of both Ago and RISC. These siRNAs bind the target messenger RNA at the polyA signal and are capable of redirecting a small amount of polyadenylation to downstream polyA sites when present, however, the majority of the activity appears to be due to inhibition of polyadenylation or deadenylation of the transcript, followed by exosomal degradation of the immature mRNA.

Novel Strategies for Upstream and Downstream Processing of Tannin Acyl Hydrolase

PubMed Central

Rodríguez-Durán, Luis V.; Valdivia-Urdiales, Blanca; Contreras-Esquivel, Juan C.; Rodríguez-Herrera, Raúl; Aguilar, Cristóbal N.

2011-01-01

Tannin acyl hydrolase also referred as tannase is an enzyme with important applications in several science and technology fields. Due to its hydrolytic and synthetic properties, tannase could be used to reduce the negative effects of tannins in beverages, food, feed, and tannery effluents, for the production of gallic acid from tannin-rich materials, the elucidation of tannin structure, and the synthesis of gallic acid esters in nonaqueous media. However, industrial applications of tannase are still very limited due to its high production cost. Thus, there is a growing interest in the production, recovery, and purification of this enzyme. Recently, there have been published a number of papers on the improvement of upstream and downstream processing of the enzyme. These papers dealt with the search for new tannase producing microorganisms, the application of novel fermentation systems, optimization of culture conditions, the production of the enzyme by recombinant microorganism, and the design of efficient protocols for tannase recovery and purification. The present work reviews the state of the art of basic and biotechnological aspects of tannin acyl hydrolase, focusing on the recent advances in the upstream and downstream processing of the enzyme. PMID:21941633

Investigation of Hyporheic Thermal Flux and Downstream Attenuation Driven by Hydropeaking in the Colorado River, Austin, Texas

NASA Astrophysics Data System (ADS)

Watson, J. A.; Cardenas, M. B.; Neilson, B. T.; Bennett, P. C.

2015-12-01

Thermal flux related to regulated river hydropeaking has been extensively researched at the single-study site scale, but little work has been done quantifying the downstream attenuation of a single regulated flood pulse at multiple sites. In order to better understand this flood pulse attenuation we instrumented four sites with temperature probes along a 91 km stretch of the Colorado River downstream of longhorn dam, Austin, TX. Piezometer transects perpendicular to the river at each site were instrumented with HOBO thermistors over a 1.4m screened interval within the saturated zone at 20cm spacing. As flood pulses are attenuated downstream, temperature gradients and distance of lateral temperature pulse penetration into the bank are hypothesized to decrease. The data collected in this investigation will test this hypothesis by providing 2D temperature cross-sections along an attenuating flood pulse, providing detailed spatial data on temperature gradients adjacent to the river.

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. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The chromodomain of Tf1 integrase promotes binding to cDNA and mediates target site selection.

PubMed

Chatterjee, Atreyi Ghatak; Leem, Young Eun; Kelly, Felice D; Levin, Henry L

2009-03-01

The long terminal repeat (LTR) retrotransposon Tf1 of Schizosaccharomyces pombe integrates specifically into the promoters of pol II-transcribed genes. Its integrase (IN) contains a C-terminal chromodomain related to the chromodomains that bind to the N-terminal tail of histone H3. Although we have been unable to detect an interaction between histone tails and the chromodomain of Tf1 IN, it is possible that the chromodomain plays a role in directing IN to its target sites. To test this idea, we generated transposons with single amino acid substitutions in highly conserved residues of the chromodomain and created a chromodomain-deleted mutant. The mutations, V1290A, Y1292A, W1305A, and CHDDelta, substantially reduced transposition activity in vivo. Blotting assays showed that there was little or no reduction in the levels of IN or cDNA. By measuring the homologous recombination between cDNA and the plasmid copy of Tf1, we found that two of the mutations did not reduce the import of cDNA into the nucleus, while another caused a 33% reduction. Chromatin immunoprecipitation assays revealed that CHDDelta caused an approximately threefold reduction in the binding of IN to the downstream LTR of the cDNA. These data indicate that the chromodomain contributed directly to integration. We therefore tested whether the chromodomain contributed to selecting insertion sites. Results of a target plasmid assay showed that the deletion of the chromodomain resulted in a drastic reduction in the preference for pol II promoters. Collectively, these data indicate that the chromodomain promotes binding of cDNA and plays a key role in efficient targeting.

Metabolite profiling of antidepressant drug action reveals novel drug targets beyond monoamine elevation.

PubMed

Webhofer, C; Gormanns, P; Tolstikov, V; Zieglgänsberger, W; Sillaber, I; Holsboer, F; Turck, C W

2011-12-13

Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery.