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.

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.

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

Deep Sequencing Reveals Direct Targets of Gammaherpesvirus-Induced mRNA Decay and Suggests That Multiple Mechanisms Govern Cellular Transcript Escape

PubMed Central

Clyde, Karen; Glaunsinger, Britt A.

2011-01-01

One characteristic of lytic infection with gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and murine herpesvirus 68 (MHV68), is the dramatic suppression of cellular gene expression in a process known as host shutoff. The alkaline exonuclease proteins (KSHV SOX, MHV-68 muSOX and EBV BGLF5) have been shown to induce shutoff by destabilizing cellular mRNAs. Here we extend previous analyses of cellular mRNA abundance during lytic infection to characterize the effects of SOX and muSOX, in the absence of other viral genes, utilizing deep sequencing technology (RNA-seq). Consistent with previous observations during lytic infection, the majority of transcripts are downregulated in cells expressing either SOX or muSOX, with muSOX acting as a more potent shutoff factor than SOX. Moreover, most cellular messages fall into the same expression class in both SOX- and muSOX-expressing cells, indicating that both factors target similar pools of mRNAs. More abundant mRNAs are more efficiently downregulated, suggesting a concentration effect in transcript targeting. However, even among highly expressed genes there are mRNAs that escape host shutoff. Further characterization of select escapees reveals multiple mechanisms by which cellular genes can evade downregulation. While some mRNAs are directly refractory to SOX, the steady state levels of others remain unchanged, presumably as a consequence of downstream effects on mRNA biogenesis. Collectively, these studies lay the framework for dissecting the mechanisms underlying the susceptibility of mRNA to destruction during lytic gammaherpesvirus infection. PMID:21573023

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.

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

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.

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

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

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

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...

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

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

PubMed Central

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

2014-01-01

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

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.

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.

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.

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.

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

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.

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

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.

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.

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.

Neural stem cells rescue nervous purkinje neurons by restoring molecular homeostasis of tissue plasminogen activator and downstream targets.

PubMed

Li, Jianxue; Imitola, Jaime; Snyder, Evan Y; Sidman, Richard L

2006-07-26

Neural stem cells (NSCs) offer special therapeutic prospects because they can be isolated from the CNS, expanded ex vivo, and re-implanted into diseased CNS where they not only migrate and differentiate according to cues from host tissue but also appear to be capable of affecting host cells. In nervous (nr) mutant mice Purkinje neuron (PN) mitochondria become abnormal by the second postnatal week, and a majority of PNs die in the fourth to fifth weeks. We previously identified in nr cerebellum a 10-fold increase in tissue plasminogen activator (tPA) as a key component of the mechanism causing nr PN death. Here we report that undifferentiated wild-type murine NSCs, when transplanted into the newborn nr cerebellar cortex, do not replace host PNs but contact imperiled PNs and support their mitochondrial function, dendritic growth, and synaptogenesis, subsequently leading to the rescue of host PNs and restoration of motor coordination. This protection of nr PNs also is verified by an in vitro organotypic slice model in which nr cerebellar slices are cocultured with NSCs. Most importantly, the integrated NSCs in young nr cerebellum rectify excessive tPA mRNA and protein to close to normal levels and protect the mitochondrial voltage-dependent anion channel and neurotrophins, downstream targets of the tPA/plasmin proteolytic system. This report demonstrates for the first time that NSCs can rescue imperiled host neurons by rectifying their gene expression, elevating somatic stem cell therapeutic potential beyond solely cell replacement strategy.

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.

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.

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

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

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.

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

PubMed Central

2011-01-01

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

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

PubMed

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

2011-03-16

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

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.

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.

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.

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

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.

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

Control of Delta Avulsion by Downstream Sediment Sinks

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

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.

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.

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.

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 .

Genetic evidence suggests that GIS functions downstream of TCL1 to regulate trichome formation in Arabidopsis.

PubMed

Zhang, Na; Yang, Li; Luo, Sha; Wang, Xutong; Wang, Wei; Cheng, Yuxin; Tian, Hainan; Zheng, Kaijie; Cai, Ling; Wang, Shucai

2018-04-13

Trichome formation in Arabidopsis is regulated by a MBW complex formed by MYB, bHLH and WD40 transcriptional factors, which can activate GLABRA2 (GL2) and the R3 MYB transcription factor genes. GL2 promotes trichome formation, whereas R3 MYBs are able to block the formation of the MBW complex. It has been reported that the C2H2 transcription factor GIS (GLABROUS INFLORESCENCE STEMS) functions upstream of the MBW activator complex to regulate trichome formation, and that the expression of TCL1 is not regulated by the MBW complex. However, gis and the R3 MYB gene mutant tcl1 (trichomeless 1) have opposite inflorescence trichome phenotypes, but their relationship in regulating trichome formation remained unknown. By generating and characterization of the gis tcl1 double mutant, we found that trichome formation in the gis tcl1double and the tcl1 single mutants were largely indistinguishable, but the trichome formation in the 35S:TCL1/gis transgenic plant was similar to that in the gis mutant. By using quantitative RT-PCR analysis, we showed that expression level of GIS was increased in the triple mutant tcl1 try cpc, but the expression level of TCL1 was not affected in the gis mutant. On the other hand, trichome morphology in both gis tcl1 and 35S:TCL1/gis plants was similar to that in the gis mutant. In summary, our results indicate that GIS may work downstream of TCL1 to regulate trichome formation, and GIS has a dominant role in controlling trichome morphology.

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...

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

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.

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

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

Identification of Homeotic Target Genes in Drosophila Melanogaster Including Nervy, a Proto-Oncogene Homologue

PubMed Central

Feinstein, P. G.; Kornfeld, K.; Hogness, D. S.; Mann, R. S.

1995-01-01

In Drosophila, the specific morphological characteristics of each segment are determined by the homeotic genes that regulate the expression of downstream target genes. We used a subtractive hybridization procedure to isolate activated target genes of the homeotic gene Ultrabithorax (Ubx). In addition, we constructed a set of mutant genotypes that measures the regulatory contribution of individual homeotic genes to a complex target gene expression pattern. Using these mutants, we demonstrate that homeotic genes can regulate target gene expression at the start of gastrulation, suggesting a previously unknown role for the homeotic genes at this early stage. We also show that, in abdominal segments, the levels of expression for two target genes increase in response to high levels of Ubx, demonstrating that the normal down-regulation of Ubx in these segments is functional. Finally, the DNA sequence of cDNAs for one of these genes predicts a protein that is similar to a human proto-oncogene involved in acute myeloid leukemias. These results illustrate potentially general rules about the homeotic control of target gene expression and suggest that subtractive hybridization can be used to isolate interesting homeotic target genes. PMID:7498738

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.

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.

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.

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

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.

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.

Representational constraints on children's suggestibility.

PubMed

Ceci, Stephen J; Papierno, Paul B; Kulkofsky, Sarah

2007-06-01

In a multistage experiment, twelve 4- and 9-year-old children participated in a triad rating task. Their ratings were mapped with multidimensional scaling, from which euclidean distances were computed to operationalize semantic distance between items in target pairs. These children and age-mates then participated in an experiment that employed these target pairs in a story, which was followed by a misinformation manipulation. Analyses linked individual and developmental differences in suggestibility to children's representations of the target items. Semantic proximity was a strong predictor of differences in suggestibility: The closer a suggested distractor was to the original item's representation, the greater was the distractor's suggestive influence. The triad participants' semantic proximity subsequently served as the basis for correctly predicting memory performance in the larger group. Semantic proximity enabled a priori counterintuitive predictions of reverse age-related trends to be confirmed whenever the distance between representations of items in a target pair was greater for younger than for older children.

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.

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

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.

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

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

Nam, Heerim; Lim, Do Hoon; Kim, Sung

2008-06-01

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

Model-guided suggestions for targeted surveillance based on cattle shipments in the U.S.

PubMed

Gorsich, Erin E; McKee, Clifton D; Grear, Daniel A; Miller, Ryan S; Portacci, Katie; Lindström, Tom; Webb, Colleen T

2018-02-01

Risk-based sampling is an essential component of livestock health surveillance because it targets resources towards sub-populations with a higher risk of infection. Risk-based surveillance in U.S. livestock is limited because the locations of high-risk herds are often unknown and data to identify high-risk herds based on shipments are often unavailable. In this study, we use a novel, data-driven network model for the shipments of cattle in the U.S. (the U.S. Animal Movement Model, USAMM) to provide surveillance suggestions for cattle imported into the U.S. from Mexico. We describe the volume and locations where cattle are imported and analyze their predicted shipment patterns to identify counties that are most likely to receive shipments of imported cattle. Our results suggest that most imported cattle are sent to relatively few counties. Surveillance at 10 counties is predicted to sample 22-34% of imported cattle while surveillance at 50 counties is predicted to sample 43%-61% of imported cattle. These findings are based on the assumption that USAMM accurately describes the shipments of imported cattle because their shipments are not tracked separately from the remainder of the U.S. herd. However, we analyze two additional datasets - Interstate Certificates of Veterinary Inspection and brand inspection data - to ensure that the characteristics of potential post-import shipments do not change on an annual scale and are not dependent on the dataset informing our analyses. Overall, these results highlight the utility of USAMM to inform targeted surveillance strategies when complete shipment information is unavailable. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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

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

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.

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

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

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.

Target Site Recognition by a Diversity-Generating Retroelement

PubMed Central

Guo, Huatao; Tse, Longping V.; Nieh, Angela W.; Czornyj, Elizabeth; Williams, Steven; Oukil, Sabrina; Liu, Vincent B.; Miller, Jeff F.

2011-01-01

Diversity-generating retroelements (DGRs) are in vivo sequence diversification machines that are widely distributed in bacterial, phage, and plasmid genomes. They function to introduce vast amounts of targeted diversity into protein-encoding DNA sequences via mutagenic homing. Adenine residues are converted to random nucleotides in a retrotransposition process from a donor template repeat (TR) to a recipient variable repeat (VR). Using the Bordetella bacteriophage BPP-1 element as a prototype, we have characterized requirements for DGR target site function. Although sequences upstream of VR are dispensable, a 24 bp sequence immediately downstream of VR, which contains short inverted repeats, is required for efficient retrohoming. The inverted repeats form a hairpin or cruciform structure and mutational analysis demonstrated that, while the structure of the stem is important, its sequence can vary. In contrast, the loop has a sequence-dependent function. Structure-specific nuclease digestion confirmed the existence of a DNA hairpin/cruciform, and marker coconversion assays demonstrated that it influences the efficiency, but not the site of cDNA integration. Comparisons with other phage DGRs suggested that similar structures are a conserved feature of target sequences. Using a kanamycin resistance determinant as a reporter, we found that transplantation of the IMH and hairpin/cruciform-forming region was sufficient to target the DGR diversification machinery to a heterologous gene. In addition to furthering our understanding of DGR retrohoming, our results suggest that DGRs may provide unique tools for directed protein evolution via in vivo DNA diversification. PMID:22194701

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.

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.

Therapeutic Approaches Targeting MYC-Driven Prostate Cancer

PubMed Central

Rebello, Richard J.; Pearson, Richard B.; Hannan, Ross D.; Furic, Luc

2017-01-01

The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth. MYC activity also cooperates with the dysregulation of the phosphoinositol-3-kinase (PI3K)/AKT/mTOR pathway to promote PC cell survival. Recent advances in the understanding of these interactions through the use of animal models have provided significant insight into the therapeutic efficacy of targeting MYC activity by interfering with its transcriptional program, and indirectly by targeting downstream cellular events linked to MYC transformation potential. PMID:28212321

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

Targeting the Epigenome in Lung Cancer: Expanding Approaches to Epigenetic Therapy

PubMed Central

Jakopovic, Marko; Thomas, Anish; Balasubramaniam, Sanjeeve; Schrump, David; Giaccone, Giuseppe; Bates, Susan E.

2013-01-01

Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer

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

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.

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.

Androgen receptor activation: a prospective therapeutic target for bladder cancer?

PubMed

Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

2017-03-01

Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

Evaluation of targeted and untargeted effects-based monitoring tools to assess impacts of contaminants of emerging concern on fish in the South Platte River, CO.

PubMed

Ekman, Drew R; Keteles, Kristen; Beihoffer, Jon; Cavallin, Jenna E; Dahlin, Kenneth; Davis, John M; Jastrow, Aaron; Lazorchak, James M; Mills, Marc A; Murphy, Mark; Nguyen, David; Vajda, Alan M; Villeneuve, Daniel L; Winkelman, Dana L; Collette, Timothy W

2018-08-01

Rivers in the arid Western United States face increasing influences from anthropogenic contaminants due to population growth, urbanization, and drought. To better understand and more effectively track the impacts of these contaminants, biologically-based monitoring tools are increasingly being used to complement routine chemical monitoring. This study was initiated to assess the ability of both targeted and untargeted biologically-based monitoring tools to discriminate impacts of two adjacent wastewater treatment plants (WWTPs) on Colorado's South Platte River. A cell-based estrogen assay (in vitro, targeted) determined that water samples collected downstream of the larger of the two WWTPs displayed considerable estrogenic activity in its two separate effluent streams. Hepatic vitellogenin mRNA expression (in vivo, targeted) and NMR-based metabolomic analyses (in vivo, untargeted) from caged male fathead minnows also suggested estrogenic activity downstream of the larger WWTP, but detected significant differences in responses from its two effluent streams. The metabolomic results suggested that these differences were associated with oxidative stress levels. Finally, partial least squares regression was used to explore linkages between the metabolomics responses and the chemical contaminants that were detected at the sites. This analysis, along with univariate statistical approaches, identified significant covariance between the biological endpoints and estrone concentrations, suggesting the importance of this contaminant and recommending increased focus on its presence in the environment. These results underscore the benefits of a combined targeted and untargeted biologically-based monitoring strategy when used alongside contaminant monitoring to more effectively assess ecological impacts of exposures to complex mixtures in surface waters. Published by Elsevier Ltd.

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

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

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

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.

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

Downstream mixing of sediment and tracers in agricultural catchments: Evidence of changing sediment sources and fluvial processes?

NASA Astrophysics Data System (ADS)

Ralph, Timothy; Wethered, Adam; Smith, Hugh; Heijnis, Henk

2014-05-01

Land clearance, soil tillage and grazing in agricultural catchments have liberated sediment and altered hydrological connectivity between hillslopes and channels, leading to increased sediment availability, mobilisation and delivery to rivers. The type and amount of sediment supplied to rivers is critical for fluvial geomorphology and aquatic ecosystem health. Contemporary sediment dynamics are routinely investigated using environmental radionuclides such as caesium-137 (Cs-137) and excess lead-210 (Pb-210ex), which can provide information regarding sediment source types and fluvial processes if sediment sources can be distinguished from one another and mixing models applied to representative samples. However, downstream transport, mixing and dilution of radionuclide-labelled sediment (especially from sources with low initial concentrations) can obliterate the tracer signal; sometimes before anything of geomorphological importance happens in the catchment. Can these findings be used as evidence of sediment source variations and fluvial processes when the limits of detection (of Cs-137 in particular) are being exceeded so rapidly downstream? Sediment sources and downstream sediment dynamics were investigated in Coolbaggie Creek, a major supplier of sediment to the Macquarie River in an agricultural catchment with temperate to semi-arid climate in Australia. Radionuclides were used to discriminate between the <63 micron fraction of sediment sources including forested topsoils (Cs-137 11.28 +/- 0.75 Bq/kg; Pb-210ex 181.87 +/- 20.00 Bq/kg), agricultural topsoils (Cs-137 3.21 +/- 0.26 Bq/kg; Pb-210ex 29.59 +/- 10.94 Bq/kg) and sub-soils from channel banks and gullies (Cs-137 1.45 +/- 0.47 Bq/kg; Pb-210ex 4.67 +/- 1.93 Bq/kg). Within the trunk stream, suspended sediment, organic matter and Cs-137 and Pb-210ex concentrations declined downstream. Results from a mixing model suggest that agricultural topsoils account for 95% of fine sediment entering the channel in the

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.

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

Small larvae in large rivers: observations on downstream movement of European grayling Thymallus thymallus during early life stages.

PubMed

Van Leeuwen, C H A; Dokk, T; Haugen, T O; Kiffney, P M; Museth, J

2017-06-01

Behaviour of early life stages of the salmonid European grayling Thymallus thymallus was investigated by assessing the timing of larval downstream movement from spawning areas, the depth at which larvae moved and the distribution of juvenile fish during summer in two large connected river systems in Norway. Trapping of larvae moving downstream and electrofishing surveys revealed that T. thymallus larvae emerging from the spawning gravel moved downstream predominantly during the night, despite light levels sufficient for orientation in the high-latitude study area. Larvae moved in the water mostly at the bottom layer close to the substratum, while drifting debris was caught in all layers of the water column. Few young-of-the-year still resided close to the spawning areas in autumn, suggesting large-scale movement (several km). Together, these observations show that there may be a deliberate, active component to downstream movement of T. thymallus during early life stages. This research signifies the importance of longitudinal connectivity for T. thymallus in Nordic large river systems. Human alterations of flow regimes and the construction of reservoirs for hydropower may not only affect the movement of adult fish, but may already interfere with active movement behaviour of fish during early life stages. © 2017 The Fisheries Society of the British Isles.

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.

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

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

Blocking Signaling at the Level of GLI Regulates Downstream Gene Expression and Inhibits Proliferation of Canine Osteosarcoma Cells

PubMed Central

Shahi, Mehdi Hayat; Holt, Roseline; Rebhun, Robert B.

2014-01-01

The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors. PMID:24810746

Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.

PubMed

Shahi, Mehdi Hayat; Holt, Roseline; Rebhun, Robert B

2014-01-01

The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.

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.

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

Regionally coherent, downstream propagating trends of river bed incision and aggradation in glaciated basins of western Washington, USA

NASA Astrophysics Data System (ADS)

Anderson, S. W.; Konrad, C. P.

2016-12-01

Understanding the connections between climate and river bed morphology is relevant both for interpreting the geologic record and understanding modern channel change. Here, we use changing stage-discharge relations at USGS stream-gage sites in western Washington State to infer local bed-elevation changes over the past 50 to 90 years. A network of gages in a large, unregulated basin with active glaciation show decadal periods of aggradation and incision that are strongly correlated when lagged. Best-fit lag times indicate the downstream propagation of single coherent signal at a slope-dependent velocity of 1-4 km/yr. This same pattern of change is observed at the outlets of regional rivers with glaciated headwaters but is absent in unglaciated river systems. Sites high in glaciated river systems also show coherency across basins, suggesting that the similarity in the downstream trends across glaciated basins is the result of the downstream propagation of a regionally coherent headwater signal. Incisional trends emanating from headwaters between 1950 and 1980 match a period when regional glaciers were stable or advancing, but assigning causation is complicated by hydroclimatic trends with similar temporal patterns. The recent trend is aggradational, though current bed elevations are generally similar to those prior to 1950, and are consistent with regional data indicating that sediment production in glaciated basins from 1950 to 1980 was anomalously low relative to conditions over the past several hundred years. Regionally, our results suggest the possibility of forecasting periods of aggradation and increased flood hazards several years to decades in advance in populated downstream settings. More broadly, the methods used in this analysis involve simple calculations on publically available data and provide a low-cost means of assessing local channel change wherever USGS stream-gages have been operated.

Optimizing prognosis-related key miRNA-target interactions responsible for cancer metastasis.

PubMed

Zhao, Hongying; Yuan, Huating; Hu, Jing; Xu, Chaohan; Liao, Gaoming; Yin, Wenkang; Xu, Liwen; Wang, Li; Zhang, Xinxin; Shi, Aiai; Li, Jing; Xiao, Yun

2017-12-12

Increasing evidence suggests that the abnormality of microRNAs (miRNAs) and their downstream targets is frequently implicated in the pathogenesis of human cancers, however, the clinical benefit of causal miRNA-target interactions has been seldom studied. Here, we proposed a computational method to optimize prognosis-related key miRNA-target interactions by combining transcriptome and clinical data from thousands of TCGA tumors across 16 cancer types. We obtained a total of 1,956 prognosis-related key miRNA-target interactions between 112 miRNAs and 1,443 their targets. Interestingly, these key target genes are specifically involved in tumor progression-related functions, such as 'cell adhesion' and 'cell migration'. Furthermore, they are most significantly correlated with 'tissue invasion and metastasis', a hallmark of metastasis, in ten distinct types of cancer through the hallmark analysis. These results implicated that the prognosis-related key miRNA-target interactions were highly associated with cancer metastasis. Finally, we observed that the combination of these key miRNA-target interactions allowed to distinguish patients with good prognosis from those with poor prognosis both in most TCGA cancer types and independent validation sets, highlighting their roles in cancer metastasis. We provided a user-friendly database named miRNATarget (freely available at http://biocc.hrbmu.edu.cn/miRNATar/), which provides an overview of the prognosis-related key miRNA-target interactions across 16 cancer types.

Targeting G protein-coupled receptor kinases (GRKs) in Heart Failure

PubMed Central

Brinks, Henriette; Koch, Walter J

2010-01-01

In the human body, over 1000 different G protein-coupled receptors (GPCRs) mediate a broad spectrum of extracellular signals at the plasma membrane, transmitting vital physiological features such as pain, sight, smell, inflammation, heart rate and contractility of muscle cells. Signaling through these receptors is primarily controlled and regulated by a group of kinases, the GPCR kinases (GRKs), of which only seven are known and thus, interference with these common downstream GPCR regulators suggests a powerful therapeutic strategy. Molecular modulation of the kinases that are ubiquitously expressed in the heart has proven GRK2, and also GRK5, to be promising targets for prevention and reversal of one of the most severe pathologies in man, chronic heart failure (HF). In this article we will focus on the structural aspects of these GRKs important for their physiological and pathological regulation as well as well known and novel therapeutic approaches that target these GRKs in order to overcome the development of cardiac injury and progression of HF. PMID:21218155

Targeted killing of myofibroblasts by biosurfactant di-rhamnolipid suggests a therapy against scar formation

PubMed Central

Shen, Chong; Jiang, Lifang; Shao, Huawei; You, Chuangang; Zhang, Guoliang; Ding, Sitong; Bian, Tingwei; Han, Chunmao; Meng, Qin

2016-01-01

Pathological myofibroblasts are often involved in skin scarring via generating contractile force and over-expressing collagen fibers, but no compound has been found to inhibit the myofibroblasts without showing severe toxicity to surrounding physiological cells. Here we report that di-rhamnolipid, a biosurfactant secreted by Pseudomonas aeruginosa, showed potent effects on scar therapy via a unique mechanism of targeted killing the myofibroblasts. In cell culture, the fibroblasts-derived myofibroblasts were more sensitive to di-rhamnolipid toxicity than fibroblasts at a concentration-dependent manner, and could be completely inhibited of their specific functions including α-SMA expression and collagen secretion/contraction. The anti-fibrotic function of di-rhamnolipid was further verified in rabbit ear hypertrophic scar models by presenting the significant reduction of scar elevation index, type I collagen fibers and α-SMA expression. In this regard, di-rhamnolipid treatment could be suggested as a therapy against skin scarring. PMID:27901027

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.

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.

Headwater Stream Management Dichotomies: Local Amphibian Habitat vs. Downstream Fish Habitat

NASA Astrophysics Data System (ADS)

Jackson, C. R.

2002-12-01

Small headwater streams in mountainous areas of the Pacific Northwest often do not harbor fish populations because of low water depth and high gradients. Rather, these streams provide habitat for dense assemblages of stream-dwelling amphibians. A variety of management goals have been suggested for such streams such as encouraging large woody debris recruitment to assist in sediment trapping and valley floor formation, encouraging large woody debris recruitment to provide downstream wood when debris flows occur, providing continuous linear stream buffers within forest harvest areas to provide shade and bank stability, etc. A basic problem with analying the geomorphic or biotic benefits of any of these strategies is the lack of explicit management goals for such streams. Should managers strive to optimize downstream fish habitat, local amphibian habitat, or both? Through observational data and theoretical considerations, it will be shown that these biotic goals will lead to very different geomorphic management recommendations. For instance, woody debris greater than 60 cm diameter may assist in valley floor development, but it is likely to create subsurface channel flow of unknown value to amphibians. Trapping and retention of fine sediments within headwater streams may improve downstream spawning gravels, but degrades stream-dwelling amphibian habitat. In response to the need for descriptive information on habitat and channel morphology specific to small, non-fish-bearing streams in the Pacific Northwest, morphologies and wood frequencies in forty-two first- and second-order forested streams less than four meters wide were surveyed. Frequencies and size distributions of woody debris were compared between small streams and larger fish-bearing streams as well as between second-growth and virgin timber streams. Statistical models were developed to explore dominant factors affecting channel morphology and habitat. Findings suggest geomorphological relationships

Economic valuation of the downstream hydrological effects of land use change: Large hydroelectric reservoirs

NASA Astrophysics Data System (ADS)

Aylward, Bruce Allan

1998-12-01

Land use change that accompanies economic development and population growth is intended to raise the economic productivity of land. An inevitable by product of this process is the alteration of natural vegetation and downstream hydrological function. This dissertation explores hydrological externalities of land use change in detail, particularly with regard to their economic impact on large hydroelectric reservoirs (LHRs). A review of the linkages between land use, hydrological function and downstream economic activity suggests that on theoretical grounds the net welfare effect of land use change on hydrological function will be indeterminate. Review of the literature suggests that, though the effects of downstream sedimentation will typically be negative, they may often be of little practical significance. The literature on water quantity impacts is sparse at best. This is most surprising in the case of the literature on LHRs where the potentially important and positive effects of increased water yield are typically ignored in favor of simplistic efforts to document the negative effects of reservoir sedimentation. In order to improve the methodological basis for the economic valuation of hydrological externalities, the dissertation considers existing techniques for the evaluation of non-marketed goods and services, clarifying the manner in which they have been and, in the future, may be applied to the topic at hand. A deterministic simulation model is then constructed for the case of LHRs. The model incorporates the effect of changes in water yield, the seasonal pattern of water yield and sedimentation of live and dead storage volumes as they affect reservoir operation and the production of hydroelectricity. The welfare effects of changes in the productivity of the LHR in the short run and changes to the power system expansion plan in the long run are evaluated using the marginal opportunity costs of alternative power sources and power plants, respectively. A case

Enhanced diamagnetic perturbations and electric currents observed downstream of the high power helicon

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

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

2011-05-15

The high power helicon (HPH) is capable of producing a high density plasma (10{sup 17}-10{sup 18} m{sup -3}) and directed ion energies greater than 20 eV that continue to increase tens of centimeters downstream of the thruster. In order to understand the coupling mechanism between the helicon antenna and the plasma outside the immediate source region, measurements were made in the plasma plume downstream from the thruster of the propagating wave magnetic field and the perturbation of the axial bulk field using a type 'R' helicon antenna. This magnetic field perturbation ({Delta}B) peaks at more than 15 G in strengthmore » downstream of the plasma source, and is 3-5 times larger than those previously reported from HPH. Taking the curl of this measured magnetic perturbation and assuming azimuthal symmetry suggests that this magnetic field is generated by a (predominantly) azimuthal current ring with a current density on the order of tens of kA m{sup -2}. At this current density the diamagnetic field is intense enough to cancel out the B{sub 0} axial magnetic field near the source region. The presence of the diamagnetic current is important as it demonstrates modification of the vacuum fields well beyond the source region and signifies the presence of a high density, collimated plasma stream. This diamagnetic current also modifies the propagation of the helicon wave, which facilitates a better understanding of coupling between the helicon wave and the resultant plasma acceleration.« less

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.

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

PubMed

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

2016-06-01

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

EVI1 Interferes with Myeloid Maturation via Transcriptional Repression of Cebpa, via Binding to Two Far Downstream Regulatory Elements*

PubMed Central

Wilson, Michael; Tsakraklides, Vasiliki; Tran, Minh; Xiao, Ying-Yi; Zhang, Yi; Perkins, Archibald S.

2016-01-01

One mechanism by which oncoproteins work is through perturbation of cellular maturation; understanding the mechanisms by which this occurs can lead to the development of targeted therapies. EVI1 is a zinc finger oncoprotein involved in the development of acute myeloid leukemia; previous work has shown it to interfere with the maturation of granulocytes from immature precursors. Here we investigate the mechanism by which that occurs, using an immortalized hematopoietic progenitor cell line, EML-C1, as a model system. We document that overexpression of EVI1 abrogates retinoic acid-induced maturation of EML cells into committed myeloid cells, a process that can be documented by the down-regulation of stem cell antigen-1 and acquisition of responsiveness to granulocyte-macrophage colony-stimulating factor. We show that this requires DNA binding capacity of EVI1, suggesting that downstream target genes are involved. We identify the myeloid regulator Cebpa as a target gene and identify two EVI1 binding regions within evolutionarily conserved enhancer elements at +35 and +37 kb relative to the gene. EVI1 can strongly suppress Cebpa transcription, and add-back of Cebpa into EVI1-expressing EML cells partially corrects the block in maturation. We identify the DNA sequences to which EVI1 binds at +35 and +37 kb and show that mutation of one of these releases Cebpa from EVI1-induced suppression. We observe a more complex picture in primary bone marrow cells, where EVI1 suppresses Cebpa in stem cells but not in more committed progenitors. Our data thus identify a regulatory node by which EVI1 contributes to leukemia, and this represents a possible therapeutic target for treatment of EVI1-expressing leukemia. PMID:27129260

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.

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.

Signals in inferotemporal and perirhinal cortex suggest an “untangling” of visual target information

PubMed Central

Pagan, Marino; Urban, Luke S.; Wohl, Margot P.; Rust, Nicole C.

2013-01-01

Finding sought visual targets requires our brains to flexibly combine working memory information about what we are looking for with visual information about what we are looking at. To investigate the neural computations involved in finding visual targets, we recorded neural responses in inferotemporal (IT) and perirhinal (PRH) cortex as macaque monkeys performed a task that required them to find targets within sequences of distractors. We found similar amounts of total task-specific information in both areas, however, information about whether a target was in view was more accessible using a linear read-out (i.e. was more “untangled”) in PRH. Consistent with the flow of information from IT to PRH, we also found that task-relevant information arrived earlier in IT. PRH responses were well-described by a functional model in which “untangling” computations in PRH reformat input from IT by combining neurons with asymmetric tuning correlations for target matches and distractors. PMID:23792943

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.

A computational study suggests that replacing PEG with PMOZ may increase exposure of hydrophobic targeting moiety.

PubMed

Magarkar, Aniket; Róg, Tomasz; Bunker, Alex

2017-05-30

In a previous study we showed that the cause of failure of a new, proposed, targeting ligand, the AETP moiety, when attached to a PEGylated liposome, was occlusion by the poly(ethylene glycol) (PEG) layer due to its hydrophobic nature, given that PEG is not entirely hydrophilic. At the time we proposed that possible replacement with a more hydrophilic protective polymer could alleviate this problem. In this study we have used computational molecular dynamics modelling, using a model with all atom resolution, to suggest that a specific alternative protective polymer, poly(2-methyloxazoline) (PMOZ), would perform exactly this function. Our results show that when PEG is replaced by PMOZ the relative exposure to the solvent of AETP is increased to a level even greater than that we found in previous simulations for the RGD peptide, a targeting moiety that has previously been used successfully in PEGylated liposome based therapies. While the AETP moiety itself is no longer under consideration, the results of this computational study have broader significance: the use of PMOZ as an alternative polymer coating to PEG could be efficacious in the context of more hydrophobic targeting ligands. In addition to PMOZ we studied another polyoxazoline, poly(2-ethyloxazoline) (PEOZ), that has also been mooted as a possible alternate protective polymer. It was also found that the RDG peptide occlusion was significantly greater for the case of both oxazolines as opposed to PEG and that, unlike PEG, neither oxazoline entered the membrane. As far as we are aware this is the first time that polyoxazolines have been studied using molecular dynamics simulation with all atom resolution. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed

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

2000-07-01

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

The Ste20 Kinase Misshapen Regulates Both Photoreceptor Axon Targeting and Dorsal Closure, Acting Downstream of Distinct Signals

PubMed Central

Su, Yi-Chi; Maurel-Zaffran, Corinne; Treisman, Jessica E.; Skolnik, Edward Y.

2000-01-01

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

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

Discovery of host-targeted covalent inhibitors of dengue virus

PubMed Central

de Wispelaere, Mélissanne; Carocci, Margot; Liang, Yanke; Liu, Qingsong; Sun, Eileen; Vetter, Michael L.; Wang, Jinhua; Gray, Nathanael S.; Yang, Priscilla L.

2017-01-01

We report here on an approach targeting the host reactive cysteinome to identify inhibitors of host factors required for the infectious cycle of Flaviviruses and other viruses. We used two parallel cellular phenotypic screens to identify a series of covalent inhibitors, exemplified by QL-XII-47, that are active against dengue virus. We show that the compounds effectively block viral protein expression and that this inhibition is associated with repression of downstream processes of the infectious cycle, and thus significantly contributes to the potent antiviral activity of these compounds. We demonstrate that QL-XII-47’s antiviral activity requires selective, covalent modification of a host target by showing that the compound's antiviral activity is recapitulated when cells are preincubated with QL-XII-47 and then washed prior to viral infection and by showing that QL-XII-47R, a non-reactive analog, lacks antiviral activity at concentrations more than 20-fold higher than QL-XII-47's IC90. QL-XII-47’s inhibition of Zika virus, West Nile virus, hepatitis C virus, and poliovirus further suggests that it acts via a target mediating inhibition of these other medically relevant viruses. These results demonstrate the utility of screens targeting the host reactive cysteinome for rapid identification of compounds with potent antiviral activity. PMID:28034743

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.

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.

Isotopic composition of inorganic mercury and methylmercury downstream of a historical gold mining region

USGS Publications Warehouse

Donovan, Patrick M.; Blum, Joel D.; Singer, Michael B.; Marvin-DiPasquale, Mark C.; Tsui, Martin T.K.

2016-01-01

We measured total mercury (THg) and monomethyl mercury (MMHg) concentrations and mercury (Hg) isotopic compositions in sediment and aquatic organisms from the Yuba River (California, USA) to identify Hg sources and biogeochemical transformations downstream of a historical gold mining region. Sediment THg concentrations and δ202Hg decreased from the upper Yuba Fan to the lower Yuba Fan and the Feather River. These results are consistent with the release of Hg during gold mining followed by downstream mixing and dilution. The Hg isotopic composition of Yuba Fan sediment (δ202Hg = −0.38 ± 0.17‰ and Δ199Hg = 0.04 ± 0.03‰; mean ± 1 SD, n = 7) provides a fingerprint of inorganic Hg (IHg) that could be methylated locally or after transport downstream. The isotopic composition of MMHg in the Yuba River food web was estimated using biota with a range of %MMHg (the percent of THg present as MMHg) and compared to IHg in sediment, algae, and the food web. The estimated δ202Hg of MMHg prior to photodegradation (−1.29 to −1.07‰) was lower than that of IHg and we suggest this is due to mass-dependent fractionation (MDF) of up to −0.9‰ between IHg and MMHg. This result is in contrast to net positive MDF (+0.4 to +0.8‰) previously observed in lakes, estuaries, coastal oceans, and forests. We hypothesize that this unique relationship could be due to differences in the extent or pathway of biotic MMHg degradation in stream environments.

Isotopic Composition of Inorganic Mercury and Methylmercury Downstream of a Historical Gold Mining Region.

PubMed

Donovan, Patrick M; Blum, Joel D; Singer, Michael Bliss; Marvin-DiPasquale, Mark; Tsui, Martin T K

2016-02-16

We measured total mercury (THg) and monomethyl mercury (MMHg) concentrations and mercury (Hg) isotopic compositions in sediment and aquatic organisms from the Yuba River (California, USA) to identify Hg sources and biogeochemical transformations downstream of a historical gold mining region. Sediment THg concentrations and δ(202)Hg decreased from the upper Yuba Fan to the lower Yuba Fan and the Feather River. These results are consistent with the release of Hg during gold mining followed by downstream mixing and dilution. The Hg isotopic composition of Yuba Fan sediment (δ(202)Hg = -0.38 ± 0.17‰ and Δ(199)Hg = 0.04 ± 0.03‰; mean ± 1 SD, n = 7) provides a fingerprint of inorganic Hg (IHg) that could be methylated locally or after transport downstream. The isotopic composition of MMHg in the Yuba River food web was estimated using biota with a range of %MMHg (the percent of THg present as MMHg) and compared to IHg in sediment, algae, and the food web. The estimated δ(202)Hg of MMHg prior to photodegradation (-1.29 to -1.07‰) was lower than that of IHg and we suggest this is due to mass-dependent fractionation (MDF) of up to -0.9‰ between IHg and MMHg. This result is in contrast to net positive MDF (+0.4 to +0.8‰) previously observed in lakes, estuaries, coastal oceans, and forests. We hypothesize that this unique relationship could be due to differences in the extent or pathway of biotic MMHg degradation in stream environments.

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.

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.

Targeting of a chlamydial protease impedes intracellular bacterial growth.

PubMed

Christian, Jan G; Heymann, Julia; Paschen, Stefan A; Vier, Juliane; Schauenburg, Linda; Rupp, Jan; Meyer, Thomas F; Häcker, Georg; Heuer, Dagmar

2011-09-01

Chlamydiae are obligate intracellular bacteria that propagate in a cytosolic vacuole. Recent work has shown that growth of Chlamydia induces the fragmentation of the Golgi apparatus (GA) into ministacks, which facilitates the acquisition of host lipids into the growing inclusion. GA fragmentation results from infection-associated cleavage of the integral GA protein, golgin-84. Golgin-84-cleavage, GA fragmentation and growth of Chlamydia trachomatis can be blocked by the peptide inhibitor WEHD-fmk. Here we identify the bacterial protease chlamydial protease-like activity factor (CPAF) as the factor mediating cleavage of golgin-84 and as the target of WEHD-fmk-inhibition. WEHD-fmk blocked cleavage of golgin-84 as well as cleavage of known CPAF targets during infection with C. trachomatis and C. pneumoniae. The same effect was seen when active CPAF was expressed in non-infected cells and in a cell-free system. Ectopic expression of active CPAF in non-infected cells was sufficient for GA fragmentation. GA fragmentation required the small GTPases Rab6 and Rab11 downstream of CPAF-activity. These results define CPAF as the first protein that is essential for replication of Chlamydia. We suggest that this role makes CPAF a potential anti-infective therapeutic target.

Transport of perfluoroalkyl substances (PFAS) from an arctic glacier to downstream locations: implications for sources.

PubMed

Kwok, Karen Y; Yamazaki, Eriko; Yamashita, Nobuyoshi; Taniyasu, Sachi; Murphy, Margaret B; Horii, Yuichi; Petrick, Gert; Kallerborn, Roland; Kannan, Kurunthachalam; Murano, Kentaro; Lam, Paul K S

2013-03-01

Perfluoroalkyl substances (PFAS) have been globally detected in various environmental matrices, yet their fate and transport to the Arctic is still unclear, especially for the European Arctic. In this study, concentrations of 17 PFAS were quantified in two ice cores (n=26), surface snow (n=9) and surface water samples (n=14) collected along a spatial gradient in Svalbard, Norway. Concentrations of selected ions (Na(+), SO4(2-), etc.) were also determined for tracing the origins and sources of PFAS. Perfluorobutanoate (PFBA), perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) were the dominant compounds found in ice core samples. Taking PFOA, PFNA and perfluorooctane-sulfonate (PFOS) as examples, higher concentrations were detected in the middle layers of the ice cores representing the period of 1997-2000. Lower concentrations of C8-C12 perfluorocarboxylates (PFCAs) were detected in comparison with concentrations measured previously in an ice core from the Canadian Arctic, indicating that contamination levels in the European Arctic are lower. Average PFAS concentrations were found to be lower in surface snow and melted glacier water samples, while increased concentrations were observed in river water downstream near the coastal area. Perfluorohexanesulfonate (PFHxS) was detected in the downstream locations, but not in the glacier, suggesting existence of local sources of this compound. Long-range atmospheric transport of PFAS was the major deposition pathway for the glaciers, while local sources (e.g., skiing activities) were identified in the downstream locations. Copyright © 2012 Elsevier B.V. All rights reserved.

BLISTER Regulates Polycomb-Target Genes, Represses Stress-Regulated Genes and Promotes Stress Responses in Arabidopsis thaliana.

PubMed

Kleinmanns, Julia A; Schatlowski, Nicole; Heckmann, David; Schubert, Daniel

2017-01-01

HIGHLIGHTS The PRC2 interacting protein BLISTER likely acts downstream of PRC2 to silence Polycomb target genes and is a key regulator of specific stress responses in Arabidopsis . Polycomb group (PcG) proteins are key epigenetic regulators of development. The highly conserved Polycomb repressive complex 2 (PRC2) represses thousands of target genes by trimethylating H3K27 (H3K27me3). Plant specific PcG components and functions are largely unknown, however, we previously identified the plant-specific protein BLISTER (BLI) as a PRC2 interactor. BLI regulates PcG target genes and promotes cold stress resistance. To further understand the function of BLI , we analyzed the transcriptional profile of bli-1 mutants. Approximately 40% of the up-regulated genes in bli are PcG target genes, however, bli-1 mutants did not show changes in H3K27me3 levels at all tested genes, indicating that BLI regulates PcG target genes downstream of or in parallel to PRC2. Interestingly, a significant number of BLI regulated H3K27me3 target genes is regulated by the stress hormone absciscic acid (ABA). We further reveal an overrepresentation of genes responding to abiotic stresses such as drought, high salinity, or heat stress among the up-regulated genes in bli mutants. Consistently, bli mutants showed reduced desiccation stress tolerance. We conclude that the PRC2 associated protein BLI is a key regulator of stress-responsive genes in Arabidopsis : it represses ABA-responsive PcG target genes, likely downstream of PRC2, and promotes resistance to several stresses such as cold and drought.

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.

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.

Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides.

PubMed

Tran, Tuan; Childs-Disney, Jessica L; Liu, Biao; Guan, Lirui; Rzuczek, Suzanne; Disney, Matthew D

2014-04-18

We designed small molecules that bind the structure of the RNA that causes fragile X-associated tremor ataxia syndrome (FXTAS), an incurable neuromuscular disease. FXTAS is caused by an expanded r(CGG) repeat (r(CGG)(exp)) that inactivates a protein regulator of alternative pre-mRNA splicing. Our designed compounds modulate r(CGG)(exp) toxicity in cellular models of FXTAS, and pull-down experiments confirm that they bind r(CGG)(exp) in vivo. Importantly, compound binding does not affect translation of the downstream open reading frame (ORF). We compared molecular recognition properties of our optimal compound to oligonucleotides. Studies show that r(CGG)(exp)'s self-structure is a significant energetic barrier for oligonucleotide binding. A fully modified 2'-OMethyl phosphorothioate is incapable of completely reversing an FXTAS-associated splicing defect and inhibits translation of the downstream ORF, which could have deleterious effects. Taken together, these studies suggest that a small molecule that recognizes structure may be more well suited for targeting highly structured RNAs that require strand invasion by a complementary oligonucleotide.

Targeting the r(CGG) Repeats That Cause FXTAS with Modularly Assembled Small Molecules and Oligonucleotides

PubMed Central

2015-01-01

We designed small molecules that bind the structure of the RNA that causes fragile X-associated tremor ataxia syndrome (FXTAS), an incurable neuromuscular disease. FXTAS is caused by an expanded r(CGG) repeat (r(CGG)exp) that inactivates a protein regulator of alternative pre-mRNA splicing. Our designed compounds modulate r(CGG)exp toxicity in cellular models of FXTAS, and pull-down experiments confirm that they bind r(CGG)expin vivo. Importantly, compound binding does not affect translation of the downstream open reading frame (ORF). We compared molecular recognition properties of our optimal compound to oligonucleotides. Studies show that r(CGG)exp’s self-structure is a significant energetic barrier for oligonucleotide binding. A fully modified 2′-OMethyl phosphorothioate is incapable of completely reversing an FXTAS-associated splicing defect and inhibits translation of the downstream ORF, which could have deleterious effects. Taken together, these studies suggest that a small molecule that recognizes structure may be more well suited for targeting highly structured RNAs that require strand invasion by a complementary oligonucleotide. PMID:24506227

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.

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.

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.

Posthypnotic suggestion alters conscious color perception in an automatic manner.

PubMed

Kallio, Sakari; Koivisto, Mika

2013-01-01

The authors studied whether a posthypnotic suggestion to see a brief, masked target as gray can change the color experience of a hypnotic virtuoso. The visibility of the target was manipulated by varying the delay between the target and the mask that followed it. The virtuoso's subjective reports indicated that her conscious color experience was altered already at short delays between the target and the subsequent mask. The virtuoso's objectively measured pattern of responding under posthypnotic suggestion could not be mimicked either by control participants nor the virtuoso herself. Due to posthypnotic amnesia, the virtuoso was unaware of suggestions given during hypnosis. Importantly, the virtuoso could not alter her color perception without a hypnotic suggestion. These results suggest that hypnosis can affect even a highly automatic process such as color perception.

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.

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.

Particle injection and acceleration at earth's bow shock - Comparison of upstream and downstream events

NASA Technical Reports Server (NTRS)

Ellison, Donald C.; Moebius, Eberhard; Paschmann, Goetz

1990-01-01

The injection and acceleration of thermal solar wind ions at the quasi-parallel earth's bow shock during radial interplanetary magnetic field conditions is investigated. Active Magnetospheric Particle Tracer Explorers/Ion Release Module satellite observations of complete proton spectra, and of heavy ion spectra above 10 keV/Q, made on September 12, 1984 near the nose of the shock, are presented and compared to the predictions of a Monte Carlo shock simulation which includes diffusive shock acceleration. It is found that the spectral observations are in good agreement with the predictions of the simulation when it is assumed that all accelerated ions originate in the solar wind and are injected into the acceleration mechanism by thermal leakage from the downstream plasma. The efficiency, which is determined directly from the downstream observations, is high, with at least 15 percent of the solar wind energy flux going into accelerated particles. The comparisons allow constraints to be placed on the rigidity dependence of the scattering mean free path and suggest that the upstream solar wind must be slowed substantially by backstreaming accelerated ions prior to undergoing a sharp transition in the viscous subshock.

RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension.

PubMed

Barman, Scott A; Zhu, Shu; White, Richard E

2009-01-01

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling as well as inflammation. Rho-kinases (ROCKs) are one of the best-described effectors of the small G-protein RhoA, and ROCKs are involved in a variety of cellular functions including muscle cell contraction, proliferation and vascular inflammation through inhibition of myosin light chain phosphatase and activation of downstream mediators. A plethora of evidence in animal models suggests that heightened RhoA/ROCK signaling is important in the pathogenesis of pulmonary hypertension by causing enhanced constriction and remodeling of the pulmonary vasculature. Both animal and clinical studies suggest that ROCK inhibitors are effective for treatment of severe PAH with minimal risk, which supports the premise that ROCKs are important therapeutic targets in pulmonary hypertension and that ROCK inhibitors are a promising new class of drugs for this devastating disease.

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.

Integrated optimisation technique based on computer-aided capacity and safety evaluation for managing downstream lane-drop merging area of signalised junctions

NASA Astrophysics Data System (ADS)

Chen, CHAI; Yiik Diew, WONG

2017-02-01

This study provides an integrated strategy, encompassing microscopic simulation, safety assessment, and multi-attribute decision-making, to optimize traffic performance at downstream merging area of signalized intersections. A Fuzzy Cellular Automata (FCA) model is developed to replicate microscopic movement and merging behavior. Based on simulation experiment, the proposed FCA approach is able to provide capacity and safety evaluation of different traffic scenarios. The results are then evaluated through data envelopment analysis (DEA) and analytic hierarchy process (AHP). Optimized geometric layout and control strategies are then suggested for various traffic conditions. An optimal lane-drop distance that is dependent on traffic volume and speed limit can thus be established at the downstream merging area.

Downregulation of the Sonic Hedgehog/Gli pathway transcriptional target Neogenin-1 is associated with basal cell carcinoma aggressiveness.

PubMed

Casas, Bárbara S; Adolphe, Christelle; Lois, Pablo; Navarrete, Nelson; Solís, Natalia; Bustamante, Eva; Gac, Patricio; Cabané, Patricio; Gallegos, Ivan; Wainwright, Brandon J; Palma, Verónica

2017-10-13

Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1 , the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1 lox/lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non-aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes.

Downregulation of the Sonic Hedgehog/Gli pathway transcriptional target Neogenin-1 is associated with basal cell carcinoma aggressiveness

PubMed Central

Casas, Bárbara S.; Adolphe, Christelle; Lois, Pablo; Navarrete, Nelson; Solís, Natalia; Bustamante, Eva; Gac, Patricio; Cabané, Patricio; Gallegos, Ivan; Wainwright, Brandon J.; Palma, Verónica

2017-01-01

Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1, the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1lox/lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non-aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes. PMID:29137400

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.

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

Development of seawater tolerance and subsequent downstream migration in wild and stocked young-of-the-year derived Atlantic salmon Salmo salar smolts.

PubMed

Urke, H A; Arnekleiv, J V; Nilsen, T O; Nilssen, K J

2014-01-01

This study investigated the development of hypo-osmoregulatory capacity and timing of downstream migration in wild Atlantic salmon Salmo salar smolts from the River Stjørdalselva and stocked young-of-the-year (YOY), derived S. salar smolts from the tributary River Dalåa. Both wild and stocked S. salar smolts developed seawater (SW) tolerance in early May, persisting through June, measured as their ability to regulate plasma osmolality and chloride following 24 h SW (salinity = 35) exposure. Although the majority of downstream migration among the stocked S. salar smolts occurred later than observed in their wild counterparts, the development of SW tolerance occurred concurrently. The wild S. salar from Stjørdalselva and stocked YOY smolts from the River Dalåa started to migrate on the same cumulative day-degrees (D°). The study revealed no downstream migration before development of SW tolerance. This emphasizes the importance of incorporating physiological status when studying environmental triggers for downstream migration of S. salar smolts. Overall, these findings suggest that the onset of smolt migration in stocked S. salar smolts was within the smolt window from an osmoregulatory point of view. © 2014 The Fisheries Society of the British Isles.

Dynamic Target Match Signals in Perirhinal Cortex Can Be Explained by Instantaneous Computations That Act on Dynamic Input from Inferotemporal Cortex

PubMed Central

Pagan, Marino

2014-01-01

Finding sought objects requires the brain to combine visual and target signals to determine when a target is in view. To investigate how the brain implements these computations, we recorded neural responses in inferotemporal cortex (IT) and perirhinal cortex (PRH) as macaque monkeys performed a delayed-match-to-sample target search task. Our data suggest that visual and target signals were combined within or before IT in the ventral visual pathway and then passed onto PRH, where they were reformatted into a more explicit target match signal over ∼10–15 ms. Accounting for these dynamics in PRH did not require proposing dynamic computations within PRH itself but, rather, could be attributed to instantaneous PRH computations performed upon an input representation from IT that changed with time. We found that the dynamics of the IT representation arose from two commonly observed features: individual IT neurons whose response preferences were not simply rescaled with time and variable response latencies across the population. Our results demonstrate that these types of time-varying responses have important consequences for downstream computation and suggest that dynamic representations can arise within a feedforward framework as a consequence of instantaneous computations performed upon time-varying inputs. PMID:25122904

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

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

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

Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase

PubMed Central

Gao, Suyu; Cheng, Li; Hao, Bin; Li, Jiacheng; Chen, Yao; Hou, Xuemei; Chen, Lixia; Li, Hua

2017-01-01

T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo. PMID:28388576

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

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

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

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

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

Downstream cumulative effects of land use on freshwater communities

NASA Astrophysics Data System (ADS)

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

2015-12-01

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

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

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.

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

The second axis of the DARHT flash X-ray facility at Los Alamos National Laboratory (''DARHT-II'') is a multiple-pulse, 18.4 MeV, 2 kA induction electron linear accelerator [1]. A train of short ({approx}50 ns) pulses are converted via bremsstrahlung to X-rays, which are then used to make radiographic images at various times (nominally four) during a ''hydrotest'' experiment. The train of pulses is created by carving them out of a two microsecond long macropulse, using a fast switching element called a kicker [2]. The unused portion of the macropulse is absorbed in a beam dump. Thus, upstream of the kicker, twomore » microseconds of beam are transported through a vacuum system roughly sixty meters long. These conditions involve length and, specifically, time scales which are new to the transport of high-current beams. A concern under such conditions are the macroscopic interactions between the electron beam and positive ions created by impact ionization of the residual gas in the vacuum system. Over two microseconds, the ion density can develop to a hundredth or even a tenth of a percent of the beam density--small, to be sure, but large enough to have cumulative effects over such a long transport distance. Two such effects will be considered here: the ion hose instability, where transverse forces conspire to pull the electron beam farther and farther off axis, and background gas focusing, where radial forces (with respect to the beam) change the beam envelope during the course of the macropulse. The former effect can cause beam emittance growth (affecting the ability to focus the beam on the target) and eventually catastrophic beam loss; the latter can cause either serious degradation of the statically tuned final focus on the converter target, or a pinching of the beam on the surface of the main dump to the point where the heat flux causes damage. The beam transport upstream of the kicker has two distinct phases. First, the beam is created and accelerated up to

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

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.

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

PubMed

Potter, Sharyn J; Stapleton, Jane G

2011-06-01

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

Therapeutic targeting of epithelial plasticity programs – Focus on the epithelial-mesenchymal transition

PubMed Central

Malek, Reem; Wang, Hailun; Taparra, Kekoa; Tran, Phuoc T.

2017-01-01

Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer. In this review we organized our discussion on pathways and agents that can be used to target the EMT in cancer into three groups: (1) extracellular inducers of EMT; (2) the transcription factors that orchestrate the EMT transcriptome; and, (3) the downstream effectors of EMT. We highlight only briefly specific canonical pathways known to be involved in EMT such as the signal transduction pathways TGFβ, EFGR and Axl-Gas6. We emphasize in more detail pathways that are we believe are emerging novel pathways and therapeutic targets such as epigenetic therapies, glycosylation pathways and immunotherapy. The heterogeneity of tumors and the dynamic nature of epithelial plasticity in cancer cells make it likely that targeting only one EMT related process will be unsuccessful or only transiently successful. We suggest with greater understanding of epithelial plasticity regulation such as with the EMT, a more systematic targeting of multiple EMT regulatory networks will be the best path forward to improve cancer outcomes. PMID:28214899

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

On the recent destabilization of the Gulf Stream path downstream of Cape Hatteras

NASA Astrophysics Data System (ADS)

Andres, M.

2016-09-01

Mapped satellite altimetry reveals interannual variability in the position of initiation of Gulf Stream meanders downstream of Cape Hatteras. The longitude where the Gulf Stream begins meandering varies by 1500 km. There has been a general trend for the destabilization point to shift west, and 5 of the last 6 years had a Gulf Stream destabilization point upstream of the New England Seamounts. Independent in situ data suggest that this shift has increased both upper-ocean/deep-ocean interaction events at Line W and open-ocean/shelf interactions across the Middle Atlantic Bight (MAB) shelf break. Mooring data and along-track altimetry indicate a recent increase in the number of deep cyclones that stir Deep Western Boundary Current waters from the MAB slope into the deep interior. Temperature profiles from the Oleander Program suggest that recent enhanced warming of the MAB shelf may be related to shifts in the Gulf Stream's destabilization point.

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.

A Hydraulic Nexus between Geographically Isolated Wetlands and Downstream Water Bodies

NASA Astrophysics Data System (ADS)

Mclaughlin, D. L.; Kaplan, D. A.; Cohen, M. J.

2014-12-01

Geographic isolation does not imply hydrological isolation; indeed, local groundwater exchange between geographically isolated wetlands (GIWs) and surrounding uplands may yield important controls on regional hydrology. Differences in specific yield (Sy) between aquifers and inundated GIWs drive differences in water level responses to atmospheric fluxes, leading to frequent reversals in hydraulic gradients that cause GIWs to act as both groundwater sinks and sources. When distributed across the landscape, these reversals in local groundwater fluxes are predicted to collectively buffer the surficial aquifer and its regulation of baseflow delivery, a process we refer to as landscape hydrologic capacitance. To test this hypothesis, we integrated models of daily soil moisture, upland water table, and wetland stage dynamics to simulate hydrology of a low-relief landscape with GIWs. Simulations explored the influences of cumulative wetland area, individual wetland size, climate, and soil texture on water table and baseflow variation. Increasing cumulative wetland area and decreasing individual wetland size reduced water table variation and the frequency of extremely shallow and deep water tables. This buffering effect extended to baseflow deliveries, decreasing the standard deviation of daily baseflow by as much as 50%. For the same total wetland area, landscapes with fewer (i.e., larger) wetlands exhibited markedly lower hydrologic capacitance than those with more (i.e., smaller) wetlands, highlighting the important role of small GIWs in regulating regional hydrology. Recent U.S. Supreme Court rulings have limited federal protections for GIWs except where a "significant nexus" to a navigable water body is demonstrated. Our results suggest that GIWs regulate downstream baseflow, even where water in GIWs may never physically reach downstream systems, providing a significant "hydraulic" nexus to distant water bodies.

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

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

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

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

Signaling by ectopically expressed Drosophila Src64 requires the protein-tyrosine phosphatase corkscrew and the adapter downstream of receptor kinases.

PubMed

Cooper, J A; Simon, M A; Kussick, S J

1996-11-01

Vertebrate Src can be activated by specific mutations to become oncogenic. Analogous mutations in Drosophila Src64 (DSrc) induce abnormal differentiation of photoreceptor cells when expressed ectopically in the developing Drosophila adult eye. We have investigated the roles that the adapter protein, Downstream of receptor kinases (Drk), and the SH2 domain-containing tyrosine phosphatase, Corkscrew (Csw), play in this process. We find that dominant-negative mutations in either the drk or csw genes ameliorate the developmental abnormalities induced by activated DSrc. This suggests that Drk and Csw are required downstream of, or parallel to, DSrc. Csw does not act solely as an upstream activator of DSrc. The results are discussed in relation to potential roles for the vertebrate homologues of Drk and Csw (Grb2 and SHP2, respectively) in the transformation of fibroblasts by vertebrate Src.

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

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.

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

Target mimics: an embedded layer of microRNA-involved gene regulatory networks in plants.

PubMed

Meng, Yijun; Shao, Chaogang; Wang, Huizhong; Jin, Yongfeng

2012-05-21

MicroRNAs (miRNAs) play an essential role in gene regulation in plants. At the same time, the expression of miRNA genes is also tightly controlled. Recently, a novel mechanism called "target mimicry" was discovered, providing another layer for modulating miRNA activities. However, except for the artificial target mimics manipulated for functional studies on certain miRNA genes, only one example, IPS1 (Induced by Phosphate Starvation 1)-miR399 was experimentally confirmed in planta. To date, few analyses for comprehensive identification of natural target mimics have been performed in plants. Thus, limited evidences are available to provide detailed information for interrogating the questionable issue whether target mimicry was widespread in planta, and implicated in certain biological processes. In this study, genome-wide computational prediction of endogenous miRNA mimics was performed in Arabidopsis and rice, and dozens of target mimics were identified. In contrast to a recent report, the densities of target mimic sites were found to be much higher within the untranslated regions (UTRs) when compared to those within the coding sequences (CDSs) in both plants. Some novel sequence characteristics were observed for the miRNAs that were potentially regulated by the target mimics. GO (Gene Ontology) term enrichment analysis revealed some functional insights into the predicted mimics. After degradome sequencing data-based identification of miRNA targets, the regulatory networks constituted by target mimics, miRNAs and their downstream targets were constructed, and some intriguing subnetworks were further exploited. These results together suggest that target mimicry may be widely implicated in regulating miRNA activities in planta, and we hope this study could expand the current understanding of miRNA-involved regulatory networks.

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...

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

PubMed

Slemc, Lucija; Kunej, Tanja

2016-11-01

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

Synergistic Effects of Targeted PI3K Signaling Inhibition and Chemotherapy in Liposarcoma

PubMed Central

Guo, Shang; Lopez-Marquez, Hector; Fan, Kenneth C.; Choy, Edwin; Cote, Gregory; Harmon, David; Nielsen, G. Petur; Yang, Cao; Zhang, Changqing; Mankin, Henry; Hornicek, Francis J.; Borger, Darrell R.; Duan, Zhenfeng

2014-01-01

While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma. PMID:24695632

Oscillating PDF in termini of circadian pacemaker neurons and synchronous molecular clocks in downstream neurons are not sufficient for sustenance of activity rhythms in constant darkness.

PubMed

Prakash, Pavitra; Nambiar, Aishwarya; Sheeba, Vasu

2017-01-01

In Drosophila, neuropeptide Pigment Dispersing Factor (PDF) is expressed in small and large ventral Lateral Neurons (sLNv and lLNv), among which sLNv are critical for activity rhythms in constant darkness. Studies show that this is mediated by rhythmic accumulation and likely secretion of PDF from sLNv dorsal projections, which in turn synchronises molecular oscillations in downstream circadian neurons. Using targeted expression of a neurodegenerative protein Huntingtin in LNv, we evoke a selective loss of neuropeptide PDF and clock protein PERIOD from sLNv soma. However, PDF is not lost from sLNv dorsal projections and lLNv. These flies are behaviourally arrhythmic in constant darkness despite persistence of PDF oscillations in sLNv dorsal projections and synchronous PERIOD oscillations in downstream circadian neurons. We find that PDF oscillations in sLNv dorsal projections are not sufficient for sustenance of activity rhythms in constant darkness and this is suggestive of an additional component that is possibly dependent on sLNv molecular clock and PDF in sLNv soma. Additionally, despite loss of PERIOD in sLNv, their activity rhythms entrain to light/dark cycles indicating that sLNv molecular clocks are not necessary for entrainment. Under constant light, these flies lack PDF from both soma and dorsal projections of sLNv, and when subjected to light/dark cycles, show morning and evening anticipation and accurately phased morning and evening peaks. Thus, under light/dark cycles, PDF in sLNv is not necessary for morning anticipation.

Oscillating PDF in termini of circadian pacemaker neurons and synchronous molecular clocks in downstream neurons are not sufficient for sustenance of activity rhythms in constant darkness

PubMed Central

Prakash, Pavitra; Nambiar, Aishwarya; Sheeba, Vasu

2017-01-01

In Drosophila, neuropeptide Pigment Dispersing Factor (PDF) is expressed in small and large ventral Lateral Neurons (sLNv and lLNv), among which sLNv are critical for activity rhythms in constant darkness. Studies show that this is mediated by rhythmic accumulation and likely secretion of PDF from sLNv dorsal projections, which in turn synchronises molecular oscillations in downstream circadian neurons. Using targeted expression of a neurodegenerative protein Huntingtin in LNv, we evoke a selective loss of neuropeptide PDF and clock protein PERIOD from sLNv soma. However, PDF is not lost from sLNv dorsal projections and lLNv. These flies are behaviourally arrhythmic in constant darkness despite persistence of PDF oscillations in sLNv dorsal projections and synchronous PERIOD oscillations in downstream circadian neurons. We find that PDF oscillations in sLNv dorsal projections are not sufficient for sustenance of activity rhythms in constant darkness and this is suggestive of an additional component that is possibly dependent on sLNv molecular clock and PDF in sLNv soma. Additionally, despite loss of PERIOD in sLNv, their activity rhythms entrain to light/dark cycles indicating that sLNv molecular clocks are not necessary for entrainment. Under constant light, these flies lack PDF from both soma and dorsal projections of sLNv, and when subjected to light/dark cycles, show morning and evening anticipation and accurately phased morning and evening peaks. Thus, under light/dark cycles, PDF in sLNv is not necessary for morning anticipation. PMID:28558035

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

Organic carbon export from the Greenland Ice Sheet: sources, sinks and downstream fluxes

NASA Astrophysics Data System (ADS)

Wadham, J. L.; Lawson, E.; Tranter, M.; Stibal, M.; Telling, J.; Lis, G. P.; Nienow, P. W.; Anesio, A. M.; Butler, C. E.

2012-12-01

Runoff from small glacier systems has been shown to contain dissolved organic carbon (DOC) rich in low molecular weight (LMW), and hence more labile forms, designating glaciers as an important source of carbon for downstream heterotrophic activity. Here we assess glacier surfaces as potential sources of labile DOC to downstream ecosystems, presenting data from a wide range of glacier systems to determine sources and sinks of DOC in glacial and proglacial systems. We subsequently focus upon the Greenland Ice Sheet (GrIS) which is the largest source of glacial runoff at present (400 km3 yr-1), with predicted increases in future decades. We report high fluxes of particulate organic carbon (POC), DOC and LMW labile fractions from a large GrIS catchment during two contrasting melt seasons. POC dominates OC export, is sourced from the ice sheet bed and contains a significant bioreactive component (~10% carbohydrates). The LMW-DOC "labile" fraction derives almost entirely from microbial activity on the ice sheet surface, which is supported by data from glacier systems also presented here. Annual fluxes of DOC, POC and labile components were lower in 2010 than 2009, despite a ~2 fold increase in runoff fluxes in 2010, suggesting production-limited DOC/POC sources. Scaled to the entire ice sheet, combined DOC and POC fluxes are of a similar order of magnitude to other large Arctic river systems and may represent an important source of organic carbon to the North Atlantic, Greenland and Labrador Seas.

c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

PubMed

Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

2015-06-03

c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-01-01

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

Early Response of Mouse Joint Tissues to Noninvasive Knee Injury Suggests Treatment Targets

PubMed Central

Wu, P.; Holguin, N.; Silva, M. J.; Fu, M.; Liao, W.; Sandell, L. J.

2015-01-01

Objective Joint trauma can lead to a spectrum of acute lesions, including cartilage degradation, ligament or meniscus tears, and synovitis, all potentially associated with osteoarthritis. The goal of this study was to generate and validate a murine model of knee joint trauma following non-invasive controlled injurious compression in vivo and to investigate early molecular events. Methods The right knees of 8-week old mice were placed in a hyperflexed position and subjected to compressive joint loading at one of three peak forces (3, 6, 9 N) for 60 cycles in a single loading period and harvested at 5, 9 and 14 days post loading (n=3–5 mice for each time point and for each loading). The left knees were not loaded and served as the contralateral controls. Histological, immunohistochemical and ELISA analyses were performed to evaluate acute pathologic features in chondrocyte viability, cartilage matrix metabolism, synovial reaction, and serum COMP levels. Results Acute joint pathology was associated with increased injurious loads. All loading regimens induced chondrocyte apoptosis, cartilage matrix degradation, disruption of cartilage collagen fibril arrangement, and increased levels of serum COMP. We also observed that 6N loading induced mild synovitis by day 5 whereas at 9 N, with tearing of the anterior cruciate ligament, severe posttraumatic synovitis and ectopic cartilage formation were observed. Conclusion We have established and analyzed some early events in a murine model of knee joint trauma with different degrees of over-loading in vivo. These results suggest that immediate therapies particularly targeted to apoptosis and synovial cell proliferation could affect the acute posttraumatic reaction to potentially limit chronic consequences and osteoarthritis. PMID:24470303

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/

Re-modulated technology of WDM-PON employing different DQPSK downstream signals

NASA Astrophysics Data System (ADS)

Gao, Chao; Xin, Xiang-jun; Yu, Chong-xiu

2012-11-01

This paper proposes a kind of modulation architecture for wavelength-division-multiplexing passive optical network (WDMPON) employing optical differential quadrature phase shift keying (DQPSK) downstream signals and two different modulation formats of re-modulated upstream signals. At the optical line terminal (OLT), 10 Gbit/s signal is modulated with DQPSK. At the optical network unit (ONU), part of the downstream signal is re-modulated with on-off keying (OOK) or inverse-return-to-zero (IRZ). Simulation results show the impact on the system employing NRZ, RZ and carrier-suppressed return-to-zero (CSRZ). The analyses also reflect that the architecture can restrain chromatic dispersion and channel crosstalk, which makes it the best architecture of access network in the future.

Depletion of polycistronic transcripts using short interfering RNAs: cDNA synthesis method affects levels of non-targeted genes determined by quantitative PCR.

PubMed

Hanning, Jennifer E; Groves, Ian J; Pett, Mark R; Coleman, Nicholas

2013-05-21

Short interfering RNAs (siRNAs) are often used to deplete viral polycistronic transcripts, such as those encoded by human papillomavirus (HPV). There are conflicting data in the literature concerning how siRNAs targeting one HPV gene can affect levels of other genes in the polycistronic transcripts. We hypothesised that the conflict might be partly explained by the method of cDNA synthesis used prior to transcript quantification. We treated HPV16-positive cervical keratinocytes with siRNAs targeting the HPV16 E7 gene and used quantitative PCR to compare transcript levels of E7 with those of E6 and E2, viral genes located upstream and downstream of the target site respectively. We compared our findings from cDNA generated using oligo-dT primers alone with those from cDNA generated using a combination of random hexamer and oligo-dT primers. Our data show that when polycistronic transcripts are targeted by siRNAs, there is a period when untranslatable cleaved mRNA upstream of the siRNA binding site remains detectable by PCR, if cDNA is generated using random hexamer primers. Such false indications of mRNA abundance are avoided using oligo-dT primers. The period corresponds to the time taken for siRNA activity and degradation of the cleaved transcripts. Genes downstream of the siRNA binding site are detectable during this interval, regardless of how the cDNA is generated. These data emphasise the importance of the cDNA synthesis method used when measuring transcript abundance following siRNA depletion of polycistronic transcripts. They provide a partial explanation for erroneous reports suggesting that siRNAs targeting HPV E7 can have gene-specific effects.

Depletion of polycistronic transcripts using short interfering RNAs: cDNA synthesis method affects levels of non-targeted genes determined by quantitative PCR

PubMed Central

2013-01-01

Background Short interfering RNAs (siRNAs) are often used to deplete viral polycistronic transcripts, such as those encoded by human papillomavirus (HPV). There are conflicting data in the literature concerning how siRNAs targeting one HPV gene can affect levels of other genes in the polycistronic transcripts. We hypothesised that the conflict might be partly explained by the method of cDNA synthesis used prior to transcript quantification. Findings We treated HPV16-positive cervical keratinocytes with siRNAs targeting the HPV16 E7 gene and used quantitative PCR to compare transcript levels of E7 with those of E6 and E2, viral genes located upstream and downstream of the target site respectively. We compared our findings from cDNA generated using oligo-dT primers alone with those from cDNA generated using a combination of random hexamer and oligo-dT primers. Our data show that when polycistronic transcripts are targeted by siRNAs, there is a period when untranslatable cleaved mRNA upstream of the siRNA binding site remains detectable by PCR, if cDNA is generated using random hexamer primers. Such false indications of mRNA abundance are avoided using oligo-dT primers. The period corresponds to the time taken for siRNA activity and degradation of the cleaved transcripts. Genes downstream of the siRNA binding site are detectable during this interval, regardless of how the cDNA is generated. Conclusions These data emphasise the importance of the cDNA synthesis method used when measuring transcript abundance following siRNA depletion of polycistronic transcripts. They provide a partial explanation for erroneous reports suggesting that siRNAs targeting HPV E7 can have gene-specific effects. PMID:23693071

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.

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

Ultrasound Targeted Microbubble Destruction-Mediated Delivery of a Transcription Factor Decoy Inhibits STAT3 Signaling and Tumor Growth

PubMed Central

Kopechek, Jonathan A.; Carson, Andrew R.; McTiernan, Charles F.; Chen, Xucai; Hasjim, Bima; Lavery, Linda; Sen, Malabika; Grandis, Jennifer R.; Villanueva, Flordeliza S.

2015-01-01

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers where it acts to promote tumor progression. A STAT3-specific transcription factor decoy has been developed to suppress STAT3 downstream signaling, but a delivery strategy is needed to improve clinical translation. Ultrasound-targeted microbubble destruction (UTMD) has been shown to enhance image-guided local delivery of molecular therapeutics to a target site. The objective of this study was to deliver STAT3 decoy to squamous cell carcinoma (SCC) tumors using UTMD to disrupt STAT3 signaling and inhibit tumor growth. Studies performed demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles inhibited STAT3 signaling in SCC cells in vitro. Studies performed in vivo demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles induced significant tumor growth inhibition (31-51% reduced tumor volume vs. controls, p < 0.05) in mice bearing SCC tumors. Furthermore, expression of STAT3 downstream target genes (Bcl-xL and cyclin D1) was significantly reduced (34-39%, p < 0.05) in tumors receiving UTMD treatment with STAT3 decoy-loaded microbubbles compared to controls. In addition, the quantity of radiolabeled STAT3 decoy detected in tumors eight hours after treatment was significantly higher with UTMD treatment compared to controls (70-150%, p < 0.05). This study demonstrates that UTMD can increase delivery of a transcription factor decoy to tumors in vivo and that the decoy can inhibit STAT3 signaling and tumor growth. These results suggest that UTMD treatment holds potential for clinical use to increase the concentration of a transcription factor signaling inhibitor in the tumor. PMID:26681983

Wave2 activates serum response element via its VCA region and functions downstream of Rac.

PubMed

Ishiguro, Kazuhiro; Cao, Zhifang; Ilasca, Marco Lopez; Ando, Takafumi; Xavier, Ramnik

2004-12-10

WAVE2 is a member of the WASP/WAVE family of protein effectors of actin reorganization and cell movement. In this report, we demonstrate that WAVE2 overexpression induces serum response element (SRE) activation through serum response factor. A WAVE2 mutant lacking the VCA region did not induce SRE activation and actin polymerization. WAVE2-induced SRE activation was blocked by exposure of cells to Latrunculin A, or overexpression of actin mutant R62D. The DeltaVCA mutant inhibited Rac V12-induced SRE activation, suggesting that WAVE2 lies downstream of Rac. Similar deletion of the VCA domain of WASP attenuated Cdc42 V12-mediated SRE activation, suggesting that WAVE2 acts in relation to Rac as WASP acts in relation to Cdc42. WAVE2 overexpression did not activate NF-kappaB.

miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2.

PubMed

Wei, Guangxia; Xu, Yahuan; Peng, Tao; Yan, Jie

2018-03-01

Dysregulated microRNAs (miRNAs) reported to involve into the oncogenesis and progression in various human cancers. However, the roles and mechanism of miR-133 in lung adenocarcinoma remain largely unclear. In this study, qPCR assay and western blot were used to detect the expression levels of miR-133, Akt and FLOT2. Luciferase reporter assay was used to identify the target role of miR-133 on FLOT2. The cell invasion and the migration capability were performed using the transwell invasion assay and wound healing assay. We found that miR-133 expression levels were downregulated in human lung adenocarcinoma specimens and cell lines compared with the adjacent normal tissues and normal human bronchial epithelial cell. miR-133 significantly suppressed metastasis of lung adenocarcinoma cells in vitro. Furthermore, FLOT2 (flotillin-2) identified as a direct target of miR-133, and FLOT2 expression levels were inversely correlated with miR-133 expression levels in human lung adenocarcinoma specimens. And the restoration studies suggested FGF2 as a downstream effector of miR-133 which acted through Akt signalling pathway. Our study revealed the mechanism that miR-133 suppresses lung adenocarcinoma metastasis by targeting FLOT2 via Akt signalling pathway, implicating a potential prognostic biomarker and therapeutic target for lung adenocarcinoma treatment.

Stereo Particle Image Velocimetry Measurements of Transition Downstream of a Forward-Facing Step in a Swept-Wing Boundary Layer

NASA Technical Reports Server (NTRS)

Eppink, Jenna L.

2017-01-01

Stereo particle image velocimetry measurements were performed downstream of a forward-facing step in a stationary-crossflow dominated flow. Three different step heights were studied with the same leading-edge roughness configuration to determine the effect of the step on the evolution of the stationary-crossflow. Above the critical step height, which is approximately 68% of the boundary-layer thickness at the step, the step caused a significant increase in the growth of the stationary crossflow. For the largest step height studied (68%), premature transition occurred shortly downstream of the step. The stationary crossflow amplitude only reached approximately 7% of U(sub e) in this case, which suggests that transition does not occur via the high-frequency secondary instabilities typically associated with stationary crossflow transition. The next largest step of 60% delta still caused a significant impact on the growth of the stationary crossflow downstream of the step, but the amplitude eventually returned to that of the baseline case, and the transition front remained the same. The smallest step height (56%) only caused a small increase in the stationary crossflow amplitude and no change in the transition front. A final case was studied in which the roughness on the leading edge of the model was enhanced for the lowest step height case to determine the impact of the stationary crossflow amplitude on transition. The stationary crossflow amplitude was increased by approximately four times, which resulted in premature transition for this step height. However, some notable differences were observed in the behavior of the stationary crossflow mode, which indicate that the interaction mechanism which results in the increased growth of the stationary crossflow downstream of the step may be different in this case compared to the larger step heights.

Historical and Contemporary Patterns of Mercury in a Hydroelectric Reservoir and Downstream Fishery: Concentration Decline in Water and Fishes.

PubMed

Green, Derek J; Duffy, Mark; Janz, David M; McCullum, Kevin; Carrière, Gary; Jardine, Timothy D

2016-08-01

Mercury (Hg) contamination can pose risks to human and animal health as well as commercial fisheries. Reservoir construction in riverine systems produces flooded conditions amenable to Hg(II)-methylating bacteria, which can transform this relatively benign environmental contaminant into the bioaccumulative, environmentally relevant, and neurotoxic methyl-Hg (MeHg). Hg concentrations ([Hg]) in fishes from reservoirs can take decades to decrease to pre-dam levels, but less is known about Hg exported downstream and its dynamics within downstream fish populations. We examined and compared the multidecadal rates of biotic [Hg] decrease and contemporary factors affecting [Hg] in fish collected from a hydroelectric reservoir (Tobin Lake) and a related downstream fishery (Cumberland Lake) along the Saskatchewan River, Canada. Rates of [Hg] decrease were considered in four species-northern pike (Esox lucius), sauger (Sander canadensis), goldeye (Hiodon alosoides), and walleye (S. vitreus)-all of which showed a significant decrease over time (p < 0.001) and are now lower than Health Canada consumption guidelines (0.5 μg/g). Rates of decrease ranged from 0.5 to 3.9 %/year and were similar between sites in the cases of northern pike and sauger. Contemporary factors affecting [Hg] in walleye collected downstream include fish length (p < 0.001), fish age (p < 0.001), and trophic magnification through the food web (p < 0.001), and relationships between [Hg] and trophic level in predatory and prey fish are now similar to those found in non-Hg-inundated systems at a similar latitude. Together, these results suggest connected contamination between the two sites and delineate the timeline during which [Hg] in a variety of fish species decreased to nontoxic levels in both locations.

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

Autophagic-lysosomal dysregulation downstream of cathepsin B inactivation in human skin fibroblasts exposed to UVA

PubMed Central

Lamore, Sarah D.; Wondrak, Georg T.

2014-01-01

Recently, using 2D-DIGE proteomics we have identified cathepsin B as a novel target of UVA in human Hs27 skin fibroblasts. In response to chronic exposure to noncytotoxic doses of UVA (9.9 J/cm2, twice a week, 3 weeks), photooxidative impairment of cathepsin B enzymatic activity occurred with accumulation of autofluorescent aggregates colocalizing with lysosomes, an effect mimicked by pharmacological antagonism of cathepsin B using the selective inhibitor CA074Me. Here, we have further explored the mechanistic involvement of cathepsin B inactivation in UVA-induced autophagic-lysosomal alterations using autophagy-directed PCR expression array analysis as a discovery tool. Consistent with lysosomal expansion, UVA upregulated cellular protein levels of the lysosomal marker glycoprotein Lamp-1, and increased levels of the lipidated autophagosomal membrane constituent LC3-II were detected. UVA did not alter expression of beclin 1 (BECN1), an essential factor for initiation of autophagy, but upregulation of p62 (sequestosome 1, SQSTM1), a selective autophagy substrate, and α-synuclein (SNCA), an autophagic protein substrate and aggresome component, was observed at the mRNA and protein level. Moreover, UVA downregulated transglutaminase-2 (TGM2), an essential enzyme involved in autophagolysosome maturation. Strikingly, UVA effects on Lamp-1, LC3-II, beclin 1, p62, α-synuclein, and transglutaminase-2 were mimicked by CA074Me treatment. Taken together, our data suggest that UVA-induced autophagic-lysosomal alterations occur as a consequence of impaired autophagic flux downstream of cathepsin B inactivation, a novel molecular mechanism potentially involved in UVA-induced skin photodamage. PMID:21773629

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

Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations.

PubMed

Eswaran, Jeyanthy; Li, Da-Qiang; Shah, Anil; Kumar, Rakesh

2012-07-15

The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a variety of new functions for this kinase in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely upregulated in several human cancers, such as hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. Structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibility to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize recent findings about the PAK1 molecular pathways in human cancer and discuss the current status of PAK1-targeted anticancer therapies.

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.

A phorbol ester-binding protein is required downstream of Rab5 in endosome fusion.

PubMed

Aballay, A; Barbieri, M A; Colombo, M I; Arenas, G N; Stahl, P D; Mayorga, L S

1998-12-28

Previous observations indicate that a zinc and phorbol ester binding factor is necessary for endosome fusion. To further characterize the role of this factor in the process, we used an in vitro endosome fusion assay supplemented with recombinant Rab5 proteins. Both zinc depletion and addition of calphostin C, an inhibitor of protein kinase C, inhibited endosome fusion in the presence of active Rab5. Addition of the phorbol ester PMA (phorbol 12-myristate 13-acetate) reversed the inhibition of endosome fusion caused by a Rab5 negative mutant. Moreover, PMA stimulated fusion in the presence of Rab5 immunodepleted cytosol. These results suggest that the phorbol ester binding protein is acting downstream of Rab5 in endosome fusion.

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

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

Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions

PubMed Central

Fu, Chen; Gombos, Dan S; Lee, Jared; George, Goldy C; Hess, Kenneth; Whyte, Andrew; Hong, David S

2017-01-01

Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity. Trials cited by FDA labels were retrieved, and a combination search in Medline, Google Scholar, the Cochrane database, and the NIH Clinical Trials Database was conducted. The majority of ocular toxicities reported were low severity, and the most common were conjunctivitis and “visual disturbances.” However, severe events including incidents of blindness, retinal vascular occlusion, and corneal ulceration occurred. The frequency and severity at which ocular toxicities occur merits a more multidisciplinary approach to managing patients with agents that are known to cause ocular issues. We suggest a standardized methodology for referral and surveillance of patients who are potentially at risk of severe ocular toxicity. PMID:28938590

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

Targeting Src and tubulin in mucinous ovarian carcinoma

PubMed Central

Liu, Tao; Hu, Wei; Dalton, Heather J.; Choi, Hyun Jin; Huang, Jie; Kang, Yu; Pradeep, Sunila; Miyake, Takahito; Song, Jian H.; Wen, Yunfei; Lu, Chunhua; Pecot, Chad V.; Bottsford-Miller, Justin; Zand, Behrouz; Jennings, Nicholas B; Ivan, Cristina; Gallick, Gary E.; Baggerly, Keith A; Hangauer, David G.; Coleman, Robert L.; Frumovitz, Michael; Sood, Anil K.

2013-01-01

Purpose To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental design The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. Results In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2/M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. Conclusion Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma. PMID:24100628

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

Distant downstream steady-state flow studies of a mechanical heart valve: PIV study of secondary flow in a model aortic arch

NASA Astrophysics Data System (ADS)

Fix, Brandon R.; Popma, Christopher J.; Bulusu, Kartik V.; Plesniak, Michael W.

2013-11-01

Each year, hundreds of thousands of aortic and mitral heart valves are replaced with prosthetic valves. In efforts to develop a valve that does not require lifelong anticoagulation therapy, previous experimental research has been devoted to analyzing the hemodynamics of various heart valve designs, limited to the flow up to only 2 diameters downstream of the valve. Two-component, two-dimensional (2C-2D) particle image velocimetry (PIV) was used in this study to examine secondary flow velocity fields in a curved tube modeling an aorta at five locations (0-, 45-, 90-, 135-, 180-degrees). A bileaflet valve, opened to 30-, 45-, and 59-degrees, and one (no-valve) baseline condition were examined under three steady flow inflows (Re = 218, 429, 634). In particular, variations in the two-dimensional turbulent shear stresses at each cross sectional plane were analyzed. The results suggest that bileaflet valves in the aortic model produce significant turbulence and vorticity up to 5.5 downstream diameters, i.e. up to the 90-degrees location. Expanding this research towards aortic heart valve hemodynamics highlights a need for additional studies extending beyond the typical few diameters downstream to fully characterize valvular function. Supported by the NSF Grant No. CBET- 0828903 and GW Center for Biomimetics and Bioinspired Engineering.

The σ70 region 1.2 regulates promoter escape by unwinding DNA downstream of the transcription start site

PubMed Central

Bochkareva, Aleksandra; Zenkin, Nikolay

2013-01-01

The mechanisms of abortive synthesis and promoter escape during initiation of transcription are poorly understood. Here, we show that, after initiation of RNA synthesis, non-specific interaction of σ70 region 1.2, present in all σ70 family factors, with the non-template strand around position −4 relative to the transcription start site facilitates unwinding of the DNA duplex downstream of the transcription start site. This leads to stabilization of short RNA products and allows their extension, i.e. promoter escape. We show that this activity of σ70 region 1.2 is assisted by the β-lobe domain, but does not involve the β′-rudder or the β′-switch-2, earlier proposed to participate in promoter escape. DNA sequence independence of this function of σ70 region 1.2 suggests that it may be conserved in all σ70 family factors. Our results indicate that the abortive nature of initial synthesis is caused, at least in part, by failure to open the downstream DNA by the β-lobe and σ region 1.2. PMID:23430153

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.

Vimentin is a target of PKCβ phosphorylation in MCP-1-activated primary human monocytes

PubMed Central

Thiagarajan, Praveena S.; Akbasli, Ayse C.; Kinter, Michael T.; Willard, Belinda; Cathcart, Martha K.

2013-01-01

Objective and design We designed a study to detect downstream phosphorylation targets of PKCβ in MCP-1-induced human monocytes. Methods 2-dimensional gel electrophoresis was performed for monocytes treated with MCP-1 in the presence or absence of PKCβ antisense oligodeoxyribonucleotides (AS-ODN) or a PKCβ inhibitor peptide, followed by phospho- and total protein staining. Proteins that stained less intensely with the phospho-stain, when normalized to the total protein stain, in the presence of PKCβ AS-ODN or the PKC β inhibitor peptide were sequenced. Results Of the proteins identified, vimentin was consistently identified using both experimental approaches. Upon 32P-labeling and vimentin immunoprecipitation, increased phosphorylation of vimentin was observed in MCP-1 treated monocytes as compared to the untreated monocytes. Both PKCβ AS-ODN and the PKCβ inhibitor reduced MCP-1-induced vimentin phosphorylation. IP of monocytes with anti-vimentin antibody and immunoblotting with a PKCβ antibody revealed that increased PKCβ becomes associated with vimentin upon MCP-1 activation. Upon MCP-1 treatment, monocytes were shown to secrete vimentin and secretion depended on PKCβ expression and activity. Conclusions We conclude that vimentin, a major intermediate filament protein, is a phosphorylation target of PKCβ in MCP-1-treated monocytes and that PKCβ phosphorylation is essential for vimentin secretion. Our recently published studies have implicated vimentin as a potent stimulator of the innate immune receptor Dectin-1 [1]. Taken together our findings suggest that inhibition of PKCβ regulates vimentin secretion and thereby, its interaction with Dectin-1 and downstream stimulation of superoxide anion production. Thus PKCβ phosphorylation of vimentin likely plays an important role in propagating inflammatory responses. PMID:23974215

Vimentin is a target of PKCβ phosphorylation in MCP-1-activated primary human monocytes.

PubMed

Thiagarajan, Praveena S; Akbasli, Ayse C; Kinter, Michael T; Willard, Belinda; Cathcart, Martha K

2013-11-01

We designed a study to detect downstream phosphorylation targets of PKCβ in MCP-1-induced human monocytes. Two-dimensional gel electrophoresis was performed for monocytes treated with MCP-1 in the presence or absence of PKCβ antisense oligodeoxyribonucleotides (AS-ODN) or a PKCβ inhibitor peptide, followed by phospho- and total protein staining. Proteins that stained less intensely with the phospho-stain, when normalized to the total protein stain, in the presence of PKCβ AS-ODN or the PKCβ inhibitor peptide, were sequenced. Of the proteins identified, vimentin was consistently identified using both experimental approaches. Upon (32)P-labeling and vimentin immunoprecipitation, increased phosphorylation of vimentin was observed in MCP-1 treated monocytes as compared to the untreated monocytes. Both PKCβ AS-ODN and the PKCβ inhibitor reduced MCP-1-induced vimentin phosphorylation. The IP of monocytes with anti-vimentin antibody and immunoblotting with a PKCβ antibody revealed that increased PKCβ becomes associated with vimentin upon MCP-1 activation. Upon MCP-1 treatment, monocytes were shown to secrete vimentin and secretion depended on PKCβ expression and activity. We conclude that vimentin, a major intermediate filament protein, is a phosphorylation target of PKCβ in MCP-1-treated monocytes and that PKCβ phosphorylation is essential for vimentin secretion. Our recently published studies have implicated vimentin as a potent stimulator of the innate immune receptor Dectin-1 as reported by Thiagarajan et al. (Cardiovasc Res 99:494-504, 2013). Taken together our findings suggest that inhibition of PKCβ regulates vimentin secretion and, thereby, its interaction with Dectin-1 and downstream stimulation of superoxide anion production. Thus, PKCβ phosphorylation of vimentin likely plays an important role in propagating inflammatory responses.

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

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.

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.

Geomorphic response of rivers to glacial retreat and increasing peak flows downstream from Mount Rainier, Washington

NASA Astrophysics Data System (ADS)

Czuba, J. A.; Barnas, C. R.; Magirl, C. S.; Voss, F. D.

2010-12-01

On Mount Rainier, Washington, the National Park Service has documented widespread aggradation of as much as 10 m since the early 20th century, of rivers draining the glaciated stratovolcano. This rapid sedimentation appears to be related to glacial retreat and also may be a function of the increased magnitude and timing of peak flows that mobilize and transport sediment. We are conducting an assessment of the Puget Lowland rivers that drain Mount Rainier, 25-100 km downstream from the park boundary, to document the geomorphic response of the downstream reaches given the widespread aggradation upstream. These downstream reaches provide critical aquatic habitat for spawning and rearing of several species of salmonids, including endangered Chinook salmon and steelhead. Fluvial sedimentation can have both deleterious and beneficial effects on aquatic habitat depending on sediment particle size, river slope and width, and river management. To date, our work shows sedimentation of as much as 2 m between 1984 and 2009 in these lowland rivers. Aggradation rates that were calculated by comparing channel change at 156 cross sections, ranged between 4.8 and 9.1 cm/yr in reaches where rivers exit the mountain front and enter the lowland. Analysis of streamflow-gaging station data from throughout the watersheds draining Mount Rainier show rapid incision and aggradation, suggesting pulses of coarse-grained bedload may be moving down the mountainous rivers as kinetic waves. Preliminary results, however, seem to indicate that the rivers in the Puget Lowland have not yet experienced significant widespread sedimentation directly related to glacial retreat. Estimating the time of arrival of mobilized alluvium is a critical need for resource managers given the potential effects of sedimentation on river flood-conveyance capacity, fish habitat, and estuarine wetlands.

Elevation of transforming growth factor beta (TGFbeta) and its downstream mediators in subcutaneous foreign body capsule tissue.

PubMed

Li, Allen G; Quinn, Matthew J; Siddiqui, Yasmin; Wood, Michael D; Federiuk, Isaac F; Duman, Heather M; Ward, W Kenneth

2007-08-01

Foreign body encapsulation represents a chronic fibrotic response and has been a major obstacle that reduces the useful life of implanted biomedical devices. The precise mechanism underlying such an encapsulation is still unknown. We hypothesized that, considering its central role in many other fibrotic conditions, transforming growth factor beta (TGFbeta) may play an important role during the formation of foreign body capsule (FBC). In the present study, we implanted mock sensors in rats subcutaneously and excised FBC samples at day 7, 21, and 48-55 postimplantation. The most abundant TGFbeta isoform in all tissues was TGFbeta1, which was expressed minimally in control tissue. The expression of both TGFbeta1 RNA and protein was significantly increased in FBC tissues at all time points, with the highest level in day 7 FBC. The number of cells stained for phosphorylated Smad2, an indication of activated TGFbeta signaling, paralleled the expression of TGFbeta. A similar dynamic change was also observed in the numbers of FBC myofibroblasts, which in response to TGFbeta, differentiate from quiescent fibroblasts and synthesize collagen. Type I collagen, the most prominent downstream target of TGFbeta in fibrosis, was found in abundance in the FBC, especially during the latter time periods. We suggest that TGFbeta plays an important role in the FBC formation. Inhibition of TGFbeta signaling could be a promising strategy in the prevention of FBC formation, thereby extending the useful life of subcutaneous implants.

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.

Mercury concentrations in fish from a Sierra Nevada foothill reservoir located downstream from historic gold-mining operations

USGS Publications Warehouse

Saiki, Michael K.; Martin, Barbara A.; May, Thomas W.; Alpers, Charles N.

2010-01-01

This study examined mercury concentrations in whole fish from Camp Far West Reservoir, an 830-ha reservoir in northern California, USA, located downstream from lands mined for gold during and following the Gold Rush of 1848–1864. Total mercury (reported as dry weight concentrations) was highest in spotted bass (mean, 0.93 μg/g; range, 0.16–4.41 μg/g) and lower in bluegill (mean, 0.45 μg/g; range, 0.22–1.96 μg/g) and threadfin shad (0.44 μg/g; range, 0.21–1.34 μg/g). Spatial patterns for mercury in fish indicated high concentrations upstream in the Bear River arm and generally lower concentrations elsewhere, including downstream near the dam. These findings coincided with patterns exhibited by methylmercury in water and sediment, and suggested that mercury-laden inflows from the Bear River were largely responsible for contaminating the reservoir ecosystem. Maximum concentrations of mercury in all three fish species, but especially bass, were high enough to warrant concern about toxic effects in fish and consumers of fish.

Repriming by PrimPol is critical for DNA replication restart downstream of lesions and chain-terminating nucleosides.

PubMed

Kobayashi, Kaori; Guilliam, Thomas A; Tsuda, Masataka; Yamamoto, Junpei; Bailey, Laura J; Iwai, Shigenori; Takeda, Shunichi; Doherty, Aidan J; Hirota, Kouji

2016-08-02

PrimPol is a DNA damage tolerance enzyme possessing both translesion synthesis (TLS) and primase activities. To uncover its potential role in TLS-mediated IgVλ hypermutation and define its interplay with other TLS polymerases, PrimPol(-/-) and PrimPol(-/-)/Polη(-/-)/Polζ (-/-) gene knockouts were generated in avian cells. Loss of PrimPol had no significant impact on the rate of hypermutation or the mutation spectrum of IgVλ. However, PrimPol(-/-) cells were sensitive to methylmethane sulfonate, suggesting that it may bypass abasic sites at the IgVλ segment by repriming DNA synthesis downstream of these sites. PrimPol(-/-) cells were also sensitive to cisplatin and hydroxyurea, indicating that it assists in maintaining / restarting replication at a variety of lesions. To accurately measure the relative contribution of the TLS and primase activities, we examined DNA damage sensitivity in PrimPol(-/-) cells complemented with polymerase or primase-deficient PrimPol. Polymerase-defective, but not primase-deficient, PrimPol suppresses the hypersensitivity of PrimPol(-/-) cells. This indicates that its primase, rather than TLS activity, is pivotal for DNA damage tolerance. Loss of TLS polymerases, Polη and Polζ has an additive effect on the sensitivity of PrimPol(-/-) cells. Moreover, we found that PrimPol and Polη-Polζ redundantly prevented cell death and facilitated unperturbed cell cycle progression. PrimPol(-/-) cells also exhibited increased sensitivity to a wide variety of chain-terminating nucleoside analogs (CTNAs). PrimPol could perform close-coupled repriming downstream of CTNAs and oxidative damage in vitro. Together, these results indicate that PrimPol's repriming activity plays a central role in reinitiating replication downstream from CTNAs and other specific DNA lesions.

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

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.

Twist1 Transcriptional Targets in the Developing Atrio-Ventricular Canal of the Mouse

PubMed Central

Vrljicak, Pavle; Cullum, Rebecca; Xu, Eric; Chang, Alex C. Y.; Wederell, Elizabeth D.; Bilenky, Mikhail; Jones, Steven J. M.; Marra, Marco A.; Karsan, Aly; Hoodless, Pamela A.

2012-01-01

Malformations of the cardiovascular system are the most common type of birth defect in humans, frequently affecting the formation of valves and septa. During heart valve and septa formation, cells from the atrio-ventricular canal (AVC) and outflow tract (OFT) regions of the heart undergo an epithelial-to-mesenchymal transformation (EMT) and invade the underlying extracellular matrix to give rise to endocardial cushions. Subsequent maturation of newly formed mesenchyme cells leads to thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix transcription factor expressed in newly formed mesenchyme cells of the AVC and OFT that has been shown to play roles in cell survival, cell proliferation and differentiation. However, the downstream targets of TWIST1 during heart valve formation remain unclear. To identify genes important for heart valve development downstream of TWIST1, we performed global gene expression profiling of AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag-seq). Using this resource we identified a novel set of 939 genes, including 123 regulators of transcription, enriched in the valve forming regions of the heart. We compared these genes to a Tag-seq library from the Twist1 null developing valves revealing significant gene expression changes. These changes were consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. To study the role of TWIST1 at the DNA level we performed chromatin immunoprecipitation and identified novel direct targets of TWIST1 in the developing heart valves. Our findings support a role for TWIST1 in the differentiation of AVC mesenchyme post-EMT in the mouse, and suggest that TWIST1 can exert its function by direct DNA binding to activate valve specific gene expression. PMID:22815831

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.

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.

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

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

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.

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.

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.

Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone

PubMed Central

Kawabata, Shigeru; Christine Hollander, M; Munasinghe, Jeeva P.; Brinster, Lauren R.; Mercado-Matos, José R.; Li, Jie; Regales, Lucia; Pao, William; Jänne, Pasi A.; Wong, Kwok-Kin; Butman, John A.; Lonser, Russell R.; Hansen, Marlan R.; Gurgel, Richard K.; Vortmeyer, Alexander O.; Dennis, Phillip A.

2015-01-01

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms. PMID:26027747

Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone.

PubMed

Kawabata, Shigeru; Hollander, M Christine; Munasinghe, Jeeva P; Brinster, Lauren R; Mercado-Matos, José R; Li, Jie; Regales, Lucia; Pao, William; Jänne, Pasi A; Wong, Kwok-Kin; Butman, John A; Lonser, Russell R; Hansen, Marlan R; Gurgel, Richard K; Vortmeyer, Alexander O; Dennis, Phillip A

2015-05-10

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.

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

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1.

PubMed

Liu, Yanwei; Yan, Wei; Zhang, Wei; Chen, Lingchao; You, Gan; Bao, Zhaoshi; Wang, Yongzhi; Wang, Hongjun; Kang, Chunsheng; Jiang, Tao

2012-09-01

The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies.

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

Numerical Simulation of Missouri River Bed Evolution Downstream of Gavins Point Dam

NASA Astrophysics Data System (ADS)

Sulaiman, Z. A.; Blum, M. D.; Lephart, G.; Viparelli, E.

2016-12-01

The Missouri River originates in the Rocky Mountains in western Montana and joins the Mississippi River near Saint Louis, Missouri. In the 1900s dam construction and river engineering works, such as river alignment, narrowing and bank protections were performed in the Missouri River basin to control the flood flows, ensure navigation and use the water for agricultural, industrial and municipal needs, for the production of hydroelectric power generation and for recreation. These projects altered the flow and the sediment transport regimes in the river and the exchange of sediment between the river and the adjoining floodplain. Here we focus on the long term effect of dam construction and channel narrowing on the 1200 km long reach of the Missouri River between Gavins Point Dam, Nebraska and South Dakota, and the confluence with the Mississippi River. Field observations show that two downstream migrating waves of channel bed degradation formed in this reach in response to the changes in flow regime, sediment load and channel geometry. We implemented a one dimensional morphodynamic model for large, low slope sand bed rivers, we validated the model at field scale by comparing the numerical results with the available field data and we use the model to 1) predict the magnitude and the migration rate of the waves of degradation at engineering time scales ( 150 years into the future), 2) quantify the changes in the sand load delivered to the Mississippi River, where field observations at Thebes, i.e. downstream of Saint Louis, suggest a decline in the mean annual sand load in the past 50 years, and 3) identify the role of the main tributaries - Little Sioux River, Platte River and Kansas River - on the wave migration speed and the annual sand load in the Missouri River main channel.

The mechanisms involved in miR-9 regulated apoptosis in cervical cancer by targeting FOXO3.

PubMed

Zhang, Haiyan; Zhang, Zhen; Wang, Surong; Zhang, Shiqian; Bi, Junying

2018-06-01

As a seriously global health problem, cervical cancer is a great risk to women which threatens their lives. Approximately 30% patients who received definitive treatment may fail to recover from this disease. Accordingly, there is an imperatively need to explore alternative therapeutic approaches for this disease. Several studies have revealed that miR-9 was a critical regulator during cervical cancer growth. Here, we reported that the miR-9 was overexpressed in cervical tumor tissue and exerted a promoting effect on human cervical cancer cell (SiHa) growth. Both in vitro and in vivo experiments confirmed that miR-9 could stimulate the proliferation and migration of SiHa cells. In contrast, inhibition of miR-9 induced apoptosis in SiHa cells. In addition, dual luciferase reporter system assay verified that there was a strong target relationship between miR-9 and FOXO3. Result of western blot assay showed that the inhibition of miR-9 increased the expression of FOXO3. Moreover, miR-9 regulated FOXO3 downstream proteins Bax, Bcl-2 and p-Akt expressions, which suggesting that miR-9 was involved in the SiHa cells apoptosis. In conclusion, our results suggest that the inhibition of miR-9 could induce apoptosis in cervical cancer by targeting FOXO3 and presented a potential molecular target for the treatment of cervical cancer patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo.

PubMed

Parisi, Federica; Riccardo, Sara; Daniel, Margaret; Saqcena, Mahesh; Kundu, Nandini; Pession, Annalisa; Grifoni, Daniela; Stocker, Hugo; Tabak, Esteban; Bellosta, Paola

2011-09-27

Genetic studies in Drosophila melanogaster reveal an important role for Myc in controlling growth. Similar studies have also shown how components of the insulin and target of rapamycin (TOR) pathways are key regulators of growth. Despite a few suggestions that Myc transcriptional activity lies downstream of these pathways, a molecular mechanism linking these signaling pathways to Myc has not been clearly described. Using biochemical and genetic approaches we tried to identify novel mechanisms that control Myc activity upon activation of insulin and TOR signaling pathways. Our biochemical studies show that insulin induces Myc protein accumulation in Drosophila S2 cells, which correlates with a decrease in the activity of glycogen synthase kinase 3-beta (GSK3β ) a kinase that is responsible for Myc protein degradation. Induction of Myc by insulin is inhibited by the presence of the TOR inhibitor rapamycin, suggesting that insulin-induced Myc protein accumulation depends on the activation of TOR complex 1. Treatment with amino acids that directly activate the TOR pathway results in Myc protein accumulation, which also depends on the ability of S6K kinase to inhibit GSK3β activity. Myc upregulation by insulin and TOR pathways is a mechanism conserved in cells from the wing imaginal disc, where expression of Dp110 and Rheb also induces Myc protein accumulation, while inhibition of insulin and TOR pathways result in the opposite effect. Our functional analysis, aimed at quantifying the relative contribution of Myc to ommatidial growth downstream of insulin and TOR pathways, revealed that Myc activity is necessary to sustain the proliferation of cells from the ommatidia upon Dp110 expression, while its contribution downstream of TOR is significant to control the size of the ommatidia. Our study presents novel evidence that Myc activity acts downstream of insulin and TOR pathways to control growth in Drosophila. At the biochemical level we found that both these pathways

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.

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.

Influences of body size and environmental factors on autumn downstream migration of bull trout in the Boise River, Idaho

USGS Publications Warehouse

Monnot, L.; Dunham, J.B.; Hoem, T.; Koetsier, P.

2008-01-01

Many fishes migrate extensively through stream networks, yet patterns are commonly described only in terms of the origin and destination of migration (e.g., between natal and feeding habitats). To better understand patterns of migration in bull trout,Salvelinus confluentus we studied the influences of body size (total length [TL]) and environmental factors (stream temperature and discharge) on migrations in the Boise River basin, Idaho. During the autumns of 2001-2003, we tracked the downstream migrations of 174 radio-tagged bull trout ranging in size from 21 to 73 cm TL. The results indicated that large bull trout (>30 cm) were more likely than small fish to migrate rapidly downstream after spawning in headwater streams in early autumn. Large bull trout also had a higher probability of arriving at the current terminus of migration in the system, Arrowrock Reservoir. The rate of migration by small bull trout was more variable and individuals were less likely to move into Arrowrock Reservoir. The rate of downstream migration by all fish was slower when stream discharge was greater. Temperature was not associated with the rate of migration. These findings indicate that fish size and environmentally related changes in behavior have important influences on patterns of migration. In a broader context, these results and other recent work suggest, at least in some cases, that commonly used classifications of migratory behavior may not accurately reflect the full range of behaviors and variability among individuals (or life stages) and environmental conditions. ?? Copyright by the American Fisheries Society 2008.

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.

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.

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

Connections between Transcription Downstream of Genes and cis-SAGe Chimeric RNA.

PubMed

Chwalenia, Katarzyna; Qin, Fujun; Singh, Sandeep; Tangtrongstittikul, Panjapon; Li, Hui

2017-11-22

cis-Splicing between adjacent genes (cis-SAGe) is being recognized as one way to produce chimeric fusion RNAs. However, its detail mechanism is not clear. Recent study revealed induction of transcriptions downstream of genes (DoGs) under osmotic stress. Here, we investigated the influence of osmotic stress on cis-SAGe chimeric RNAs and their connection to DoGs. We found,the absence of induction of at least some cis-SAGe fusions and/or their corresponding DoGs at early time point(s). In fact, these DoGs and their cis-SAGe fusions are inversely correlated. This negative correlation was changed to positive at a later time point. These results suggest a direct competition between the two categories of transcripts when total pool of readthrough transcripts is limited at an early time point. At a later time point, DoGs and corresponding cis-SAGe fusions are both induced, indicating that total readthrough transcripts become more abundant. Finally, we observed overall enhancement of cis-SAGe chimeric RNAs in KCl-treated samples by RNA-Seq analysis.

[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.

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

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.

Downstream change in leucine aminopeptidase activity and leucine assimilation by epilithic microbiota along the River Swale, northern England.

PubMed

Ainsworth, A M; Goulder, R

2000-05-05

Parallel determinations of epilithic extracellular leucine aminopeptidase activity and leucine assimilation were made at five sites along 112 km of the River Swale and also in two tributaries, the River Wiske and Cod Beck. Epilithic leucine aminopeptidase activity along the Swale increased with distance downstream; this increase was gradual, rather than stepwise in response to specific sewage-works outfalls. Epilithic leucine assimilation, in contrast, did not consistently increase along the river. Epilithic leucine aminopeptidase activity and leucine assimilation were both potentially controlled by epilithic microbial variables (bacterial abundance and chlorophyll a) while leucine aminopeptidase activity was also strongly related to water-quality variables, especially temperature, pH and conductivity. Epilithic leucine aminopeptidase activity and leucine assimilation were coupled, but the magnitude of aminopeptidase activity was always substantially greater than that of leucine assimilation. Arguments are presented, however, which suggest that this did not necessarily indicate the constant availability of excess leucine, and by inference amino-acid nitrogen, to epilithic bacteria. Values of epilithic leucine aminopeptidase activity and leucine assimilation, expressed relative to rates in overlying water, suggested that most activity and assimilation was epilithic rather than planktonic, although the planktonic contribution was proportionately greater at the deeper, more downstream, sites. In the tributaries, River Wiske and Cod Beck, values of epilithic leucine aminopeptidase activity and epilithic microbial abundance, as well as those of many water-quality variables, resembled values in the middle and lower Swale. Thus, these tributaries were essentially lowland, enriched watercourses being very different from the headstreams of the main river.

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

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

Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling.

PubMed

Yoshii, Akira; Constantine-Paton, Martha

2014-01-01

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate synaptic plasticity. TrkB triggers three downstream signaling pathways; Phosphatidylinositol 3-kinase (PI3K), Phospholipase Cγ (PLCγ) and Mitogen activated protein kinases/Extracellular signal-regulated kinases (MAPK/ERK). We previously showed two distinct mechanisms whereby BDNF-TrkB pathway controls trafficking of PSD-95, which is the major scaffold at excitatory synapses and is critical for synapse maturation. BDNF activates the PI3K-Akt pathway and regulates synaptic delivery of PSD-95 via vesicular transport (Yoshii and Constantine-Paton, 2007). BDNF-TrkB signaling also triggers PSD-95 palmitoylation and its transport to synapses through the phosphorylation of the palmitoylation enzyme ZDHHC8 by a protein kinase C (PKC; Yoshii etal., 2011). The second study used PKC inhibitors chelerythrine as well as a synthetic zeta inhibitory peptide (ZIP) which was originally designed to block the brain-specific PKC isoform protein kinase Mϖ (PKMϖ). However, recent studies raise concerns about specificity of ZIP. Here, we assessed the contribution of TrkB and its three downstream pathways to the synaptic distribution of endogenous PSD-95 in cultured neurons using chemical and genetic interventions. We confirmed that TrkB, PLC, and PI3K were critical for the postsynaptic distribution of PSD-95. Furthermore, suppression of MAPK/ERK also disrupted PSD-95 expression. Next, we examined the contribution of PKC. While both chelerythrine and ZIP suppressed the postsynaptic localization of PSD-95, RNA interference for PKMϖ did not have a significant effect. This result suggests that the ZIP peptide, widely used as the "specific" PKMϖ antagonist by many investigators may block a PKC variant other than PKMϖ such as PKCλ/ι. Our results indicate that TrkB regulates postsynaptic localization of PSD-95 through all three downstream pathways, but also recommend further work to identify other PKC variants that

ZNF750 is a p63 Target Gene that Induces KLF4 to Drive Terminal Epidermal Differentiation

PubMed Central

Sen, George L.; Boxer, Lisa D.; Webster, Dan E.; Bussat, Rose T.; Qu, Kun; Zarnegar, Brian J.; Johnston, Danielle; Siprashvili, Zurab; Khavari, Paul A.

2012-01-01

SUMMARY Disrupted epidermal differentiation characterizes numerous diseases that impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for ZNF750 in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation. ZNF750 binds to KLF4 at multiple sites flanking the transcriptional start site and controls its expression. ZNF750 thus directly links a tissue-specifying factor, p63, to an effector of terminal differentiation, KLF4, and represents a potential future target for disorders of this process. PMID:22364861

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

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.

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.

An experimental investigation of the unsteady response of a stator located downstream of a propeller ingesting broadband turbulence

NASA Astrophysics Data System (ADS)

Lynch, Denis Aloysius, III

This experimental investigation examined the unsteady response of a stator located downstream of a four- or ten-bladed propeller encountering broadband turbulence. The response is manifested in a radiated acoustic field which can be directly attributed to the unsteady surface pressure loading on the stator by the turbulent flowfield. In order to characterize the unsteady response of the stator, a thorough analysis of the turbulent flowfield downstream of the propeller was completed. The analysis of the turbulent flowfield is organized in a manner which reflects the causal relationship between influences on the flowfield and the evolution of the flowfield itself. Mathematical models for each of these contributions, including the broadband and periodic contributions of the propeller wakes and modification of the inflow turbulence by the propeller, are presented and analyzed. A further mathematical model involving the prediction of correlation length scale aids in the accurate prediction of the radiated acoustic pressure based solely on fundamental turbulent flowfield measurements. Unsteady surface pressure measurements, originally intended to provide additional information about the response of the stator as it relates to the incoming flowfield, were found to be heavily contaminated by vibrational effects. Therefore, techniques involving cross-correlation measurements are developed to mathematically isolate the unsteady pressure signal. The success of these techniques suggests the strong possibility of future application in this area. Finally, the mathematical models developed to describe the flowfield downstream of the propeller are applied to the case of a twenty-bladed propeller. This case was selected due to the anticipated increased levels of modification of the inflow turbulence. Results provide further evidence that this complex flowfield may be fully and accurately represented using simple mathematical models supported by baseline empirical information.

Development of schooling behaviour during the downstream migration of Atlantic salmon Salmo salar smolts in a chalk stream.

PubMed

Riley, W D; Ibbotson, A T; Maxwell, D L; Davison, P I; Beaumont, W R C; Ives, M J

2014-10-01

The downstream migratory behaviour of wild Atlantic salmon Salmo salar smolts was monitored using passive integrated transponder (PIT) antennae systems over 10 years in the lower reaches of a small chalk stream in southern England, U.K. The timing of smolt movements and the likely occurrence of schooling were investigated and compared to previous studies. In nine of the 10 consecutive years of study, the observed diel downstream patterns of S. salar smolt migration appeared to be synchronized with the onset of darkness. The distribution of time intervals between successive nocturnal detections of PIT-tagged smolts was as expected if generated randomly from observed hourly rates. There were, however, significantly more short intervals than expected for smolts detected migrating during the day. For each year from 2006 to 2011, the observed 10th percentile of the daytime intervals was <4 s, compared to ≥55 s for the simulated random times, indicating greater incidence of groups of smolts. Groups with the shortest time intervals between successive PIT tag detections originated from numerous parr tagging sites (used as a proxy for relatedness). The results suggest that the ecological drivers influencing daily smolt movements in the lower reaches of chalk stream catchments are similar to those previously reported at the onset of migration for smolts leaving their natal tributaries; that smolts detected migrating during the night are moving independently following initiation by a common environmental factor (presumably darkness), whereas those detected migrating during the day often move in groups, and that such schools may not be site (kin)-structured. The importance of understanding smolt migratory behaviour is considered with reference to stock monitoring programmes and enhancing downstream passage past barriers. © 2014 Crown copyright. Journal of Fish Biology © 2014 The Fisheries Society of the British Isles.

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.

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.

In Silico Prediction and Validation of Gfap as an miR-3099 Target in Mouse Brain.

PubMed

Abidin, Shahidee Zainal; Leong, Jia-Wen; Mahmoudi, Marzieh; Nordin, Norshariza; Abdullah, Syahril; Cheah, Pike-See; Ling, King-Hwa

2017-08-01

MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms (miRDB, miRanda, TargetScan, and DIANA-micro-T-CDS) with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms (324 genes) were subjected to DAVID bioinformatics analysis to understand their overall functional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization (ISH) expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes (Dnmt3a, Gabpa, Gfap, Itga4, Lxn, Smad7, and Tbx18) having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset.

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

Evaluation of Downstream Regulatory Element Antagonistic Modulator Gene in Human Multinodular Goiter

PubMed Central

Shinzato, Amanda; Lerario, Antonio M.; Lin, Chin J.; Danilovic, Debora S.; Marui, Suemi; Trarbach, Ericka B.

2015-01-01

Background DREAM (Downstream Regulatory Element Antagonistic Modulator) is a neuronal calcium sensor that was suggested to modulate TSH receptor activity and whose overexpression provokes an enlargement of the thyroid gland in transgenic mice. The aim of this study was to investigate somatic mutations and DREAM gene expression in human multinodular goiter (MNG). Material/Methods DNA and RNA samples were obtained from hyperplastic thyroid glands of 60 patients (54 females) with benign MNG. DREAM mutations were evaluated by PCR and direct automatic sequencing, whereas relative quantification of mRNA was performed by real-time PCR. Over- and under-expression were defined as a 2-fold increase and decrease in comparison to normal thyroid tissue, respectively. RQ M (relative quantification mean); SD (standard deviation). Results DREAM expression was detected in all nodules evaluated. DREAM mRNA was overexpressed in 31.7% of MNG (RQ M=6.26; SD=5.08), whereas 53.3% and 15% had either normal (RQ M=1.16; SD=0.46) or underexpression (RQ M=0.30; SD=0.10), respectively. Regarding DREAM mutations analysis, only previously described intronic polymorphisms were observed. Conclusions We report DREAM gene expression in the hyperplastic thyroid gland of MNG patients. However, DREAM expression did not vary significantly, and was somewhat underexpressed in most patients, suggesting that DREAM upregulation does not significantly affect nodular development in human goiter. PMID:26319784

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.

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

A novel class of Pseudoautosomal region 1 deletions downstream of SHOX is associated with Leri-Weill dyschondrosteosis.

PubMed

Benito-Sanz, Sara; Thomas, N Simon; Huber, Céline; Huber, Celine; Gorbenko del Blanco, Darya; Del Blanco, Darya Gorbenko; Aza-Carmona, Miriam; Crolla, John A; Maloney, Vivienne; Rappold, Gudrun; Argente, Jesús; Argente, Jesus; Campos-Barros, Angel; Cormier-Daire, Valérie; Cormier-Daire, Valerie; Heath, Karen E

2005-10-01

Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the "Madelung deformity." SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in approximately 60% of LWD cases, whereas, in the remaining approximately 40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least approximately 30-530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.

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

Seasonal and downstream alterations of dissolved organic matter and dissolved inorganic ions in a human-impacted mountainous tributary of the Yellow River, China.

PubMed

Zhang, Shurong; Bai, Yijuan; Wen, Xin; Ding, Aizhong; Zhi, Jianhui

2018-04-22

Human activities impose important disturbances on both organic and inorganic chemistry in fluvial systems. In this study, we investigated the intra-annual and downstream variations of dissolved organic carbon (DOC), dissolved organic matter (DOM) excitation-emission matrix fluorescence (EEM) with parallel factor analysis (PARAFAC), major ions, and dissolved inorganic nitrogen (DIN) species in a mountainous tributary of the Yellow River, China. Both DOM quantity and quality, as represented by DOC and DOM fluorescence respectively, changed spatially and seasonally in the studied region. Fluorescence intensity of tryptophan-like components (C3) were found much higher at the populated downstream regions than in the undisturbed forested upstream regions. Seasonally, stronger fluorescence intensity of protein-like components (C3 and C4) was observed in the low-flow period (December) and in the medium-flow period (March) than in the high-flow period (May), particularly for the downstream reaches, reflecting the dominant impacts of wastewater pollution in the downstream regions. In contrast to the protein-like fluorescence, humic-like fluorescence components C1 and C2 exhibited distinctly higher intensity in the high-flow period with smaller spatial variation indicating strong flushing effect of increasing water discharge on terrestrial-sourced humic-like materials in the high-flow period. Pollution-affected dissolved inorganic ions, particularly Na + , Cl - , and NH 4 + -N, showed similar spatial and seasonal variations with protein-like fluorescence of DOM. The significant positive correlations between protein-like fluorescence of DOM and pollution-affected ions, particularly Na + , Cl - , and NH 4 + -N, suggested that there were similar pollution sources and transportation pathways of both inorganic and organic pollutants in the region. The combination of DOM fluorescence properties and inorganic ions could provide an important reference for the pollution source

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.

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.

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

A large-area, spatially continuous assessment of land cover map error and its impact on downstream analyses.

PubMed

Estes, Lyndon; Chen, Peng; Debats, Stephanie; Evans, Tom; Ferreira, Stefanus; Kuemmerle, Tobias; Ragazzo, Gabrielle; Sheffield, Justin; Wolf, Adam; Wood, Eric; Caylor, Kelly

2018-01-01

Land cover maps increasingly underlie research into socioeconomic and environmental patterns and processes, including global change. It is known that map errors impact our understanding of these phenomena, but quantifying these impacts is difficult because many areas lack adequate reference data. We used a highly accurate, high-resolution map of South African cropland to assess (1) the magnitude of error in several current generation land cover maps, and (2) how these errors propagate in downstream studies. We first quantified pixel-wise errors in the cropland classes of four widely used land cover maps at resolutions ranging from 1 to 100 km, and then calculated errors in several representative "downstream" (map-based) analyses, including assessments of vegetative carbon stocks, evapotranspiration, crop production, and household food security. We also evaluated maps' spatial accuracy based on how precisely they could be used to locate specific landscape features. We found that cropland maps can have substantial biases and poor accuracy at all resolutions (e.g., at 1 km resolution, up to ∼45% underestimates of cropland (bias) and nearly 50% mean absolute error (MAE, describing accuracy); at 100 km, up to 15% underestimates and nearly 20% MAE). National-scale maps derived from higher-resolution imagery were most accurate, followed by multi-map fusion products. Constraining mapped values to match survey statistics may be effective at minimizing bias (provided the statistics are accurate). Errors in downstream analyses could be substantially amplified or muted, depending on the values ascribed to cropland-adjacent covers (e.g., with forest as adjacent cover, carbon map error was 200%-500% greater than in input cropland maps, but ∼40% less for sparse cover types). The average locational error was 6 km (600%). These findings provide deeper insight into the causes and potential consequences of land cover map error, and suggest several recommendations for land

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.

A theoretical study of mixing downstream of transverse injection into a supersonic boundary layer

NASA Technical Reports Server (NTRS)

Baker, A. J.; Zelazny, S. W.

1972-01-01

A theoretical and analytical study was made of mixing downstream of transverse hydrogen injection, from single and multiple orifices, into a Mach 4 air boundary layer over a flat plate. Numerical solutions to the governing three-dimensional, elliptic boundary layer equations were obtained using a general purpose computer program. Founded upon a finite element solution algorithm. A prototype three-dimensional turbulent transport model was developed using mixing length theory in the wall region and the mass defect concept in the outer region. Excellent agreement between the computed flow field and experimental data for a jet/freestream dynamic pressure ratio of unity was obtained in the centerplane region of the single-jet configuration. Poorer agreement off centerplane suggests an inadequacy of the extrapolated two-dimensional turbulence model. Considerable improvement in off-centerplane computational agreement occured for a multi-jet configuration, using the same turbulent transport model.

Small Molecule Targeting of a MicroRNA Associated with Hepatocellular Carcinoma.

PubMed

Childs-Disney, Jessica L; Disney, Matthew D

2016-02-19

Development of precision therapeutics is of immense interest, particularly as applied to the treatment of cancer. By analyzing the preferred cellular RNA targets of small molecules, we discovered that 5"-azido neomycin B binds the Drosha processing site in the microRNA (miR)-525 precursor. MiR-525 confers invasive properties to hepatocellular carcinoma (HCC) cells. Although HCC is one of the most common cancers, treatment options are limited, making the disease often fatal. Herein, we find that addition of 5"-azido neomycin B and its FDA-approved precursor, neomycin B, to an HCC cell line selectively inhibits production of the mature miRNA, boosts a downstream protein, and inhibits invasion. Interestingly, neomycin B is a second-line agent for hepatic encephalopathy (HE) and bacterial infections due to cirrhosis. Our results provocatively suggest that neomycin B, or second-generation derivatives, may be dual functioning molecules to treat both HE and HCC. Collectively, these studies show that rational design approaches can be tailored to disease-associated RNAs to afford potential lead therapeutics.

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

naked cuticle targets dishevelled to antagonize Wnt signal transduction

PubMed Central

Rousset, Raphaël; Mack, Judith A.; Wharton, Keith A.; Axelrod, Jeffrey D.; Cadigan, Ken M.; Fish, Matthew P.; Nusse, Roel; Scott, Matthew P.

2001-01-01

In Drosophila embryos the protein Naked cuticle (Nkd) limits the effects of the Wnt signal Wingless (Wg) during early segmentation. nkd loss of function results in segment polarity defects and embryonic death, but how nkd affects Wnt signaling is unknown. Using ectopic expression, we find that Nkd affects, in a cell-autonomous manner, a transduction step between the Wnt signaling components Dishevelled (Dsh) and Zeste-white 3 kinase (Zw3). Zw3 is essential for repressing Wg target-gene transcription in the absence of a Wg signal, and the role of Wg is to relieve this inhibition. Our double-mutant analysis shows that, in contrast to Zw3, Nkd acts when the Wg pathway is active to restrain signal transduction. Yeast two hybrid and in vitro experiments indicate that Nkd directly binds to the basic-PDZ region of Dsh. Specially timed Nkd overexpression is capable of abolishing Dsh function in a distinct signaling pathway that controls planar-cell polarity. Our results suggest that Nkd acts directly through Dsh to limit Wg activity and thus determines how efficiently Wnt signals stabilize Armadillo (Arm)/β-catenin and activate downstream genes. PMID:11274052

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.

Fisetin inhibits TNF-α/NF-κB-induced IL-8 expression by targeting PKCδ in human airway epithelial cells.

PubMed

Lee, Seoghyun; Ro, Hyunju; In, Hyun Ju; Choi, Ji-Hee; Kim, Mun-Ock; Lee, Jinhyuk; Hong, Sung-Tae; Lee, Su Ui

2018-08-01

Fisetin (3,7,3',4'-tetrahydroxyflavone), a natural flavonoid, is a therapeutic agent for respiratory inflammatory diseases such as chronic obstructive pulmonary disease (COPD). However, detailed molecular mechanisms regarding the target protein of fisetin remain unknown. Fisetin significantly reduces tumour necrosis factor alpha (TNF-α)-induced interleukin (IL)-8 levels by inhibiting both nuclear factor kappa B (NF-κB) transcriptional activity and the phosphorylation of its upstream effectors. We show that fisetin prevents interactions between protein kinase C (PKC)δ and TNF receptor-associated factor 2 (TRAF2), thereby inhibiting the inhibitor of kappa B kinase (IKK)/NF-κB downstream signalling cascade. Furthermore, we found that fisetin directly binds to PKCδ in vitro. Our findings provide evidence that fisetin inhibits the TNF-α-activated IKK/NF-κB cascade by targeting PKCδ, thereby mediating inflammatory diseases such as COPD. These data suggest that fisetin is a good therapeutic drug for the treatment of inflammatory lung diseases, such as COPD, by inhibiting the TNF-α/NF-κB signalling pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

MicroRNA-590-5p Inhibits Intestinal Inflammation by Targeting YAP.

PubMed

Yu, Minhao; Luo, Yang; Cong, Zhijie; Mu, Yifei; Qiu, Yier; Zhong, Ming

2018-04-18

Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, survival, apoptosis, and stem cell self-renewal. In addition, Hippo signaling is profoundly implicated in intestinal regeneration and cancer. However, its roles in the pathogenesis of Crohn's disease (CD) remain largely unexplored. Quantitative real-time PCR was performed to identify the deregulated molecules in Hippo signaling. Expression of the highly upregulated Yes Associated Protein 1 (YAP) was subsequently examined by qRT-PCR, western blotting and immunohistochemistry in the intestinal tissues of CD patients and the colons of 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis mice. The miRNAs predicted to target YAP were explored by transfection of miR-590-5p mimics or inhibitors and analyzed by luciferase reporter assay. The role of the miR-590-5p/YAP axis in CD and colorectal cancer were studied in experimental colitis mice and colorectal cancer cell lines. YAP mRNA was significantly upregulated in intestinal epithelial cells in CD patients and TNBS-induced colitis mice. MiR-590-5p suppressed YAP expression by directly targeting the YAP 3'-untranslated region in Caco-2 cells and SW620 cells. Upregulation of miR-590-5p in colon reduced YAP level and its downstream targets in IECs. Treatment of miR-590-5p or YAP inhibitor Verteporfin alleviated experimental colitis. Targeting the miR-590-5p/YAP axis inhibited cell proliferation and invasiveness of CRC cells in vitro. Our results suggest that miR-590-5p inhibits intestinal inflammation in mouse colon and tumorigenesis of colorectal cancer cells by inhibiting YAP. The miR-590-5p/YAP axis may be an important novel mechanism in the pathogenesis of CD and colorectal cancer.

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.

Inoculating against eyewitness suggestibility via interpolated verbatim vs. gist testing.

PubMed

Pansky, Ainat; Tenenboim, Einat

2011-01-01

In real-life situations, eyewitnesses often have control over the level of generality in which they choose to report event information. In the present study, we adopted an early-intervention approach to investigate to what extent eyewitness memory may be inoculated against suggestibility, following two different levels of interpolated reporting: verbatim and gist. After viewing a target event, participants responded to interpolated questions that required reporting of target details at either the verbatim or the gist level. After 48 hr, both groups of participants were misled about half of the target details and were finally tested for verbatim memory of all the details. The findings were consistent with our predictions: Whereas verbatim testing was successful in completely inoculating against suggestibility, gist testing did not reduce it whatsoever. These findings are particularly interesting in light of the comparable testing effects found for these two modes of interpolated testing.

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...

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

MiR-592 functions as a tumor suppressor in glioma by targeting IGFBP2.

PubMed

Peng, Tao; Zhou, Lixiang; Qi, Hui; Wang, Guangming; Luan, Yongxin; Zuo, Ling

2017-07-01

A growing body of evidence suggests that microRNA-592 is involved in tumor initiation and development in several types of human cancers. However, the biological functions and molecular mechanism of microRNA-592 in glioma remain unclear. In this study, we explored the potential role of microRNA-592 in glioma as well as the possible molecular mechanisms. Our results proved that microRNA-592 expression was significantly downregulated in glioma tissues and cell lines (p < 0.01). Functional assays revealed that overexpression of microRNA-592 dramatically reduced the cell proliferation, migration, and invasion and induced cell arrest at G1/G0 phase in vitro. Mechanistic investigations defined insulin-like growth factor binding protein 2 as a direct and functional downstream target of microRNA-592, which was involved in the microRNA-592-mediated tumor-suppressive effects in glioma cells. Moreover, the in vivo study showed that microRNA-592 overexpression produced the smaller tumor volume and weight in nude mice. In summary, these results elucidated the function of microRNA-592 in glioma progression and suggested a promising application of it in glioma treatment.

Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues

PubMed Central

2013-01-01

Background Fasting induces specific molecular and metabolic adaptions in most organisms. In biomedical research fasting is used in metabolic studies to synchronize nutritional states of study subjects. Because there is a lack of standardization for this procedure, we need a deeper understanding of the dynamics and the molecular mechanisms in fasting. Results We investigated the dynamic changes of liver gene expression and serum parameters of mice at several time points during a 48 hour fasting experiment and then focused on the global gene expression changes in epididymal white adipose tissue (WAT) as well as on pathways common to WAT, liver, and skeletal muscle. This approach produced several intriguing insights: (i) rather than a sequential activation of biochemical pathways in fasted liver, as current knowledge dictates, our data indicates a concerted parallel response; (ii) this first characterization of the transcriptome signature of WAT of fasted mice reveals a remarkable activation of components of the transcription apparatus; (iii) most importantly, our bioinformatic analyses indicate p53 as central node in the regulation of fasting in major metabolic tissues; and (iv) forced expression of Ddit4, a fasting-regulated p53 target gene, is sufficient to augment lipolysis in cultured adipocytes. Conclusions In summary, this combination of focused and global profiling approaches provides a comprehensive molecular characterization of the processes operating during fasting in mice and suggests a role for p53, and its downstream target Ddit4, as novel components in the transcriptional response to food deprivation. PMID:24191950

Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.

PubMed

Seiki, Stephanie; Frishman, William H

2009-01-01

Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.

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.

Role of Vascular and Lymphatic Endothelial Cells in Hantavirus Pulmonary Syndrome Suggests Targeted Therapeutic Approaches

PubMed Central

Gorbunova, Elena E.; Dalrymple, Nadine A.; Gavrilovskaya, Irina N.

2013-01-01

Abstract Background Hantaviruses in the Americas cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect microvascular and lymphatic endothelial cells and cause dramatic changes in barrier functions without disrupting the endothelium. Hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions. The endothelium of arteries, veins, and lymphatic vessels are unique and central to the function of vast pulmonary capillary beds that regulate pulmonary fluid accumulation. Results We have found that HPS-causing hantaviruses alter vascular barrier functions of microvascular and lymphatic endothelial cells by altering receptor and signaling pathway responses that serve to permit fluid tissue influx and clear tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to cause acute pulmonary edema, as well as potential therapeutic targets for reducing the severity of HPS disease. Conclusions Here we discuss interactions of HPS-causing hantaviruses with the endothelium, roles for unique lymphatic endothelial responses in HPS, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease. PMID:24024573

Role of vascular and lymphatic endothelial cells in hantavirus pulmonary syndrome suggests targeted therapeutic approaches.

PubMed

Mackow, Erich R; Gorbunova, Elena E; Dalrymple, Nadine A; Gavrilovskaya, Irina N

2013-09-01

Hantaviruses in the Americas cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect microvascular and lymphatic endothelial cells and cause dramatic changes in barrier functions without disrupting the endothelium. Hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions. The endothelium of arteries, veins, and lymphatic vessels are unique and central to the function of vast pulmonary capillary beds that regulate pulmonary fluid accumulation. We have found that HPS-causing hantaviruses alter vascular barrier functions of microvascular and lymphatic endothelial cells by altering receptor and signaling pathway responses that serve to permit fluid tissue influx and clear tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to cause acute pulmonary edema, as well as potential therapeutic targets for reducing the severity of HPS disease. Here we discuss interactions of HPS-causing hantaviruses with the endothelium, roles for unique lymphatic endothelial responses in HPS, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease.

Does targeted, disease-specific public research funding influence pharmaceutical innovation?

PubMed

Blume-Kohout, Margaret E

2012-01-01

Public funding for biomedical research is often justified as a means to encourage development of more (and better) treatments for disease. However, few studies have investigated the relationship between these expenditures and downstream pharmaceutical innovation. In particular, although recent analyses have shown a clear contribution of federally funded research to drug development, there exists little evidence to suggest that increasing targeted public research funding for any specific disease will result in increased development of drugs to treat that disease. This paper evaluates the impact of changes in the allocation of U. S. National Institutes of Health (NIH) extramural research grant funding across diseases on the number of drugs entering clinical testing to treat those diseases, using new longitudinal data on NIH extramural research grants awarded by disease for years 1975 through 2006. Results from a variety of distributed lag models indicate that a sustained 10 percent increase in targeted, disease-specific NIH funding yields approximately a 4. 5 percent increase in the number of related drugs entering clinical testing (phase I trials) after a lag of up to 12 years, reflecting the continuing influence of NIH funding on discovery and testing of new molecular entities. In contrast, we do not see evidence that increases in NIH extramural grant funding for research focused on specific diseases will increase the number of related treatments investigated in the more expensive, late-stage (phase III) trials.

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.

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.

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.

Characterization of sediment transport upstream and downstream from Lake Emory on the Little Tennessee River near Franklin, North Carolina, 2014–15

USGS Publications Warehouse

Huffman, Brad A.; Hazell, William F.; Oblinger, Carolyn J.

2017-09-06

suspended-sediment load at the downstream site was about 28,300 short tons greater than the upstream site over the study period.As expected, high-flow events (the top 5 percent of daily mean flows) accounted for the majority of the sediment load; 80 percent at the upstream site and 90 percent at the downstream site. A similar relation between turbidity (the top 5 percent of daily mean turbidity) and high loads was also noted. In general, when instantaneous streamflows at the upstream site exceeded 5,000 cubic feet per second, increased daily loads were computed at the downstream site. During low to moderate flows, estimated suspended-sediment loads were lower at the downstream site when compared to the upstream site, which suggests that sediment deposition may be occurring in the intervening reach during those conditions. During the high-flow events, the estimated suspended-sediment loads were higher at the downstream site; however, it is impossible to say with certainty whether the increase in loading was due to scouring of lake sediment, contributions from the additional source area, model error, or a combination of one or more of these factors. The computed loads for a one-week period (December 24–31, 2015), during which the two largest high-flow events of the study period occurred, were approximately 52 percent of the 2015 annual sediment load (36 percent of 2-year load) at the upstream site and approximately 72 percent of the 2015 annual sediment load (57 percent of 2-year load) at the downstream site. Six bedload samples were collected during three events; two high-flow events and one base-flow event. The contribution of bedload to the total sediment load was determined to be insignificant for sampled flows. In general, streamflows for long-term streamgages in the study area were below normal for the majority of the study period; however, flows during the last 3 months of the study period were above normal, including the extreme events during the last week of the

Sodic alkaline stress mitigation by exogenous melatonin in tomato needs nitric oxide as a downstream signal.

PubMed

Liu, Na; Gong, Biao; Jin, Zhiyong; Wang, Xiufeng; Wei, Min; Yang, Fengjuan; Li, Yan; Shi, Qinghua

2015-08-15

The present study was designed to determine the interactive effect of exogenous melatonin and nitric oxide (NO) on sodic alkaline stress mitigation in tomato seedlings. It was observed that exogenous melatonin treatment elevated NO levels in alkaline-stressed tomato roots. However, exogenous NO had little effects on melatonin levels. Importantly, melatonin-induced NO generation was accompanied by increased tolerance to alkaline stress. Chemical scavenging of NO reduced melatonin-induced alkaline stress tolerance and defense genes' expression. However, inhibition of melatonin biosynthesis had a little effect on NO-induced alkaline stress tolerance. These results strongly suggest that NO, acting as a downstream signal, is involved in the melatonin-induced tomato tolerance to alkaline stress. This process creates a new signaling pathway for improving stress tolerance in plant. Copyright © 2015 Elsevier GmbH. All rights reserved.

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

Spatial Optimization of Cropping Pattern in an Agricultural Watershed for Food and Biofuel Production with Minimum Downstream Pollution

NASA Astrophysics Data System (ADS)

Pv, F.; Sudheer, K.; Chaubey, I.; RAJ, C.; Her, Y.

2013-05-01

is proposed to link SWAT model with an optimization algorithm, whose objective is to identify the optimal cropping pattern that results in maximum biomass production for biofuel generation as well as a minimum guaranteed amount of grain production. The optimal allocation ensures that the downstream water quality in the river is within a desirable limit. The study employed probabilistic information in order to address the uncertainty in model simulations. The residual variance of the model is used to transform the deterministic simulations in to probabilistic information. The proposed framework is illustrated using data pertaining to an agricultural watershed in the USA. The preliminary results of the study are encouraging and suggest that an appropriate combination of Corn, Soyabean, Miscanthus, Switch Grass and Pasture land can be arrived at through the developed framework. The placement of Miscanthus and Switch Grass in the watershed help improve the downstream water quality, while Corn and Soyabean makes it deteriorated. The spatial allocation of these crops therefore certainly plays a major role in the downstream water quality.

A Novel Class of Pseudoautosomal Region 1 Deletions Downstream of SHOX Is Associated with Léri-Weill Dyschondrosteosis

PubMed Central

Benito-Sanz, Sara; Thomas, N. Simon; Huber, Céline; del Blanco, Darya Gorbenko; Aza-Carmona, Miriam; Crolla, John A.; Maloney, Vivienne; Argente, Jesús; Campos-Barros, Ángel; Cormier-Daire, Valérie; Heath, Karen E.

2005-01-01

Léri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the “Madelung deformity.” SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in ∼60% of LWD cases, whereas, in the remaining ∼40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least ∼30–530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS. PMID:16175500

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.

Occurrence of polybrominated diphenyl ethers in fish and shellfish downstream from electronic-waste recycling plants.

PubMed

Jiang, Jinhua; Shi, Shidi; Chen, Tao

2010-01-01

We measured 39 polybrominated diphenyl ethers (PBDEs) in the muscle tissue of three species of fish (Sciaenops ocellatus, Sparus macrocephalus, and Lateolabraxjaponicus) and four species of shellfish (Tegillarca granosa, Cyclina sinensis, Sinonovacula constricta, and Ostrea cucullata) that were collected downstream of electronic-waste recycling plants in Taizhou, China. A total of 24 PBDE congeners (PBDE24) in the samples were detected. The sigma PBDE24 (total PBDE) ranged from 545.4 to 1688.7 ng/kg ww (wet weight). The mean sigma PBDE24 concentration was 1382.6 ng/kg ww in fish and 858.1 ng/kg ww in shellfish. The lower brominated congeners were detected at relatively high concentrations in all species. The penta-products, produced from e-waste, were found at relatively low levels. A principal component analysis suggested a significant correlation among di-, tri-, tetra-, and hepta-BDEs for the three species of fish. Similarly, we found a significant correlation between mono- and tri-BDEs in the shellfish. Our results suggested that the processes of PBDE metabolism and elimination were similar in both fish and shellfish. In addition, the primary source of PBDEs appeared to be from the debromination of high brominated PBDEs.

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

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

Spinal serum-inducible and glucocorticoid-inducible kinase 1 mediates neuropathic pain via kalirin and downstream PSD-95-dependent NR2B phosphorylation in rats.

PubMed

Peng, Hsien-Yu; Chen, Gin-Den; Lai, Cheng-Yuan; Hsieh, Ming-Chun; Lin, Tzer-Bin

2013-03-20

The coupling of the spinal postsynaptic density-95 (PSD-95) with the glutamatergic N-methyl-d-aspartate receptor NR2B subunit and the subsequent NR2B phosphorylation contribute to pain-related plasticity. Increasing evidence reveals that kalirin, a Rho-guanine nucleotide exchange factor, modulates PSD-95-NR2B-dependent neuroplasticity. Our laboratory recently demonstrated that serum-inducible and glucocorticoid-inducible kinase 1 (SGK1) participates in inflammation-associated pain hypersensitivity by modulating spinal glutamatergic neurotransmission. Because kalirin is one of the proteins in PSD that is highly phosphorylated by various kinases, we tested whether kalirin could be a downstream target of spinal SGK1 that participates in neuropathic pain development via regulation of the PSD-95-NR2B coupling-dependent phosphorylation of NR2B. We observed that spinal nerve ligation (SNL, L5) in male Sprague Dawley rats resulted in behavioral allodynia, which was associated with phosphorylated SGK1 (pSGK1), kalirin, and phosphorylated NR2B (pNR2B) expression and an increase in pSGK1-kalirin-PSD-95-pNR2B coprecipitation in the ipsilateral dorsal horn (L4-L5). SNL-enhanced kalirin immunofluorescence was coincident with pSGK1, PSD-95, and pNR2B immunoreactivity. Small-interfering RNA (siRNA) that targeted spinal kalirin mRNA expression (10 μg, 10 μl; i.t.) reduced SNL-induced allodynia, kalirin and pNR2B expression, as well as kalirin-PSD-95 and PSD-95-pNR2B coupling and costaining without affecting SGK1 phosphorylation. Daily administration of GSK-650394 (an SGK1 antagonist; 100 nm, 10 μl, i.t.) not only exhibited effects similar to the kalirin mRNA-targeting siRNA but also attenuated pSGK1-kalirin costaining and SGK1-kalirin coupling. We suggest that nerve injury could induce spinal SGK1 phosphorylation that subsequently interacts with and upregulates kalirin to participate in neuropathic pain development via PSD-95-NR2B coupling-dependent NR2B phosphorylation.

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.

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.

Suggestion-Induced Modulation of Semantic Priming during Functional Magnetic Resonance Imaging

PubMed Central

Ulrich, Martin; Kiefer, Markus; Bongartz, Walter; Grön, Georg; Hoenig, Klaus

2015-01-01

Using functional magnetic resonance imaging during a primed visual lexical decision task, we investigated the neural and functional mechanisms underlying modulations of semantic word processing through hypnotic suggestions aimed at altering lexical processing of primes. The priming task was to discriminate between target words and pseudowords presented 200 ms after the prime word which was semantically related or unrelated to the target. In a counterbalanced study design, each participant performed the task once at normal wakefulness and once after the administration of hypnotic suggestions to perceive the prime as a meaningless symbol of a foreign language. Neural correlates of priming were defined as significantly lower activations upon semantically related compared to unrelated trials. We found significant suggestive treatment-induced reductions in neural priming, albeit irrespective of the degree of suggestibility. Neural priming was attenuated upon suggestive treatment compared with normal wakefulness in brain regions supporting automatic (fusiform gyrus) and controlled semantic processing (superior and middle temporal gyri, pre- and postcentral gyri, and supplementary motor area). Hence, suggestions reduced semantic word processing by conjointly dampening both automatic and strategic semantic processes. PMID:25923740

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

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.

Turbulence downstream of subcoronary stentless and stented aortic valves.

PubMed

Funder, Jonas Amstrup; Frost, Markus Winther; Wierup, Per; Klaaborg, Kaj-Erik; Hjortdal, Vibeke; Nygaard, Hans; Hasenkam, J Michael

2011-08-11

Regions of turbulence downstream of bioprosthetic heart valves may cause damage to blood components, vessel wall as well as to aortic valve leaflets. Stentless aortic heart valves are known to posses several hemodynamic benefits such as larger effective orifice areas, lower aortic transvalvular pressure difference and faster left ventricular mass regression compared with their stented counterpart. Whether this is reflected by diminished turbulence formation, remains to be shown. We implanted either stented pericardial valve prostheses (Mitroflow), stentless valve prostheses (Solo or Toronto SPV) in pigs or they preserved their native valves. Following surgery, blood velocity was measured in the cross sectional area downstream of the valves using 10MHz ultrasonic probes connected to a dedicated pulsed Doppler equipment. As a measure of turbulence, Reynolds normal stress (RNS) was calculated at two different blood pressures (baseline and 50% increase). We found no difference in maximum RNS measurements between any of the investigated valve groups. The native valve had significantly lower mean RNS values than the Mitroflow (p=0.004), Toronto SPV (p=0.008) and Solo valve (p=0.02). There were no statistically significant differences between the artificial valve groups (p=0.3). The mean RNS was significantly larger when increasing blood pressure (p=0.0006). We, thus, found no advantages for the stentless aortic valves compared with stented prosthesis in terms of lower maximum or mean RNS values. Native valves have a significantly lower mean RNS value than all investigated bioprostheses. Copyright © 2011 Elsevier Ltd. All rights reserved.

Tidal Influence on Water Quality of Kapuas Kecil River Downstream

NASA Astrophysics Data System (ADS)

Purnaini, Rizki; Sudarmadji; Purwono, Suryo

2018-02-01

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

Identifying antimalarial compounds targeting dihydrofolate reductase-thymidylate synthase (DHFR-TS) by chemogenomic profiling.

PubMed

Aroonsri, Aiyada; Akinola, Olugbenga; Posayapisit, Navaporn; Songsungthong, Warangkhana; Uthaipibull, Chairat; Kamchonwongpaisan, Sumalee; Gbotosho, Grace O; Yuthavong, Yongyuth; Shaw, Philip J

2016-07-01

The mode of action of many antimalarial drugs is unknown. Chemogenomic profiling is a powerful method to address this issue. This experimental approach entails disruption of gene function and phenotypic screening for changes in sensitivity to bioactive compounds. Here, we describe the application of reverse genetics for chemogenomic profiling in Plasmodium. Plasmodium falciparum parasites harbouring a transgenic insertion of the glmS ribozyme downstream of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene were used for chemogenomic profiling of antimalarial compounds to identify those which target DHFR-TS. DHFR-TS expression can be attenuated by exposing parasites to glucosamine. Parasites with attenuated DHFR-TS expression were significantly more sensitive to antifolate drugs known to target DHFR-TS. In contrast, no change in sensitivity to other antimalarial drugs with different modes of action was observed. Chemogenomic profiling was performed using the Medicines for Malaria Venture (Switzerland) Malaria Box compound library, and two compounds were identified as novel DHFR-TS inhibitors. We also tested the glmS ribozyme in Plasmodium berghei, a rodent malaria parasite. The expression of reporter genes with downstream glmS ribozyme could be attenuated in transgenic parasites comparable with that obtained in P. falciparum. The chemogenomic profiling method was applied in a P. berghei line expressing a pyrimethamine-resistant Toxoplasma gondii DHFR-TS reporter gene under glmS ribozyme control. Parasites with attenuated expression of this gene were significantly sensitised to antifolates targeting DHFR-TS, but not other drugs with different modes of action. In conclusion, these data show that the glmS ribozyme reverse genetic tool can be applied for identifying primary targets of antimalarial compounds in human and rodent malaria parasites. Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

Dams and Rivers: A Primer on the Downstream Effects of Dams

USGS Publications Warehouse

Collier, Michael; Webb, Robert H.; Schmidt, John C.

1996-01-01

The U.S. Geological Survey is charged with monitoring the water and mineral resources of the United States. Beginning in 1889, the Survey established a network of water gaging stations across most of the country's rivers; some also measured sediment content of the water. Consequently, we now have valuable long-term data with which to track water supply, sediment transport, and the occurrence of floods. Many variables affect the flow of water from mountain brook to river delta. Some are short-term perturbations like summer thunderstorms. Others occur over a longer period of time, like the El Ninos that might be separated by a decade or more. We think of these variables as natural occurrences, but humans have exerted some of the most important changes -- water withdrawals for agriculture, inter-basin transfers, and especially the construction of an extensive system of dams. Dams have altered the flow of many of the Nation's rivers to meet societal needs. We expect floods to be contained. Irrigation is possible where deserts once existed. And water is released downstream not according to natural cycles but as dictated by a region's hour-by-hour needs for water or electricity. As a result, river channels below dams have changed dramatically. Depending on annual flow, flood peaks, and a river's sediment load, we might see changes such as sand building up in one channel, vegetation crowding into another, and extensive bank erosion in another. This Circular explores the emerging scientific arena of change in rivers below dams. This science tries first to understand and then anticipate changes to river beds and banks, and to riparian habitats and animal communities. To some degree, these downstream changes can be influenced by specific strategies of dam management. Scientists and resource managers have a duty to assemble this information and present it without bias to the rest of society. Society can then more intelligently choose a balance between the benefits and adverse