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Sample records for synergistically increase transcription

  1. Synergistic cooperation of MDM2 and E2F1 contributes to TAp73 transcriptional activity

    International Nuclear Information System (INIS)

    Kasim, Vivi; Huang, Can; Zhang, Jing; Jia, Huizhen; Wang, Yunxia; Yang, Li; Miyagishi, Makoto; Wu, Shourong

    2014-01-01

    Highlights: • MDM2 is a novel positive regulator of TAp73 transcriptional activity. • MDM2 colocalizes together and physically interacts with E2F1. • Synergistic cooperation of MDM2 and E2F1 is crucial for TAp73 transcription. • MDM2 regulates TAp73 transcriptional activity in a p53-independent manner. - Abstract: TAp73, a structural homologue of p53, plays an important role in tumorigenesis. E2F1 had been reported as a transcriptional regulator of TAp73, however, the detailed mechanism remains to be elucidated. Here we reported that MDM2-silencing reduced the activities of the TAp73 promoters and the endogenous TAp73 expression level significantly; while MDM2 overexpression upregulated them. We further revealed that the regulation of TAp73 transcriptional activity occurs as a synergistic effect of MDM2 and E2F1, most probably through their physical interaction in the nuclei. Furthermore, we also suggested that MDM2 might be involved in DNA damage-induced TAp73 transcriptional activity. Finally, we elucidated that MDM2-silencing reduced the proliferation rate of colon carcinoma cells regardless of the p53 status. Our data show a synergistic effect of MDM2 and E2F1 on TAp73 transcriptional activity, suggesting a novel regulation pathway of TAp73

  2. Transcription factors TFIIF and TFIIS promote transcript elongation by RNA polymerase II by synergistic and independent mechanisms.

    Science.gov (United States)

    Schweikhard, Volker; Meng, Cong; Murakami, Kenji; Kaplan, Craig D; Kornberg, Roger D; Block, Steven M

    2014-05-06

    Recent evidence suggests that transcript elongation by RNA polymerase II (RNAPII) is regulated by mechanical cues affecting the entry into, and exit from, transcriptionally inactive states, including pausing and arrest. We present a single-molecule optical-trapping study of the interactions of RNAPII with transcription elongation factors TFIIS and TFIIF, which affect these processes. By monitoring the response of elongation complexes containing RNAPII and combinations of TFIIF and TFIIS to controlled mechanical loads, we find that both transcription factors are independently capable of restoring arrested RNAPII to productive elongation. TFIIS, in addition to its established role in promoting transcript cleavage, is found to relieve arrest by a second, cleavage-independent mechanism. TFIIF synergistically enhances some, but not all, of the activities of TFIIS. These studies also uncovered unexpected insights into the mechanisms underlying transient pauses. The direct visualization of pauses at near-base-pair resolution, together with the load dependence of the pause-entry phase, suggests that two distinct mechanisms may be at play: backtracking under forces that hinder transcription and a backtrack-independent activity under assisting loads. The measured pause lifetime distributions are inconsistent with prevailing views of backtracking as a purely diffusive process, suggesting instead that the extent of backtracking may be modulated by mechanisms intrinsic to RNAPII. Pauses triggered by inosine triphosphate misincorporation led to backtracking, even under assisting loads, and their lifetimes were reduced by TFIIS, particularly when aided by TFIIF. Overall, these experiments provide additional insights into how obstacles to transcription may be overcome by the concerted actions of multiple accessory factors.

  3. Ocean warming and acidification synergistically increase coral mortality

    Science.gov (United States)

    Prada, F.; Caroselli, E.; Mengoli, S.; Brizi, L.; Fantazzini, P.; Capaccioni, B.; Pasquini, L.; Fabricius, K. E.; Dubinsky, Z.; Falini, G.; Goffredo, S.

    2017-01-01

    Organisms that accumulate calcium carbonate structures are particularly vulnerable to ocean warming (OW) and ocean acidification (OA), potentially reducing the socioeconomic benefits of ecosystems reliant on these taxa. Since rising atmospheric CO2 is responsible for global warming and increasing ocean acidity, to correctly predict how OW and OA will affect marine organisms, their possible interactive effects must be assessed. Here we investigate, in the field, the combined temperature (range: 16-26 °C) and acidification (range: pHTS 8.1-7.4) effects on mortality and growth of Mediterranean coral species transplanted, in different seasonal periods, along a natural pH gradient generated by a CO2 vent. We show a synergistic adverse effect on mortality rates (up to 60%), for solitary and colonial, symbiotic and asymbiotic corals, suggesting that high seawater temperatures may have increased their metabolic rates which, in conjunction with decreasing pH, could have led to rapid deterioration of cellular processes and performance. The net calcification rate of the symbiotic species was not affected by decreasing pH, regardless of temperature, while in the two asymbiotic species it was negatively affected by increasing acidification and temperature, suggesting that symbiotic corals may be more tolerant to increasing warming and acidifying conditions compared to asymbiotic ones.

  4. Synergistic interaction between prolonged increased glycemic exposure and mildly increased urinary albumin excretion on diabetic retinopathy.

    Science.gov (United States)

    Moon, Shinje; Yoo, Hyung-Joon; Ahn, You-Hern; Kim, Gheun-Ho; Yu, Jae Myung; Park, Joon-Sung

    2018-01-01

    The association of mild increase in urinary albumin excretion with diabetic retinopathy (DR) in clinical studies is controversial. The aim of this study is to clarify the interaction between increased glycemic exposure and mild increase in urinary albumin excretion on risk of DR.Data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2012. Overall, data from 953 participants without microalbuminuria (477 men and 476 women) were assessed. Logistic regression analysis was constructed to evaluate the association between DR and related clinical parameters, including urinary albumin-creatinine ratio (UACR, mg/g creatinine). The biological interaction of glycemic status and UACR on DR was evaluated by 3 indices: RERI, the relative excess risk due to the interaction; AP, the attributable proportion due to the interaction; and S, the additive interaction index of synergy.We found that UACR, glycated hemoglobin (HbA1c), and diabetic duration were deeply associated with increased risk of DR (UACR, odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.02-1.07; HbA1c, OR = 1.16, 95% CI = 1.04-1.30; diabetic duration, OR = 1.06, 95% CI = 1.04-1.07). Furthermore, our interaction analysis demonstrated that synergistic interaction between HbA1c and UACR on development of DR was prominent in participants with diabetic duration of ≥10 years (adjusted RERI = 0.92, 95% CI = 0.10-1.74; adjusted AP = 0.29, 95% CI = -0.82-1.41; adjusted S = 1.76, 95% CI = 1.27-2.25), but not subjects with shorter diabetic duration.These findings imply that there is the interaction between prolonged hyperglycemic exposure and increased urinary albumin excretion may exert additive synergistic effect on vascular endothelial dysfunction in the eye, even before the appearance of overt diabetic nephropathy. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

  5. A synergistic interaction between transcription factors nuclear factor-κB and signal transducers and activators of transcription 3 promotes gastric cancer cell migration and invasion

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    Yoon Jiyeon

    2013-02-01

    Full Text Available Abstract Background The transcription factor nuclear factor-κB (NF-κB has been implicated in gastric cancer metastasis, but the underlying molecular mechanisms remain unclear. We investigated the role of the interaction between NF-κB and signal transducers and activators of transcription 3 (STAT3 in controlling metastatic potential of gastric cancer cells. Methods Immunohistochemistry for NF-κB p65 (RelA, phospho-Tyr705-STAT3 (pSTAT3, or matrix metalloproteinase 9 (MMP9 was performed on tissue array slides containing 255 gastric carcinoma specimens. NF-κB inhibition in SNU-638 and MKN1 gastric cancer cell lines were performed by transduction with a retroviral vector containing NF-κB repressor mutant of IκBα, and STAT3 was silenced by RNA interference. We also did luciferase reporter assay, double immunofluorescence staining and immunoblotting. Cell migration and invasion were determined by wound-healing assay and invasion assay, respectively. Results NF-κB and STAT3 were constitutively activated and were positively correlated (P = 0.038 in gastric cancer tissue specimens. In cell culture experiments, NF-κB inhibition reduced STAT3 expression and activation, whereas STAT3 silencing did not affect NF-κB activation. Moreover, both NF-κB inhibition and STAT3 silencing decreased gastric cancer cell migration and invasion in a synergistic manner. In addition, both NF-κB activation and STAT3 activation were positively correlated with MMP9 in gastric cancer tissues (P = 0.001 and P = 0.022, respectively, decreased E-cadherin expression and increased Snail and MMP9 expressions in cultured cells. Conclusion NF-κB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Thus, dual use of NF-κB and STAT3 inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.

  6. Proto-oncogene FBI-1 (Pokemon) and SREBP-1 Synergistically Activate Transcription of Fatty-acid Synthase Gene (FASN)*S⃞

    Science.gov (United States)

    Choi, Won-Il; Jeon, Bu-Nam; Park, Hyejin; Yoo, Jung-Yoon; Kim, Yeon-Sook; Koh, Dong-In; Kim, Myung-Hwa; Kim, Yu-Ri; Lee, Choong-Eun; Kim, Kyung-Sup; Osborne, Timothy F.; Hur, Man-Wook

    2008-01-01

    FBI-1 (Pokemon/ZBTB7A) is a proto-oncogenic transcription factor of the BTB/POZ (bric-à-brac, tramtrack, and broad complex and pox virus zinc finger) domain family. Recent evidence suggested that FBI-1 might be involved in adipogenic gene expression. Coincidentally, expression of FBI-1 and fatty-acid synthase (FASN) genes are often increased in cancer and immortalized cells. Both FBI-1 and FASN are important in cancer cell proliferation. SREBP-1 is a major regulator of many adipogenic genes, and FBI-1 and SREBP-1 (sterol-responsive element (SRE)-binding protein 1) interact with each other directly via their DNA binding domains. FBI-1 enhanced the transcriptional activation of SREBP-1 on responsive promoters, pGL2-6x(SRE)-Luc and FASN gene. FBI-1 and SREBP-1 synergistically activate transcription of the FASN gene by acting on the proximal GC-box and SRE/E-box. FBI-1, Sp1, and SREBP-1 can bind to all three SRE, GC-box, and SRE/E-box. Binding competition among the three transcription factors on the GC-box and SRE/E-box appears important in the transcription regulation. FBI-1 is apparently changing the binding pattern of Sp1 and SREBP-1 on the two elements in the presence of induced SREBP-1 and drives more Sp1 binding to the proximal promoter with less of an effect on SREBP-1 binding. The changes induced by FBI-1 appear critical in the synergistic transcription activation. The molecular mechanism revealed provides insight into how proto-oncogene FBI-1 may attack the cellular regulatory mechanism of FASN gene expression to provide more phospholipid membrane components needed for rapid cancer cell proliferation. PMID:18682402

  7. Synergistic effect of CART (cocaine- and amphetamine-regulated transcript peptide and cholecystokinin on food intake regulation in lean mice

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    Kiss Alexander

    2008-10-01

    Full Text Available Abstract Background CART (cocaine- and amphetamine-regulated transcript peptide and cholecystokinin (CCK are neuromodulators involved in feeding behavior. This study is based on previously found synergistic effect of leptin and CCK on food intake and our hypothesis on a co-operation of the CART peptide and CCK in food intake regulation and Fos activation in their common targets, the nucleus tractus solitarii of the brainstem (NTS, the paraventricular nucleus (PVN, and the dorsomedial nucleus (DMH of the hypothalamus. Results In fasted C57BL/6 mice, the anorexigenic effect of CART(61-102 in the doses of 0.1 or 0.5 μg/mouse was significantly enhanced by low doses of CCK-8 of 0.4 or 4 μg/kg, while 1 mg/kg dose of CCK-A receptor antagonist devazepide blocked the effect of CART(61-102 on food intake. After simultaneous administration of 0.1 μg/mouse CART(61-102 and of 4 μg/kg of CCK-8, the number of Fos-positive neurons in NTS, PVN, and DMH was significantly higher than after administration of each particular peptide. Besides, CART(61-102 and CCK-8 showed an additive effect on inhibition of the locomotor activity of mice in an open field test. Conclusion The synergistic and long-lasting effect of the CART peptide and CCK on food intake and their additive effect on Fos immunoreactivity in their common targets suggest a co-operative action of CART peptide and CCK which could be related to synergistic effect of leptin on CCK satiety.

  8. Synergistic interactions of ecosystem services: florivorous pest control boosts crop yield increase through insect pollination

    Science.gov (United States)

    Albrecht, Matthias

    2016-01-01

    Insect pollination and pest control are pivotal functions sustaining global food production. However, they have mostly been studied in isolation and how they interactively shape crop yield remains largely unexplored. Using controlled field experiments, we found strong synergistic effects of insect pollination and simulated pest control on yield quantity and quality. Their joint effect increased yield by 23%, with synergistic effects contributing 10%, while their single contributions were 7% and 6%, respectively. The potential economic benefit for a farmer from the synergistic effects (12%) was 1.8 times greater than their individual contributions (7% each). We show that the principal underlying mechanism was a pronounced pest-induced reduction in flower lifetime, resulting in a strong reduction in the number of pollinator visits a flower receives during its lifetime. Our findings highlight the importance of non-additive interactions among ecosystem services (ES) when valuating, mapping or predicting them and reveal fundamental implications for ecosystem management and policy aimed at maximizing ES for sustainable agriculture. PMID:26865304

  9. Decreased miR-128 and increased miR-21 synergistically cause podocyte injury in sepsis.

    Science.gov (United States)

    Wang, Shanshan; Wang, Jun; Zhang, Zengdi; Miao, Hongjun

    2017-08-01

    Glomerular podocytes are injured in sepsis. We studied, in a sepsis patient, whether microRNAs (miRNAs) play a role in the podocyte injury. Podocytes were cultured and treated with lipopolysaccharide (LPS). Filtration barrier function of podocyte was analyzed with albumin influx assay. Nephrin level was analyzed with reverse transcription polymerase chain reaction (RT-PCR) and western blot. MiRNAs were detected using miRNAs PCR Array and in situ hybridization. MiRNA target sites were evaluated with luciferase reporter assays. LPS impaired the filtration barrier function of podocytes. MiR-128 level was decreased and miR-21 level was increased in podocytes in vitro and in the sepsis patient. The decrease in miR-128 was sufficient to induce the loss of nephrin and the impairment of filtration barrier function, while the increase of miR-21 exacerbated the process. Snail and phosphatase and tensin homolog (PTEN) were identified as the targets of miR-128 and miR-21. Decreased miR-128 induced Snail expression, and the increased miR-21 stabilized Snail by regulating the PTEN/Akt/GSK3β pathway. Supplementation of miR-128 and inhibition of miR-21 suppressed Snail expression and prevented the podocyte injury induced by LPS. Our study suggests that decreased miR-128 and increased miR-21 synergistically cause podocyte injury and are the potential therapeutic targets in sepsis.

  10. Transcriptome analysis of wild-type and afsS deletion mutant strains identifies synergistic transcriptional regulator of afsS for a high antibiotic-producing strain of Streptomyces coelicolor A3(2).

    Science.gov (United States)

    Kim, Min Woo; Lee, Bo-Rahm; You, SungYong; Kim, Eun-Jung; Kim, Ji-Nu; Song, Eunjung; Yang, Yung-Hun; Hwang, Daehee; Kim, Byung-Gee

    2018-04-01

    Most secondary metabolism in Actinobacteria is controlled by multi-layered, gene-regulatory networks. These regulatory mechanisms are not easily identified due to their complexity. As a result, when a strong transcriptional regulator (TR) governs activation of biosynthetic pathways of target antibiotics such as actinorhodin (ACT), additional enhancement of the biosynthesis is difficult in combination with other TRs. To find out any "synergistic transcriptional regulators (sTRs)" that show an additive effect on the major, often strong, transcriptional regulator (mTR), here, we performed a clustering analysis using the transcriptome datasets of an mTR deletion mutant and wild-type strain. In the case of ACT biosynthesis in Streptomyces coelicolor, PhoU (SCO4228) and RsfA (SCO4677) were selected through the clustering analysis, using AfsS (SCO4425) as a model mTR, and experimentally validated their roles as sTRs. Furthermore, through analysis of synergistic effects, we were able to suggest a novel regulation mechanism and formulate a strategy to maximize the synergistic effect. In the case of the double TR mutant strain (ΔrsfA pIBR25::afsS), it was confirmed that the increase of cell mass was the major cause of the synergistic effect. Therefore, the strategy to increase the cell mass of double mutant was further attempted by optimizing the expression of efflux pump, which resulted in 2-fold increase in the cell mass and 24-fold increase in the production of ACT. This result is the highest ACT yield from S. coelicolor ever reported.

  11. Synergistic infection of two viruses MCMV and SCMV increases the accumulations of both MCMV and MCMV-derived siRNAs in maize.

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    Xia, Zihao; Zhao, Zhenxing; Chen, Ling; Li, Mingjun; Zhou, Tao; Deng, Congliang; Zhou, Qi; Fan, Zaifeng

    2016-02-11

    The co-infection of Maize chlorotic mottle virus (MCMV) and Sugarcane mosaic virus (SCMV) can cause maize lethal necrosis. However, the mechanism underlying the synergistic interaction between these two viruses remains elusive. In this study, we found that the co-infection of MCMV and SCMV increased the accumulation of MCMV. Moreover, the profiles of virus-derived siRNAs (vsiRNAs) from MCMV and SCMV in single- and co-infected maize plants were obtained by high-throughput sequencing. Our data showed that synergistic infection of MCMV and SCMV increased remarkably the accumulation of vsiRNAs from MCMV, which were mainly 22 and 21 nucleotides in length. The single-nucleotide resolution maps of vsiRNAs revealed that vsiRNAs were almost continuously but heterogeneously distributed throughout MCMV and SCMV genomic RNAs, respectively. Moreover, we predicted and annotated dozens of host transcript genes targeted by vsiRNAs. Our results also showed that maize DCLs and several AGOs RNAs were differentially accumulated in maize plants with different treatments (mock, single or double inoculations), which were associated with the accumulation of vsiRNAs. Our findings suggested possible roles of vsiRNAs in the synergistic interaction of MCMV and SCMV in maize plants.

  12. Increasing Pleurotus ostreatus laccase production by culture medium optimization and copper/lignin synergistic induction.

    Science.gov (United States)

    Tinoco, Raunel; Acevedo, Abisaí; Galindo, Enrique; Serrano-Carreón, Leobardo

    2011-04-01

    Laccases have great biotechnological potential in diverse industries as they catalyze the oxidation of a broad variety of chemical compounds. Production of laccases by basidiomycetes has been broadly studied as they secrete the enzymes, grow on cheap substrates, and they generally produce more than one isoenzyme (constitutive and/or inducible). Laccase production and isoenzyme profile can be modified through medium composition and the use of inducers. The objective of this work was to increase laccase production by Pleurotus ostreatus CP-50 through culture medium optimization and the simultaneous use of copper and lignin as inducers. Increased fungal growth was obtained through the use of a factorial fractional experimental design 2⁶⁻² where the influence of the nature and concentration of carbon and nitrogen sources was assessed. Although specific laccase production (U/mg biomass) decreased when malt extract medium was supplemented with carbon and nitrogen sources, fungal growth and laccase volumetric activity increased four and sixfold, respectively. The effect of media supplementation with copper and/or lignin on laccase production by P. ostreatus CP-50 was studied. A positive synergistic effect between copper and lignin was observed on laccase production. Overall, the use of an optimized medium and the simultaneous addition of copper and lignin improved growth, laccase volumetric activity, and process productivity by 4-, 60-, and 10-fold, respectively.

  13. Synergistic interactions with a high intraoperative expander fill volume increase the risk for mastectomy flap necrosis.

    Science.gov (United States)

    Khavanin, Nima; Jordan, Sumanas; Lovecchio, Francis; Fine, Neil A; Kim, John

    2013-12-01

    Prosthetic-based breast reconstruction is performed with increasing frequency in the United States. Major mastectomy skin flap necrosis is a significant complication with outcomes ranging from poor aesthetic appearance to reconstructive failure. The present study aimed to explore the interactions between intraoperative fill and other risk factors on the incidence of flap necrosis in patients undergoing mastectomy with immediate expander/implant-based reconstruction. A retrospective review of 966 consecutive patients (1,409 breasts) who underwent skin or nipple sparing mastectomy with immediate tissue expander reconstruction at a single institution was conducted. Age, body mass index, hypertension, smoking status, premastectomy and postmastectomy radiation, acellular dermal matrix use, and application of the tumescent mastectomy technique were analyzed as potential predictors of flap necrosis both independently and as synergistic variables with high intraoperative fill. The following three measures of interaction were calculated: relative excess risk due to interaction, attributable proportion of risk due to interaction, and synergy index (SI). Intraoperative tissue expander fill volume was high (≥66.7% of the maximum volume) in 40.9% (576 of 1,409 breasts) of cases. The unadjusted flap necrosis rate was greater in the high intraoperative fill cohort than in the low fill cohort (10.4% vs. 7.1%, p=0.027). Multivariate logistic regression did not identify high intraoperative fill volume as an independent risk factor for flap necrosis (odds ratio 1.442, 95% confidence interval 0.973-2.137, p=0.068). However, four risk factors were identified that interacted significantly with intraoperative fill volume, namely tumescence, age, hypertension, and obesity. The SI, or the departure from additive risks, was largest for tumescence (SI, 25.3), followed by hypertension (SI, 2.39), obesity (SI, 2.28), and age older than 50 years (SI, 1.17). In the postmastectomy, hypovascular

  14. Synergistic effects of hypoxia and increasing CO2 on benthic invertebrates of the central Chilean coast

    KAUST Repository

    Steckbauer, Alexandra

    2015-07-10

    Ocean acidification (OA) and hypoxic events are an increasing worldwide problem, but the synergetic effects of these factors are seldom explored. However, this synergetic occurrence of stressors is prevalent. The coastline of Chile not only suffers from coastal hypoxia but the cold, oxygen-poor waters in upwelling events are also supersaturated in CO2, a study site to explore the combined effect of OA and hypoxia. We experimentally evaluated the metabolic response of different invertebrate species (2 anthozoans, 9 molluscs, 4 crustaceans, 2 echinoderms) of the coastline of central Chile (33°30′S, 71°37′W) to hypoxia and OA within predicted levels and in a full factorial design. Organisms were exposed to 4 different treatments (ambient, low oxygen, high CO2, and the combination of low oxygen and high CO2) and metabolism was measured after 3 and 6 days. We show that the combination of hypoxia and increased pCO2 reduces the respiration significantly, compared to a single stressor. The evaluation of synergistic pressures, a more realistic scenario than single stressors, is crucial to evaluate the effect of future changes for coastal species and our results provide the first insight on what might happen in the next 100 years.

  15. Synergistic effects of hypoxia and increasing CO2 on benthic invertebrates of the central Chilean coast

    Directory of Open Access Journals (Sweden)

    Alexandra eSteckbauer

    2015-07-01

    Full Text Available Ocean acidification and hypoxic events are an increasing worldwide problem, but the synergetic effects of these factors are seldom explored. However, this synergetic occurrence of stressors is prevalent. The coastline of Chile not only suffers from coastal hypoxia but the cold, oxygen-poor waters in upwelling events are also supersaturated in CO2, a study site to explore the combined effect of ocean acidification and hypoxia. We experimentally evaluated the metabolic response of different invertebrate species (2 anthozoans, 9 molluscs, 4 crustaceans, 2 echinoderms of the coastline of central Chile (33°30’S, 71°37’W to hypoxia and ocean acidification within predicted levels and in a full factorial design. Organisms were exposed to 4 different treatments (ambient, low oxygen, high CO2, and the combination of low oxygen and high CO2 and metabolism was measured after 3 and 6 days. We show that the combination of hypoxia and increased pCO2 reduces the respiration significantly, compared to a single stressor. The evaluation of synergistic pressures, a more realistic scenario than single stressors, is crucial to evaluate the effect of future changes for coastal species and our results provide the first insight on what might happen in the next 100 years.

  16. Home Remodeling and Food Allergy Interact Synergistically to Increase the Risk of Atopic Dermatitis

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    Won Seok Lee

    2017-01-01

    Full Text Available Purpose. The purpose of this study was to investigate the effects of home remodeling and food allergy (FA on the development of atopic dermatitis (AD in children. Methods. The Modified International Study of Asthma and Allergies in Childhood questionnaire was used to survey 4,111 children recruited from 3 kindergartens and 6 elementary schools from Seongnam, Korea. Participants’ parents agreed for them to participate in physical examinations, skin prick tests, and blood tests. Results. Home remodeling in the past 12 months (adjusted odds ratio [aOR] 3.40, P=0.006, lifetime diagnosis of FA (aOR 3.95, P<0.001, parental history of AD (aOR 2.67, P=0.001, and FA (aOR 2.35, P=0.004 were independent risk factors for lifetime diagnosis of AD ever. When history of home remodeling and FA were combined, the risk for moderate-to-severe AD by scoring atopic dermatitis (SCORAD score increased (aOR, 7.19, P=0.011, P for interaction = 0.034. Conclusion. Home remodeling, lifetime diagnosis of FA, parental history of AD, and parental history of FA were independent risk factors for AD. In addition, we observed a synergistic interaction between home remodeling and FA in the risk of moderate-to-severe AD.

  17. Dicalcium Phosphate Coated with Graphene Synergistically Increases Osteogenic Differentiation In Vitro

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    Jun Jae Lee

    2017-12-01

    Full Text Available In recent years, graphene and its derivatives have attracted much interest in various fields, including biomedical applications. In particular, increasing attention has been paid to the effects of reduced graphene oxide (rGO on cellular behaviors. On the other hand, dicalcium phosphate (DCP has been widely used in dental and pharmaceutical fields. In this study, DCP composites coated with rGO (DCP-rGO composites were prepared at various concentration ratios (DCP to rGO concentration ratios of 5:2.5, 5:5, and 5:10 μg/mL, respectively, and their physicochemical properties were characterized. In addition, the effects of DCP-rGO hybrid composites on MC3T3-E1 preosteoblasts were investigated. It was found that the DCP-rGO composites had an irregular granule-like structure with a diameter in the range order of the micrometer, and were found to be partially covered and interconnected with a network of rGO. The zeta potential analysis showed that although both DCP microparticles and rGO sheets had negative surface charge, the DCP-rGO composites could be successfully formed by the unique structural properties of rGO. In addition, it was demonstrated that the DCP-rGO composites significantly increased alkaline phosphatase activity and extracellular calcium deposition, indicating that the DCP-rGO hybrid composites can accelerate the osteogenic differentiation by the synergistic effects of rGO and DCP. Therefore, in conclusion, it is suggested that the DCP-rGO hybrid composites can be potent factors in accelerating the bone tissue regeneration.

  18. Synergistic effect of intervention of glypican-3 gene transcription combined with antitumor drugs in inhibiting hepatoma cell proliferation

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    YANG Jie

    2016-12-01

    .20 μmol/L, 7.85±2.00 nmol/L, and 18.36±0.56 μmol/L, respectively, and their combination with shRNA1 had an HepG2 cell inhibition rate of 95.11%. ConclusionIntervention of GPC3 gene transcription with specific shRNA can inhibit hepatoma cell proliferation, migration and movement, and invasion ability, induce hepatoma cell apoptosis, and inhibit hepatoma cell proliferation when combined with antitumor drugs in a synergistic manner. This suggests that GPC3 may be an effective therapeutic target for liver cancer and that combined targeted therapy can provide better strategies for the treatment of liver cancer.

  19. Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage

    OpenAIRE

    Barker, Catherine R.; McNamara, Anne V.; Rackstraw, Stephen A.; Nelson, David E.; White, Mike R.; Watson, Alastair J. M.; Jenkins, John R.

    2006-01-01

    Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the inc...

  20. Synergistic nuclear import of NeuroD1 and its partner transcription factor, E47, via heterodimerization

    Energy Technology Data Exchange (ETDEWEB)

    Mehmood, Rashid; Yasuhara, Noriko [Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871 (Japan); Oe, Souichi; Nagai, Masahiro [Department of Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Yoneda, Yoshihiro, E-mail: yyoneda@anat3.med.osaka-u.ac.jp [Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871 (Japan); Department of Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan)

    2009-06-10

    The transition from undifferentiated pluripotent cells to terminally differentiated neurons is coordinated by a repertoire of transcription factors. NeuroD1 is a type II basic helix loop helix (bHLH) transcription factor that plays critical roles in neuronal differentiation and maintenance in the central nervous system. Its dimerization with E47, a type I bHLH transcription factor, leads to the transcriptional regulation of target genes. Mounting evidence suggests that regulating the localization of transcription factors contributes to the regulation of their activity during development as defects in their localization underlie a variety of developmental disorders. In this study, we attempted to understand the nuclear import mannerisms of NeuroD1 and E47. We found that the nuclear import of NeuroD1 and E47 is energy-dependent and involves the Ran-mediated pathway. Herein, we demonstrate that NeuroD1 and E47 can dimerize inside the cytoplasm before their nuclear import. Moreover, this dimerization promotes nuclear import as the nuclear accumulation of NeuroD1 was enhanced in the presence of E47 in an in vitro nuclear import assay, and NLS-deficient NeuroD1 was successfully imported into the nucleus upon E47 overexpression. NeuroD1 also had a similar effect on the nuclear accumulation of NLS-deficient E47. These findings suggest a novel role for dimerization that may promote, at least partially, the nuclear import of transcription factors allowing them to function efficiently in the nucleus.

  1. Synergistic nuclear import of NeuroD1 and its partner transcription factor, E47, via heterodimerization

    International Nuclear Information System (INIS)

    Mehmood, Rashid; Yasuhara, Noriko; Oe, Souichi; Nagai, Masahiro; Yoneda, Yoshihiro

    2009-01-01

    The transition from undifferentiated pluripotent cells to terminally differentiated neurons is coordinated by a repertoire of transcription factors. NeuroD1 is a type II basic helix loop helix (bHLH) transcription factor that plays critical roles in neuronal differentiation and maintenance in the central nervous system. Its dimerization with E47, a type I bHLH transcription factor, leads to the transcriptional regulation of target genes. Mounting evidence suggests that regulating the localization of transcription factors contributes to the regulation of their activity during development as defects in their localization underlie a variety of developmental disorders. In this study, we attempted to understand the nuclear import mannerisms of NeuroD1 and E47. We found that the nuclear import of NeuroD1 and E47 is energy-dependent and involves the Ran-mediated pathway. Herein, we demonstrate that NeuroD1 and E47 can dimerize inside the cytoplasm before their nuclear import. Moreover, this dimerization promotes nuclear import as the nuclear accumulation of NeuroD1 was enhanced in the presence of E47 in an in vitro nuclear import assay, and NLS-deficient NeuroD1 was successfully imported into the nucleus upon E47 overexpression. NeuroD1 also had a similar effect on the nuclear accumulation of NLS-deficient E47. These findings suggest a novel role for dimerization that may promote, at least partially, the nuclear import of transcription factors allowing them to function efficiently in the nucleus.

  2. Zinc finger protein 521 overexpression increased transcript levels of ...

    Indian Academy of Sciences (India)

    2016-02-12

    Feb 12, 2016 ... Zfp521 enhanced transcription levels of both EGFP and endogenous Fndc5. This result was confirmed by overexpression the aforementioned vectors in HEK cells and indicated that Zfp521 functions upstream of Fndc5 expression. It is most likely that Zfp521 may act through the binding to its response ...

  3. Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency.

    Science.gov (United States)

    Prasad, Mahadesh A J; Ungerbäck, Jonas; Åhsberg, Josefine; Somasundaram, Rajesh; Strid, Tobias; Larsson, Malin; Månsson, Robert; De Paepe, Ayla; Lilljebjörn, Henrik; Fioretos, Thoas; Hagman, James; Sigvardsson, Mikael

    2015-06-25

    Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia. © 2015 by The American Society of Hematology.

  4. Increasing accuracy of daily evapotranspiration through synergistic use of MSG and MERIS/AATSR

    Science.gov (United States)

    Timmermans, Joris; van der Tol, Christiaan; Su, Zhongbo

    2010-05-01

    extrapolate the instantaneous estimates to daily values. In the Surface Energy Balance System (SEBS) algorithm the SEBI method is used. The method introduced an evaporative fraction that provides information on water-limiting cases for evapotranspiration. SEBS calculates the daily evapotranspiration assuming like many other researches the evaporative fraction constant per day. However recent investigations have shown that this is only valid in certain cases, and that in particular scenarios the evaporative fraction has a diurnal cycle. The objective of this research is to improve the accuracy of the daily evapotranspiration estimates through the synergistic use of MSG and AATSR/MERIS. The research investigates the methodology of coupling the two evaporative fractions in order to merge high temporal and high spatial resolution data. In order to extrapolate the instantaneous evapotranspiration estimates, the diurnal evaporative fraction from the geostationary satellite is coupled to the instantaneous high resolution spatial resolution of the AATSR/MERIS. The result of this coupling is a evapotranspiration map with high-temporal and high-spatial resolution. Also the comparison of instantaneous evapotranspiration by MSG and AATSR/MERIS creates a method for quantifying objectively the uncertainty in the evapotranspiration estimates.

  5. Dexamethasone Enhances 1α,25-Dihydroxyvitamin D3 Effects by Increasing Vitamin D Receptor Transcription*

    Science.gov (United States)

    Hidalgo, Alejandro A.; Deeb, Kristin K.; Pike, J. Wesley; Johnson, Candace S.; Trump, Donald L.

    2011-01-01

    Calcitriol, the active form of vitamin D, in combination with the glucocorticoid dexamethasone (Dex) has been shown to increase the antitumor effects of calcitriol in squamous cell carcinoma. In this study we found that pretreatment with Dex potentiates calcitriol effects by inhibiting cell growth and increasing vitamin D receptor (VDR) and VDR-mediated transcription. Treatment with actinomycin D inhibits Vdr mRNA synthesis, indicating that Dex regulates VDR expression at transcriptional level. Real time PCR shows that treatment with Dex increases Vdr transcripts in a time- and a dose-dependent manner, indicating that Dex directly regulates expression of Vdr. RU486, an inhibitor of glucocorticoids, inhibits Dex-induced Vdr expression. In addition, the silencing of glucocorticoid receptor (GR) abolishes the induction of Vdr by Dex, indicating that Dex increases Vdr transcripts in a GR-dependent manner. A fragment located 5.2 kb upstream of Vdr transcription start site containing two putative glucocorticoid response elements (GREs) was evaluated using a luciferase-based reporter assay. Treatment with 100 nm Dex induces transcription of luciferase driven by the fragment. Deletion of the GRE distal to transcription start site was sufficient to abolish Dex induction of luciferase. Also, chromatin immunoprecipitation reveals recruitment of GR to distal GRE with Dex treatment. We conclude that Dex increases VDR and vitamin D effects by increasing Vdr de novo transcription in a GR-dependent manner. PMID:21868377

  6. Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage.

    Science.gov (United States)

    Barker, Catherine R; McNamara, Anne V; Rackstraw, Stephen A; Nelson, David E; White, Mike R; Watson, Alastair J M; Jenkins, John R

    2006-01-01

    Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90-topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death.

  7. Functional behavior of bio-electrochemical treatment system with increasing azo dye concentrations: Synergistic interactions of biocatalyst and electrode assembly.

    Science.gov (United States)

    Sreelatha, S; Velvizhi, G; Naresh Kumar, A; Venkata Mohan, S

    2016-08-01

    Treatment of dye bearing wastewater through biological machinery is particularly challenging due to its recalcitrant and inhibitory nature. In this study, functional behavior and treatment efficiency of bio-electrochemical treatment (BET) system was evaluated with increasing azo dye concentrations (100, 200, 300 and 500mg dye/l). Maximum dye removal was observed at 300mg dye/l (75%) followed by 200mg dye/l (65%), 100mg dye/l (62%) and 500mg dye/l (58%). Concurrent increment in dye load resulted in enhanced azo reductase and dehydrogenase activities respectively (300mg dye/l: 39.6U; 4.96μg/ml). Derivatives of cyclic voltammograms also supported the involvement of various membrane bound redox shuttlers, viz., cytochrome-c, cytochrome-bc1 and flavoproteins during the electron transfer. Bacterial respiration during BET operation utilized various electron acceptors such as electrodes and dye intermediates with simultaneous bioelectricity generation. This study illustrates the synergistic interaction of biocatalyst with electrode assembly for efficient treatment of azo dye wastewater. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer.

    Science.gov (United States)

    Chen, Weiqian; Zou, Peng; Zhao, Zhongwei; Chen, Xi; Fan, Xiaoxi; Vinothkumar, Rajamanickam; Cui, Ri; Wu, Fazong; Zhang, Qianqian; Liang, Guang; Ji, Jiansong

    2016-12-01

    Mechanistic/mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce cell apoptosis and tumor regression which has hampered its clinical application. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of rapamycin. In our present study, we have investigated the combination of rapamycin and a reactive oxygen species (ROS) inducer EF24 in gastric cancer. We show that rapamycin increases intracellular ROS levels and displays selective synergistic antitumor activity with EF24 in gastric cancer cells. This activity was mediated through the activation of c-Jun N terminal kinase and endoplasmic reticulum stress (ER) pathways in cancer cells. We also show that inhibiting ROS accumulation reverses ER stress and prevents apoptosis induced by the combination of rapamycin and EF24. These mechanisms were confirmed using human gastric cancer xenografts in immunodeficient mice. Taken together, our work provides a novel therapeutic strategy for the treatment of gastric cancer. The work reveals that ROS generation could be an important target for the development of new combination therapies for cancer treatment. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Transcriptional regulation by triiodothyronine requires synergistic action of the thyroid receptor with another trans-acting factor.

    Science.gov (United States)

    Voz, M L; Peers, B; Wiedig, M J; Jacquemin, P; Belayew, A; Martial, J A

    1992-09-01

    Human placental lactogen B (hCS-B) promoter activity is strongly stimulated by triiodothyronine (T3) in pituitary GC cells through interaction between the thyroid receptor and a thyroid receptor-binding element (TBE) spanning coordinates -67 to -41. This TBE is adjacent to the binding site for pituitary factor GHF1 (-95 to -68) which seems necessary for T3 stimulation of hCS-B promoter activity (M. L. Voz, B. Peers, A. Belayew, and J. A. Martial, J. Biol. Chem. 266:13397-13404, 1991). We here demonstrate actual synergy between the thyroid receptor and GHF1. Indeed, in placental JEG-3 cells devoid of factor GHF1, hCS promoter activity is barely stimulated by T3, while a strong response is observed in pituitary GC cells. In the latter, furthermore, neither the TBE nor the GHF1-binding site alone is sufficient to render the thymidine kinase promoter responsive to T3, while in combination they promote strong T3 stimulation. Close proximity between these sites is required for optimal synergy: T3 stimulation globally decreases with increased spacing. Furthermore, synergy occurs not only with a GHF1-binding site but also with all other factor recognition sequences tested (Sp1, NF1, CP1, Oct1, and CACCC boxes) and even with two other copies of the TBE. Nor is it specific to hCS TBE, since the palindromic sequence TCAGGTCA TGACCTGA (TREpal) also exhibits cooperativity.

  10. Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus.

    Science.gov (United States)

    Zhang, Tie-Yuan; Keown, Christopher L; Wen, Xianglan; Li, Junhao; Vousden, Dulcie A; Anacker, Christoph; Bhattacharyya, Urvashi; Ryan, Richard; Diorio, Josie; O'Toole, Nicholas; Lerch, Jason P; Mukamel, Eran A; Meaney, Michael J

    2018-01-19

    Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications. Here, we report comprehensive DNA methylome, hydroxymethylome and transcriptome data sets from mouse dorsal and ventral DG. We find genome-wide transcriptional and methylation differences between dorsal and ventral DG, including at key developmental transcriptional factors. Peripubertal environmental enrichment increases hippocampal volume and enhances dorsal DG-specific differences in gene expression. Enrichment also enhances dorsal-ventral differences in DNA methylation, including at binding sites of the transcription factor NeuroD1, a regulator of adult neurogenesis. These results indicate a dorsal-ventral asymmetry in transcription and methylation that parallels well-known functional and anatomical differences, and that may be enhanced by environmental enrichment.

  11. Reverse transcription using random pentadecamer primers increases yield and quality of resulting cDNA

    DEFF Research Database (Denmark)

    Stangegaard, Michael; Dufva, I.H.; Dufva, Hans Martin

    2006-01-01

    Reverse transcription of RNA is an invaluable method for gene expression analysis by real-time PCR or microarray methods. Random primers of varying lengths were compared with respect to their efficiency of priming reverse transcription reactions. The results showed that l5-nucleotide-long random...... that random pentadecamers can replace random hexamers in reverse transcription reactions on both poly(A) RNA and amplified RNA, resulting in higher cDNA yields and quality....... with cDNA generated with random hexamers. The increased efficiency of priming using random pentadecamers resulted in reverse transcription of > 80% of the template aRNA, while random hexamers induced reverse transcription of only 40% of the template aRNA. This suggests a better coverage...

  12. Tetrahydrobiopterin, l-Arginine and Vitamin C Act Synergistically to Decrease Oxidant Stress and Increase Nitric Oxide That Increases Blood Flow Recovery after Hindlimb Ischemia in the Rat

    Science.gov (United States)

    Yan, Jinglian; Tie, Guodong; Messina, Louis M

    2012-01-01

    Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is a potent vasodilator and signaling molecule that plays essential roles in neovascularization. During limb ischemia, decreased NO bioavailability occurs secondary to increased oxidant stress, decreased l-arginine and tetrahydrobiopterin. This study tested the hypothesis that dietary cosupplementation with tetrahydrobiopterin (BH4), l-arginine and vitamin C acts synergistically to decrease oxidant stress, increase NO and thereby increase blood flow recovery after hindlimb ischemia. Rats were fed normal chow, chow supplemented with BH4 or l-arginine (alone or in combination) or chow supplemented with BH4 + l-arginine + vitamin C for 1 wk before induction of hindlimb ischemia. In the is-chemic hindlimb, cosupplementation with BH4 + l-arginine resulted in greater eNOS and phospho-eNOS (P-eNOS) expression, Ca2+-dependent NOS activity and NO concentration in the ischemic calf region (gastrocnemius), as well as greater NO concentration in the region of collateral arteries (gracilis). Rats receiving cosupplementation of BH4 + l-arginine led to greater recovery of foot perfusion and greater collateral enlargement than did rats receiving either agent separately. The addition of vitamin C to the BH4 + l-arginine regimen further increased these dependent variables. In addition, rats given all three supplements showed significantly less Ca2+-independent activity, less nitrotyrosine accumulation, greater glutathione (GSH)–to–glutathione disulfide (GSSG) ratio and less gastrocnemius muscle necrosis, on both macroscopic and microscopic levels. In conclusion, co-supplementation with BH4 + l-arginine + vitamin C significantly increased blood flow recovery after hindlimb ischemia by reducing oxidant stress, increasing NO bioavailability, enlarging collateral arteries and reducing muscle necrosis. Oral cosupplementation of BH4, l-arginine and vitamin C holds promise as a biological therapy to induce

  13. Increased frequency of single base substitutions in a population of transcripts expressed in cancer cells

    Directory of Open Access Journals (Sweden)

    Bianchetti Laurent

    2012-11-01

    Full Text Available Abstract Background Single Base Substitutions (SBS that alter transcripts expressed in cancer originate from somatic mutations. However, recent studies report SBS in transcripts that are not supported by the genomic DNA of tumor cells. Methods We used sequence based whole genome expression profiling, namely Long-SAGE (L-SAGE and Tag-seq (a combination of L-SAGE and deep sequencing, and computational methods to identify transcripts with greater SBS frequencies in cancer. Millions of tags produced by 40 healthy and 47 cancer L-SAGE experiments were compared to 1,959 Reference Tags (RT, i.e. tags matching the human genome exactly once. Similarly, tens of millions of tags produced by 7 healthy and 8 cancer Tag-seq experiments were compared to 8,572 RT. For each transcript, SBS frequencies in healthy and cancer cells were statistically tested for equality. Results In the L-SAGE and Tag-seq experiments, 372 and 4,289 transcripts respectively, showed greater SBS frequencies in cancer. Increased SBS frequencies could not be attributed to known Single Nucleotide Polymorphisms (SNP, catalogued somatic mutations or RNA-editing enzymes. Hypothesizing that Single Tags (ST, i.e. tags sequenced only once, were indicators of SBS, we observed that ST proportions were heterogeneously distributed across Embryonic Stem Cells (ESC, healthy differentiated and cancer cells. ESC had the lowest ST proportions, whereas cancer cells had the greatest. Finally, in a series of experiments carried out on a single patient at 1 healthy and 3 consecutive tumor stages, we could show that SBS frequencies increased during cancer progression. Conclusion If the mechanisms generating the base substitutions could be known, increased SBS frequency in transcripts would be a new useful biomarker of cancer. With the reduction of sequencing cost, sequence based whole genome expression profiling could be used to characterize increased SBS frequency in patient’s tumor and aid diagnostic.

  14. Increased frequency of single base substitutions in a population of transcripts expressed in cancer cells

    International Nuclear Information System (INIS)

    Bianchetti, Laurent; Kieffer, David; Féderkeil, Rémi; Poch, Olivier

    2012-01-01

    Single Base Substitutions (SBS) that alter transcripts expressed in cancer originate from somatic mutations. However, recent studies report SBS in transcripts that are not supported by the genomic DNA of tumor cells. We used sequence based whole genome expression profiling, namely Long-SAGE (L-SAGE) and Tag-seq (a combination of L-SAGE and deep sequencing), and computational methods to identify transcripts with greater SBS frequencies in cancer. Millions of tags produced by 40 healthy and 47 cancer L-SAGE experiments were compared to 1,959 Reference Tags (RT), i.e. tags matching the human genome exactly once. Similarly, tens of millions of tags produced by 7 healthy and 8 cancer Tag-seq experiments were compared to 8,572 RT. For each transcript, SBS frequencies in healthy and cancer cells were statistically tested for equality. In the L-SAGE and Tag-seq experiments, 372 and 4,289 transcripts respectively, showed greater SBS frequencies in cancer. Increased SBS frequencies could not be attributed to known Single Nucleotide Polymorphisms (SNP), catalogued somatic mutations or RNA-editing enzymes. Hypothesizing that Single Tags (ST), i.e. tags sequenced only once, were indicators of SBS, we observed that ST proportions were heterogeneously distributed across Embryonic Stem Cells (ESC), healthy differentiated and cancer cells. ESC had the lowest ST proportions, whereas cancer cells had the greatest. Finally, in a series of experiments carried out on a single patient at 1 healthy and 3 consecutive tumor stages, we could show that SBS frequencies increased during cancer progression. If the mechanisms generating the base substitutions could be known, increased SBS frequency in transcripts would be a new useful biomarker of cancer. With the reduction of sequencing cost, sequence based whole genome expression profiling could be used to characterize increased SBS frequency in patient’s tumor and aid diagnostic

  15. Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients

    DEFF Research Database (Denmark)

    Brudek, Tomasz; Christensen, Tove; Hansen, Hans Jacob

    2008-01-01

    , this production correlated with the synergistic cell proliferations whereas we did not find such a correlation in healthy controls. Our findings suggest that the increased production of IFN-gamma and the induced imbalance in Th1/Th2 responses favouring the inflammatory reactions in MS patients may lead...... effect on cell-mediated immune responses, which tend to be higher in MS patients in comparison with healthy individuals. Here, we investigate whether these synergistic immune responses are reflected in changes in the production of proinflammatory cytokines. Using enzyme-linked immunosorbent assays...... (ELISAs), we have performed a comparative study between MS patients and healthy controls to investigate the production of interferon (IFN)-gamma, interleukin (IL) 2, or IL-10 as well as the balance between Th1 and Th2 responses in supernatants from peripheral blood mononuclear cells (PBMC) stimulated...

  16. Enhanced Biofilm Formation and Increased Resistance to Antimicrobial Agents and Bacterial Invasion Are Caused by Synergistic Interactions in Multispecies Biofilms

    DEFF Research Database (Denmark)

    Burmølle, Mette; Webb, J.S.; Rao, D.

    2006-01-01

    from the surface of the marine alga Ulva australis, were screened for synergistic interactions within biofilms when present together in different combinations. Four isolates, Microbacterium phyllosphaerae, Shewanella japonica, Dokdonia donghaensis, and Acinetobacter lwoffii, were found to interact......-species biofilms resisted invasion to a greater extent than did the biofilms formed by the single species. Replacement of each strain by its cell-free culture supernatant suggested that synergy was dependent both on species-specific physical interactions between cells and on extracellular secreted factors or less...

  17. Changes in transcriptional orientation are associated with increases in evolutionary rates of enterobacterial genes

    Directory of Open Access Journals (Sweden)

    Hsiung Chao

    2011-10-01

    Full Text Available Abstract Background Changes in transcriptional orientation (“CTOs” occur frequently in prokaryotic genomes. Such changes usually result from genomic inversions, which may cause a conflict between the directions of replication and transcription and an increase in mutation rate. However, CTOs do not always lead to the replication-transcription confrontation. Furthermore, CTOs may cause deleterious disruptions of operon structure and/or gene regulations. The currently existing CTOs may indicate relaxation of selection pressure. Therefore, it is of interest to investigate whether CTOs have an independent effect on the evolutionary rates of the affected genes, and whether these genes are subject to any type of selection pressure in prokaryotes. Methods Three closely related enterbacteria, Escherichia coli, Klebsiella pneumoniae and Salmonella enterica serovar Typhimurium, were selected for comparisons of synonymous (dS and nonsynonymous (dN substitution rate between the genes that have experienced changes in transcriptional orientation (changed-orientation genes, “COGs” and those that do not (same-orientation genes, “SOGs”. The dN/dS ratio was also derived to evaluate the selection pressure on the analyzed genes. Confounding factors in the estimation of evolutionary rates, such as gene essentiality, gene expression level, replication-transcription confrontation, and decreased dS at gene terminals were controlled in the COG-SOG comparisons. Results We demonstrate that COGs have significantly higher dN and dS than SOGs when a series of confounding factors are controlled. However, the dN/dS ratios are similar between the two gene groups, suggesting that the increase in dS can sufficiently explain the increase in dN in COGs. Therefore, the increases in evolutionary rates in COGs may be mainly mutation-driven. Conclusions Here we show that CTOs can increase the evolutionary rates of the affected genes. This effect is independent of the

  18. Over-expression of Dof-type transcription factor increases lipid production in Chlamydomonas reinhardtii.

    Science.gov (United States)

    Ibáñez-Salazar, Alejandro; Rosales-Mendoza, Sergio; Rocha-Uribe, Alejandro; Ramírez-Alonso, Jocelín Itzel; Lara-Hernández, Ignacio; Hernández-Torres, Araceli; Paz-Maldonado, Luz María Teresita; Silva-Ramírez, Ana Sonia; Bañuelos-Hernández, Bernardo; Martínez-Salgado, José Luis; Soria-Guerra, Ruth Elena

    2014-08-20

    The high demand for less polluting, newer, and cheaper fuel resources has increased the search of the most innovative options for the production of the so-called biofuels. Chlamydomonas reinhardtii is a photosynthetic unicellular algae with multiple biotechnological advantages such as easy handling in the laboratory, a simple scale-up to industrial levels, as well as a feasible genetic modification at nuclear and chloroplast levels. Besides, its fatty acids can be used to produce biofuels. Previous studies in plants have found that the over expression of DOF-type transcription factor genes increases the synthesis and the accumulation of total lipids in seeds. In this context, the over-expression of a DOF-type transcription factor in C. reinhardtii was applied as approach to increase the amount of lipids. The results indicate higher amounts (around 2-fold) of total lipids, which are mainly fatty acids, in the genetically C. reinhardtii modified strains when compared with the non-genetically modified strain. In order to elucidate the possible function of the introduced Dof-type transcription factor, we performed a transcription profile of 8 genes involved in fatty acid biosynthesis and 6 genes involved in glycerolipid biosynthesis, by quantitative real time (qRT-PCR). Differential expression profile was observed, which can explain the increase in lipid accumulation. However, these strains did not show notable changes in the fatty acid profile. This work represents an early effort in generating a strategy to increase fatty acids production in C. reinhardtii and their use in biofuel synthesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. p53 increases intra-cellular calcium release by transcriptional regulation of calcium channel TRPC6 in GaQ3-treated cancer cells.

    Directory of Open Access Journals (Sweden)

    Esha Madan

    Full Text Available p53 and calcium signaling are inter-dependent and are known to show both synergistic and antagonistic effects on each other in the cellular environment. However, no molecular mechanism or cellular pathway is known which shows direct regulation between these important cellular signaling molecules. Here we have shown that in cancer cells treated with anti-neoplastic drug GaQ3, p53, there is an increase in intracellular calcium levels by transcriptional regulation of a novel calcium channel gene TRPC6. p53 directly binds to a 22 bp response element in the TRPC6 gene promoter and increase its mRNA and protein expression. Over-expression of TRPC6 results in calcium-dependent apoptotic death and activation of apoptotic genes in a variety of cancer cells. This research work shows that p53 and its transcriptional activity is critical in regulation of calcium signaling and an increase in the intracellular calcium level might be one of the anti-cancer strategies to induce apoptosis in cancer cells.

  20. p53 increases intra-cellular calcium release by transcriptional regulation of calcium channel TRPC6 in GaQ3-treated cancer cells.

    Science.gov (United States)

    Madan, Esha; Gogna, Rajan; Keppler, Bernhard; Pati, Uttam

    2013-01-01

    p53 and calcium signaling are inter-dependent and are known to show both synergistic and antagonistic effects on each other in the cellular environment. However, no molecular mechanism or cellular pathway is known which shows direct regulation between these important cellular signaling molecules. Here we have shown that in cancer cells treated with anti-neoplastic drug GaQ3, p53, there is an increase in intracellular calcium levels by transcriptional regulation of a novel calcium channel gene TRPC6. p53 directly binds to a 22 bp response element in the TRPC6 gene promoter and increase its mRNA and protein expression. Over-expression of TRPC6 results in calcium-dependent apoptotic death and activation of apoptotic genes in a variety of cancer cells. This research work shows that p53 and its transcriptional activity is critical in regulation of calcium signaling and an increase in the intracellular calcium level might be one of the anti-cancer strategies to induce apoptosis in cancer cells.

  1. Strong negative self regulation of Prokaryotic transcription factors increases the intrinsic noise of protein expression

    Directory of Open Access Journals (Sweden)

    Jenkins Dafyd J

    2008-01-01

    Full Text Available Abstract Background Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. Results We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Conclusion Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic

  2. Synergistic Exposure of Rice Seeds to Different Doses of γ-Ray and Salinity Stress Resulted in Increased Antioxidant Enzyme Activities and Gene-Specific Modulation of TC-NER Pathway

    Directory of Open Access Journals (Sweden)

    Anca Macovei

    2014-01-01

    Full Text Available Recent reports have underlined the potential of gamma (γ-rays as tools for seed priming, a process used in seed industry to increase seed vigor and to enhance plant tolerance to biotic/abiotic stresses. However, the impact of γ-rays on key aspects of plant metabolism still needs to be carefully evaluated. In the present study, rice seeds were challenged with different doses of γ-rays and grown in absence/presence of NaCl to assess the impact of these treatments on the early stages of plant life. Enhanced germination efficiency associated with increase in radicle and hypocotyl length was observed, while at later stages no increase in plant tolerance to salinity stress was evident. APX, CAT, and GR were enhanced at transcriptional level and in terms of enzyme activity, indicating the activation of antioxidant defence. The profiles of DNA damage accumulation were obtained using SCGE and the implication of TC-NER pathway in DNA damage sensing and repair mechanisms is discussed. OsXPB2, OsXPD, OsTFIIS, and OsTFIIS-like genes showed differential modulation in seedlings and plantlets in response to γ-irradiation and salinity stress. Altogether, the synergistic exposure to γ-rays and NaCl resulted in enhanced oxidative stress and proper activation of antioxidant mechanisms, thus being compatible with plant survival.

  3. Transcriptional effects of glucocorticoid receptors in the dentate gyrus increase anxiety-related behaviors.

    Directory of Open Access Journals (Sweden)

    Nadège Sarrazin

    Full Text Available The Glucocorticoid Receptor (GR is a transcription factor ubiquitously expressed in the brain. Activation of brain GRs by high levels of glucocorticoid (GC hormones modifies a large variety of physiological and pathological-related behaviors. Unfortunately the specific cellular targets of GR-mediated behavioral effects of GC are still largely unknown. To address this issue, we generated a mutated form of the GR called DeltaGR. DeltaGR is a constitutively transcriptionally active form of the GR that is localized in the nuclei and activates transcription without binding to glucocorticoids. Using the tetracycline-regulated system (Tet-OFF, we developed an inducible transgenic approach that allows the expression of the DeltaGR in specific brain areas. We focused our study on a mouse line that expressed DeltaGR almost selectively in the glutamatergic neurons of the dentate gyrus (DG of the hippocampus. This restricted expression of the DeltaGR increased anxiety-related behaviors without affecting other behaviors that could indirectly influence performance in anxiety-related tests. This behavioral phenotype was also associated with an up-regulation of the MAPK signaling pathway and Egr-1 protein in the DG. These findings identify glutamatergic neurons in the DG as one of the cellular substrate of stress-related pathologies.

  4. Resveratrol Prevents Diabetic Cardiomyopathy by Increasing Nrf2 Expression and Transcriptional Activity

    Directory of Open Access Journals (Sweden)

    Guan Wang

    2018-01-01

    Full Text Available Objective. This study investigated if resveratrol ameliorates diabetic cardiomyopathy by targeting associated oxidative stress mechanisms. Method. Type 1 diabetes mellitus (DM in FVB mice was induced by several intraperitoneal injections of a low dose of streptozotocin. Hyperglycemic and age-matched control mice were given resveratrol (10 mg/kg per day for 1 month and subsequently monitored for an additional 6 months. Mice were assigned to four groups: control, resveratrol, DM, and DM/resveratrol. Cardiac function and blood pressure were assessed at 1, 3, and 6 months after DM induction. Oxidative damage and cardiac fibrosis were analyzed by histopathology, real-time PCR, and Western blot. Result. Mice in the DM group exhibited increased blood glucose levels, cardiac dysfunction, and high blood pressure at 1, 3, and 6 months after DM induction. Resveratrol did not significantly affect blood glucose levels and blood pressure; however, resveratrol attenuated cardiac dysfunction and hypertrophy in DM mice. Resveratrol also reduced DM-induced fibrosis. In addition, DM mice hearts exhibited increased oxidative damage, as evidenced by elevated accumulation of 3-nitrotyrosine and 4-hydroxynonenal, which were both attenuated by resveratrol. Mechanistically, resveratrol increased NFE2-related factor 2 (Nrf2 expression and transcriptional activity, as well as Nrf2’s downstream antioxidative targets. Conclusion. We demonstrated that resveratrol prevents DM-induced cardiomyopathy, in part, by increasing Nrf2 expression and transcriptional activity.

  5. Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation

    Directory of Open Access Journals (Sweden)

    Keisuke Sato

    2014-01-01

    Full Text Available Epalrestat (EPS, approved in Japan, is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Here we report that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH, which is important for protection against oxidative injury, through transcription regulation. Treatment of Schwann cells with EPS caused a dramatic increase in intracellular GSH levels. EPS increased the mRNA levels of γ-glutamylcysteine synthetase (γ-GCS, the enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2 is a key transcription factor that plays a central role in regulating the expression of γ-GCS. ELISA revealed that EPS increased nuclear Nrf2 levels. Knockdown of Nrf2 by siRNA suppressed the EPS-induced GSH biosynthesis. Furthermore, pretreatment with EPS reduced the cytotoxicity induced by H2O2, tert-butylhydroperoxide, 2,2'-azobis (2-amidinopropane dihydrochloride, and menadione, indicating that EPS plays a role in protecting against oxidative stress. This is the first study to show that EPS induces GSH biosynthesis via the activation of Nrf2. We suggest that EPS has new beneficial properties that may prevent the development and progression of disorders caused by oxidative stress.

  6. A mechanistic study explaining the synergistic viscosity increase obtained from polyethylene oxide (PEO) and {beta}-naphthalene sulfonate (BNS) in shotcrete

    Energy Technology Data Exchange (ETDEWEB)

    Pickelmann, J.; Plank, J., E-mail: sekretariat@bauchemie.ch.tum.de

    2012-11-15

    In shotcrete, a combination of polyethylene oxide (PEO) and {beta}-naphthalene sulfonate (BNS) is commonly applied to reduce rebound. Here, the mechanism for the synergistic viscosity increase resulting from this admixture combination was investigated via x-ray diffraction (XRD), infrared and nuclear magnetic resonance (NMR) spectroscopy. It was found that the electron-rich aromatic rings present in BNS donate electrons to the alkyl protons of PEO and thus increase the electron density there. This rare interaction is known as CH-{pi} interaction and leads to the formation of a supramolecular structure whereby PEO chains bind weakly to BNS molecules. Through this mechanism a polymer network exhibiting exceptionally high molecular weight and thus viscosity is formed. Among polycondensates, sulfanilic acid-phenol-formaldehyde (SPF) provides even higher synergy with PEO than BNS while melamine (PMS), acetone (AFS) or polycarboxylate (PCE) based superplasticizers do not work at all. Effectiveness of lignosulfonates is dependent on their degree of sulfonation.

  7. CFLAP1 and CFLAP2 Are Two bHLH Transcription Factors Participating in Synergistic Regulation of AtCFL1-Mediated Cuticle Development in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Shibai Li

    2016-01-01

    Full Text Available The cuticle is a hydrophobic lipid layer covering the epidermal cells of terrestrial plants. Although many genes involved in Arabidopsis cuticle development have been identified, the transcriptional regulation of these genes is largely unknown. Previously, we demonstrated that AtCFL1 negatively regulates cuticle development by interacting with the HD-ZIP IV transcription factor HDG1. Here, we report that two bHLH transcription factors, AtCFL1 associated protein 1 (CFLAP1 and CFLAP2, are also involved in AtCFL1-mediated regulation of cuticle development. CFLAP1 and CFLAP2 interact with AtCFL1 both in vitro and in vivo. Overexpression of either CFLAP1 or CFLAP2 led to expressional changes of genes involved in fatty acids, cutin and wax biosynthesis pathways and caused multiple cuticle defective phenotypes such as organ fusion, breakage of the cuticle layer and decreased epicuticular wax crystal loading. Functional inactivation of CFLAP1 and CFLAP2 by chimeric repression technology caused opposite phenotypes to the CFLAP1 overexpressor plants. Interestingly, we find that, similar to the transcription factor HDG1, the function of CFLAP1 in cuticle development is dependent on the presence of AtCFL1. Furthermore, both HDG1 and CFLAP1/2 interact with the same C-terminal C4 zinc finger domain of AtCFL1, a domain that is essential for AtCFL1 function. These results suggest that AtCFL1 may serve as a master regulator in the transcriptional regulation of cuticle development, and that CFLAP1 and CFLAP2 are involved in the AtCFL1-mediated regulation pathway, probably through competing with HDG1 to bind to AtCFL1.

  8. Stimulated initiation of mitogen-activated protein kinase phosphatase-1 (MKP-1) gene transcription involves the synergistic action of multiple cis-acting elements in the proximal promoter.

    Science.gov (United States)

    Ryser, Stephan; Massiha, Abbas; Piuz, Isabelle; Schlegel, Werner

    2004-01-01

    Mitogen-activated protein kinases (MAPKs) are inactivated by a dual specificity phosphatase, MAPK phosphatase-1 (MKP-1). MKP-1 is transcribed as an immediate early response gene (IEG) following various stimuli. In the pituitary cell line GH4C1, MKP-1 gene transcription is strongly induced by thyrotropin-releasing hormone (TRH) as well as by epidermal growth factor (EGF) as a consequence of activated MAPK/extracellular-signal-regulated kinase (ERK) signalling. Intriguingly, reporter gene analysis with the MKP-1 promoter showed strong basal transcription, but only limited induction by TRH and EGF. Site-directed mutagenesis of the reporter construct combined with band-shift and in vivo studies revealed that part of the constitutive activity of the MKP-1 promoter resides in two GC boxes bound by Sp1 and Sp3 transcription factors in the minimal promoter. Basal transcription of transiently transfected luciferase reporter can be initiated by either of the two GC boxes or also by either of the two cAMP/Ca(2+) responsive elements or by the E-box present in the proximal promoter. On the other hand, when analysed by stable transfection, the five responsive elements are acting in synergy to transactivate the MKP-1 proximal promoter. We show in this study that the MKP-1 promoter can function as a constitutive promoter or as a rapid and transient sensor for the activation state of MAPKs/ERKs. This dual mode of transcription initiation may have different consequences for the control of a block to elongation situated in the first exon of the MKP-1 gene, as described previously [Ryser, Tortola, van Haasteren, Muda, Li and Schlegel (2001) J. Biol. Chem. 276, 33319-33327]. PMID:14609431

  9. Testosterone Administration Inhibits Hepcidin Transcription and is Associated with Increased Iron Incorporation into Red Blood Cells

    Science.gov (United States)

    Guo, Wen; Bachman, Eric; Li, Michelle; Roy, Cindy N.; Blusztajn, Jerzy; Wong, Siu; Chan, Stephen Y.; Serra, Carlo; Jasuja, Ravi; Travison, Thomas G.; Muckenthaler, Martina U.; Nemeth, Elizabeta; Bhasin, Shalender

    2013-01-01

    Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferring saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound 58Fe, the amount of 58Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to BMP-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. Conclusion: Testosterone inhibits hepcidin transcription through its interaction with BMP-Smad signaling. Testosterone administration is associated with increased iron

  10. Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity

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    Maria Abad

    2017-03-01

    Full Text Available Conversion of fibroblasts into functional cardiomyocytes represents a potential means of restoring cardiac function after myocardial infarction, but so far this process remains inefficient and little is known about its molecular mechanisms. Here we show that DAPT, a classical Notch inhibitor, enhances the conversion of mouse fibroblasts into induced cardiac-like myocytes by the transcription factors GATA4, HAND2, MEF2C, and TBX5. DAPT cooperates with AKT kinase to further augment this process, resulting in up to 70% conversion efficiency. Moreover, DAPT promotes the acquisition of specific cardiomyocyte features, substantially increasing calcium flux, sarcomere structure, and the number of spontaneously beating cells. Transcriptome analysis shows that DAPT induces genetic programs related to muscle development, differentiation, and excitation-contraction coupling. Mechanistically, DAPT increases binding of the transcription factor MEF2C to the promoter regions of cardiac structural genes. These findings provide mechanistic insights into the reprogramming process and may have important implications for cardiac regeneration therapies.

  11. Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients

    DEFF Research Database (Denmark)

    Brudek, T; Christensen, T; Hansen, H J

    2008-01-01

    (ELISAs), we have performed a comparative study between MS patients and healthy controls to investigate the production of interferon (IFN)-gamma, interleukin (IL) 2, or IL-10 as well as the balance between Th1 and Th2 responses in supernatants from peripheral blood mononuclear cells (PBMC) stimulated...... with HERV and herpes antigen combinations. We have found a significant disproportion in Th1/Th2 responses in PBMCs from MS patients caused by the joint presence of HERV and herpes antigens. The results also showed a significantly higher IFN-gamma production in cells from MS patients; additionally......, this production correlated with the synergistic cell proliferations whereas we did not find such a correlation in healthy controls. Our findings suggest that the increased production of IFN-gamma and the induced imbalance in Th1/Th2 responses favouring the inflammatory reactions in MS patients may lead...

  12. Transcription Factors Synergistically Activated at the Crossing of the Restriction Point between G1 and S Cell Cycle Phases. Pathologic Gate Opening during Multi-Hit Malignant Transformation

    Directory of Open Access Journals (Sweden)

    Nicoletta Castagnino

    2016-12-01

    Full Text Available Transcription factors (TFs represent key regulators of gene-expression patterns controlling cell behavior. TFs are active at nuclear – chromatin levels. TFs do not act in isolation; small sets of TFs cooperate toward the transcription of sets of mRNAs and consequently the translation of new proteins (the molecular phenotypes of a cell. Most TFs are activated through a cascade of biochemical reactions mediated by receptors expressed on the target cell surface. Nuclear Receptors (NRs are transcription factors activated instead by small hydrophobic molecules capable of crossing the plasma membrane. The convergence of different pathways on TFs and their posttranslational modifications ensure that the external stimuli generate appropriate and integrated responses. The reconstruction of the molecular anatomy of these pathways through Molecular Interactions Maps (MIMs can depict these intricate interactions. A mathematical modeling approach simulates/mimics their mechanism of action in normal and pathological conditions. We can simulate the effect of virtual hits in neoplastic transformation as mutations/alterations in these pathways. We can also simulate the effect of targeted inhibitors on these deregulated pathways. This strategy can help to guide an appropriate combination of targeted drugs in the treatment of a cancer patient, a major innovative perspective of incoming years.

  13. Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity

    International Nuclear Information System (INIS)

    Schlottmann, Silke; Erkizan, Hayriye V.; Barber-Rotenberg, Julie S.; Knights, Chad; Cheema, Amrita; Üren, Aykut; Avantaggiati, Maria L.; Toretsky, Jeffrey A.

    2012-01-01

    Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor growth. However, its regulation is still enigmatic. To date, no functionally significant post-translational modifications of EWS-FLI1 have been shown. Since ES are sensitive to histone deacetylase inhibitors (HDI), and these inhibitors are advancing in clinical trials, we sought to identify if EWS-FLI1 is directly acetylated. We convincingly show acetylation of the C-terminal FLI1 (FLI1-CTD) domain, which is the DNA binding domain of EWS-FLI1. In vitro acetylation studies showed that acetylated FLI1-CTD has higher DNA binding activity than the non-acetylated protein. Over-expression of PCAF or treatment with HDI increased the transcriptional activity of EWS-FLI1, when co-expressed in Cos7 cells. However, our data that evaluates the acetylation of full-length EWS-FLI1 in ES cells remains unclear, despite creating acetylation specific antibodies to four potential acetylation sites. We conclude that EWS-FLI1 may either gain access to chromatin as a result of histone acetylation or undergo regulation by direct acetylation. These data should be considered when patients are treated with HDAC inhibitors. Further investigation of this phenomenon will reveal if this potential acetylation has an impact on tumor response.

  14. O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver.

    Science.gov (United States)

    Guinez, Céline; Filhoulaud, Gaëlle; Rayah-Benhamed, Fadila; Marmier, Solenne; Dubuquoy, Céline; Dentin, Renaud; Moldes, Marthe; Burnol, Anne-Françoise; Yang, Xiaoyong; Lefebvre, Tony; Girard, Jean; Postic, Catherine

    2011-05-01

    Carbohydrate-responsive element-binding protein (ChREBP) is a key transcription factor that mediates the effects of glucose on glycolytic and lipogenic genes in the liver. We have previously reported that liver-specific inhibition of ChREBP prevents hepatic steatosis in ob/ob mice by specifically decreasing lipogenic rates in vivo. To better understand the regulation of ChREBP activity in the liver, we investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAc or O-GlcNAcylation), an important glucose-dependent posttranslational modification playing multiple roles in transcription, protein stabilization, nuclear localization, and signal transduction. O-GlcNAcylation is highly dynamic through the action of two enzymes: the O-GlcNAc transferase (OGT), which transfers the monosaccharide to serine/threonine residues on a target protein, and the O-GlcNAcase (OGA), which hydrolyses the sugar. To modulate ChREBP(OG) in vitro and in vivo, the OGT and OGA enzymes were overexpressed or inhibited via adenoviral approaches in mouse hepatocytes and in the liver of C57BL/6J or obese db/db mice. Our study shows that ChREBP interacts with OGT and is subjected to O-GlcNAcylation in liver cells. O-GlcNAcylation stabilizes the ChREBP protein and increases its transcriptional activity toward its target glycolytic (L-PK) and lipogenic genes (ACC, FAS, and SCD1) when combined with an active glucose flux in vivo. Indeed, OGT overexpression significantly increased ChREBP(OG) in liver nuclear extracts from fed C57BL/6J mice, leading in turn to enhanced lipogenic gene expression and to excessive hepatic triglyceride deposition. In the livers of hyperglycemic obese db/db mice, ChREBP(OG) levels were elevated compared with controls. Interestingly, reducing ChREBP(OG) levels via OGA overexpression decreased lipogenic protein content (ACC, FAS), prevented hepatic steatosis, and improved the lipidic profile of OGA-treated db/db mice. Taken together, our results reveal that O

  15. Synergistic Moel of Organizational Structure.

    Science.gov (United States)

    Wolfe, Richard O.

    1985-01-01

    Defines the concept of the synergistic model of organizational structure. The primary components of the model are cooperative action and job integration, which have as a direct result the increased energy in staff members using the model. (MD)

  16. Increased transcription of Glutathione S-transferases in acaricide exposed scabies mites

    Directory of Open Access Journals (Sweden)

    Currie Bart J

    2010-05-01

    Full Text Available Abstract Background Recent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin. Previous findings have implicated detoxification pathways in developing resistance to these acaricides. We investigated the contribution of Glutathione S-transferase (GST enzymes to permethrin and ivermectin tolerance in scabies mites using biochemical and molecular approaches. Results Increased in vitro survival following permethrin exposure was observed in S. scabiei var. hominis compared to acaricide naïve mites (p in vitro permethrin susceptibility, confirming GST involvement in permethrin detoxification. Assay of GST enzymatic activity in mites demonstrated that S. scabiei var. hominis mites showed a two-fold increase in activity compared to naïve mites (p S. scabiei var. canis- mu 1 (p S. scabiei var. hominis mites collected from a recurrent crusted scabies patient over the course of ivermectin treatment. Conclusions These findings provide further support for the hypothesis that increased drug metabolism and efflux mediate permethrin and ivermectin resistance in scabies mites and highlight the threat of emerging acaricide resistance to the treatment of scabies worldwide. This is one of the first attempts to define specific genes involved in GST mediated acaricide resistance at the transcriptional level, and the first application of such studies to S. scabiei, a historically challenging ectoparasite.

  17. Chromatin decondensation is accompanied by a transient increase in transcriptional output.

    Science.gov (United States)

    Vaňková Hausnerová, Viola; Lanctôt, Christian

    2017-01-01

    The levels of chromatin condensation usually correlate inversely with the levels of transcription. The mechanistic links between chromatin condensation and RNA polymerase II activity remain to be elucidated. In the present work, we sought to experimentally determine whether manipulation of chromatin condensation levels can have a direct effect on transcriptional activity. We generated a U-2-OS cell line in which the nascent transcription of a reporter gene could be imaged alongside chromatin compaction levels in living cells. The transcripts were tagged at their 5' end with PP7 stem loops, which can be detected upon expression of a PP7 capsid protein fused to green fluorescent protein. Cycles of global chromatin hypercondensation and decondensation were performed by perfusing culture media of different osmolarities during imaging. We used the fluorescence recovery after photobleaching technique to analyse the transcriptional dynamics in both conditions. Surprisingly, we found that, despite a drop in signal intensity, nascent transcription appeared to continue at the same rate in hypercondensed chromatin. Furthermore, quantification of transcriptional profiles revealed that chromatin decondensation was accompanied by a brief and transient spike in transcriptional output. We propose a model whereby the initiation of transcription is not impaired in condensed chromatin, but inefficient elongation in these conditions leads to the accumulation of RNA polymerase II at the transcription site. Upon chromatin decondensation, release of the RNA polymerase II halt triggers a wave of transcription, which we detect as a transient spike in activity. The results presented here shed light on the activity of RNA polymerase II during chromatin condensation and decondensation. As such, they point to a new level of transcriptional regulation. © 2016 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

  18. Novel glutamate dehydrogenase genes show increased transcript and protein abundances in mature tomato fruits.

    Science.gov (United States)

    Ferraro, Gisela; Bortolotti, Santiago; Mortera, Pablo; Schlereth, Armin; Stitt, Mark; Carrari, Fernando; Kamenetzky, Laura; Valle, Estela M

    2012-06-15

    NAD(P)H-glutamate dehydrogenase (GDH, EC 1.4.1.3) contributes to the control of glutamate homeostasis in all living organisms. In bacteria and animals, GDH is a homohexamer allosterically regulated, whereas in plants NADH-GDH (EC 1.4.1.2) is also found as heterohexamer of α- and β-subunits, but its regulation remains undefined. In tomato (Solanum lycopersicum), GDH activity increases during the fruit ripening along with the content of free glutamate, the most abundant amino acid of ripe fruit involved in conferring the genuine tomato flavour. In this work, novel Slgdh-NAD genes were identified in the recently deciphered tomato genome: three encoding the α-subunit (Slgdh-NAD;A1-3) and one additional gene encoding the β-subunit of GDH (Slgdh-NAD;B1) isolated from a genomic library. These genes are located in different chromosomes. Slgdh-NAD;A1-3 show conserved structures, whereas Slgdh-NAD;B1 includes a novel 5'-untranslated exon. Slgdh-NAD;A1-3 transcripts were detected in all tomato tissues examined, showing the highest levels in mature green fruits, contrasting with Slgdh-NAD;B1 transcripts which were detected mainly in roots or in mature fruits when treated with glutamate, NaCl or salicylic acid. Analyses of GDH activity and protein distribution in different tissues of the Micro-Tom cultivar showed that only the active homohexamer of GDH β-subunits was detected in roots while heterohexamers of GDH α- and β-subunits were found in fruits. These results indicate that GDH β-subunit could modulate the heteromeric isoforms of GDH in response to the environment and physiology of the tomato fruit. This information is relevant to manipulate glutamate contents in tomato fruits genetically. Copyright © 2012 Elsevier GmbH. All rights reserved.

  19. Passive smoking increased risk of gestational diabetes mellitus independently and synergistically with prepregnancy obesity in Tianjin, China.

    Science.gov (United States)

    Leng, Junhong; Wang, Peng; Shao, Ping; Zhang, Cuiping; Li, Weiqin; Li, Nan; Wang, Leishen; Nan, Hairong; Yu, Zhijie; Hu, Gang; Chan, Juliana C N; Yang, Xilin

    2017-03-01

    Passive smoking increased type 2 diabetes mellitus risk, but it is uncertain whether it also increased gestational diabetes mellitus (GDM) risk. We aimed to examine the association of passive smoking during pregnancy and its interaction with maternal obesity for GDM. From 2010 to 2012, 12 786 Chinese women underwent a 50-g 1-hour glucose challenge test at 24 to 28 weeks of gestation and further underwent a 75-g 2-hour oral glucose tolerance test if the glucose challenge test result was ≥7.8 mmol/L. GDM was defined by the International Association of Diabetes and Pregnancy Study Group's cut points. Self-reported passive smoking during pregnancy was collected by a questionnaire. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Additive interaction between maternal obesity and passive smoking was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). Significant RERI > 0, AP > 0, or S > 1 indicated additive interaction. A total of 8331 women (65.2%) were exposed to passive smoking during pregnancy. More women exposed to passive smoking developed GDM than nonexposed women (7.8% versus 6.3%, P = 0.002) with an adjusted OR of 1.29 (95%CI, 1.11 to 1.50). Compared with nonobesity and nonpassive smoking, prepregnancy obesity and passive smoking was associated with GDM risk with an adjusted OR of 3.09 (95%CI, 2.38-4.02) with significant additive interaction (P obesity. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Increased transcription of Glutathione S-transferases in acaricide exposed scabies mites.

    Science.gov (United States)

    Mounsey, Kate E; Pasay, Cielo J; Arlian, Larry G; Morgan, Marjorie S; Holt, Deborah C; Currie, Bart J; Walton, Shelley F; McCarthy, James S

    2010-05-18

    Recent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin. Previous findings have implicated detoxification pathways in developing resistance to these acaricides. We investigated the contribution of Glutathione S-transferase (GST) enzymes to permethrin and ivermectin tolerance in scabies mites using biochemical and molecular approaches. Increased in vitro survival following permethrin exposure was observed in S. scabiei var. hominis compared to acaricide naïve mites (p resistant S. scabiei var. canis- mu 1 (p scabies patient over the course of ivermectin treatment. These findings provide further support for the hypothesis that increased drug metabolism and efflux mediate permethrin and ivermectin resistance in scabies mites and highlight the threat of emerging acaricide resistance to the treatment of scabies worldwide. This is one of the first attempts to define specific genes involved in GST mediated acaricide resistance at the transcriptional level, and the first application of such studies to S. scabiei, a historically challenging ectoparasite.

  1. Post-transcriptional regulation tends to attenuate the mRNA noise and to increase the mRNA gain

    Science.gov (United States)

    Shi, Changhong; Wang, Shuqiang; Zhou, Tianshou; Jiang, Yiguo

    2015-10-01

    Post-transcriptional regulation is ubiquitous in prokaryotic and eukaryotic cells, but how it impacts gene expression remains to be fully explored. Here, we analyze a simple gene model in which we assume that mRNAs are produced in a constitutive manner but are regulated post-transcriptionally by a decapping enzyme that switches between the active state and the inactive state. We derive the analytical mRNA distribution governed by a chemical master equation, which can be well used to analyze the mechanism of how post-transcription regulation influences the mRNA expression level including the mRNA noise. We demonstrate that the mean mRNA level in the stochastic case is always higher than that in the deterministic case due to the stochastic effect of the enzyme, but the size of the increased part depends mainly on the switching rates between two enzyme states. More interesting is that we find that in contrast to transcriptional regulation, post-transcriptional regulation tends to attenuate noise in mRNA. Our results provide insight into the role of post-transcriptional regulation in controlling the transcriptional noise.

  2. Tetrahydrobiopterin, l-Arginine and Vitamin C Act Synergistically to Decrease Oxidative Stress, Increase Nitric Oxide and Improve Blood Flow after Induction of Hindlimb Ischemia in the Rat

    Science.gov (United States)

    Yan, Jinglian; Tie, Guodong; Messina, Louis M

    2012-01-01

    Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is a potent vasodilator and signaling molecule that plays an essential role in vascular remodeling of collateral arteries and perfusion recovery in response to hindlimb ischemia. In ischemic conditions, decreased NO bioavailability was observed because of increased oxidative stress, decreased l-arginine and tetrahy-drobiopterin. This study tested the hypothesis that dietary cosupplementation with tetrahydrobiopterin (BH4), l-arginine, and vitamin C acts synergistically to decrease oxidative stress, increase nitric oxide and improve blood flow in response to acute hindlimb ischemia. Rats were fed normal chow, chow supplemented with BH4 or l-arginine (alone or in combination) or chow supplemented with BH4 + l-arginine + vitamin C for 1 wk before induction of unilateral hindlimb ischemia. Cosupplementation with BH4 + l-arginine resulted in greater eNOS expression, Ca2+-dependent NOS activity and NO concentration in gastrocnemius from the is-chemic hindlimb, as well as greater recovery of foot perfusion and more collateral artery enlargement than did rats receiving either agent separately. The addition of vitamin C to the BH4 + l-arginine regimen did further increase these dependent variables, although only the increase in eNOS expression reached statistical significances. In addition, rats given all three supplements demonstrated significantly less Ca2+-independent activity, less nitrotyrosine accumulation, greater glutathione:glutathione disulfide (GSH:GSSG) ratio and less gastrocnemius muscle necrosis, on both macroscopic and microscopic levels. In conclusion, cosupplementation with BH4 + l-arginine + vitamin C significantly increased vascular perfusion after hindlimb ischemia by increasing eNOS activity and reducing oxidative stress and tissue necrosis. Oral cosupplementation of l-arginine, BH4 and vitamin C holds promise as a biological therapy to induce collateral artery enlargement. PMID

  3. Increased expression of PITX2 transcription factor contributes to ovarian cancer progression.

    Science.gov (United States)

    Fung, Frederic K C; Chan, David W; Liu, Vincent W S; Leung, Thomas H Y; Cheung, Annie N Y; Ngan, Hextan Y S

    2012-01-01

    Paired-like homeodomain 2 (PITX2) is a bicoid homeodomain transcription factor which plays an essential role in maintaining embryonic left-right asymmetry during vertebrate embryogenesis. However, emerging evidence suggests that the aberrant upregulation of PITX2 may be associated with tumor progression, yet the functional role that PITX2 plays in tumorigenesis remains unknown. Using real-time quantitative RT-PCR (Q-PCR), Western blot and immunohistochemical (IHC) analyses, we demonstrated that PITX2 was frequently overexpressed in ovarian cancer samples and cell lines. Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023) and clear cell subtype (P = 0.011) using Q-PCR and high-grade (PPITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect. Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.

  4. Increased expression of PITX2 transcription factor contributes to ovarian cancer progression.

    Directory of Open Access Journals (Sweden)

    Frederic K C Fung

    Full Text Available BACKGROUND: Paired-like homeodomain 2 (PITX2 is a bicoid homeodomain transcription factor which plays an essential role in maintaining embryonic left-right asymmetry during vertebrate embryogenesis. However, emerging evidence suggests that the aberrant upregulation of PITX2 may be associated with tumor progression, yet the functional role that PITX2 plays in tumorigenesis remains unknown. PRINCIPAL FINDINGS: Using real-time quantitative RT-PCR (Q-PCR, Western blot and immunohistochemical (IHC analyses, we demonstrated that PITX2 was frequently overexpressed in ovarian cancer samples and cell lines. Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023 and clear cell subtype (P = 0.011 using Q-PCR and high-grade (P<0.001 ovarian cancer by IHC analysis. Functionally, enforced expression of PITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect. CONCLUSION: Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.

  5. Increased lipid production by heterologous expression of AtWRI1 transcription factor in Nannochloropsis salina.

    Science.gov (United States)

    Kang, Nam Kyu; Kim, Eun Kyung; Kim, Young Uk; Lee, Bongsoo; Jeong, Won-Joong; Jeong, Byeong-Ryool; Chang, Yong Keun

    2017-01-01

    Genetic engineering of microalgae is necessary to produce economically feasible strains for biofuel production. Current efforts are focused on the manipulation of individual metabolic genes, but the outcomes are not sufficiently stable and/or efficient for large-scale production of biofuels and other materials. Transcription factors (TFs) are emerging as good alternatives for engineering of microalgae, not only to increase production of biomaterials but to enhance stress tolerance. Here, we investigated an AP2 type TF Wrinkled1 in Arabidopsis (AtWRI1) known as a key regulator of lipid biosynthesis in plants, and applied it to industrial microalgae, Nannochloropsis salina . We expressed AtWRI1 TF heterologously in N. salina, named NsAtWRI1, in an effort to re-enact its key regulatory function of lipid accumulation. Stable integration AtWRI1 was confirmed by RESDA PCR, and its expression was confirmed by Western blotting using the FLAG tag. Characterizations of transformants revealed that the neutral and total lipid contents were greater in NsAtWRI1 transformants than in WT under both normal and stress conditions from day 8. Especially, total lipid contents were 36.5 and 44.7% higher in NsAtWRI1 2-3 than in WT under normal and osmotic stress condition, respectively. FAME contents of NsAtWRI1 2-3 were also increased compared to WT. As a result, FAME yield of NsAtWRI1 2-3 was increased to 768 mg/L/day, which was 64% higher than that of WT under the normal condition. We identified candidates of AtWRI1-regulated genes by searching for the presence of the AW-box in promoter regions, among which lipid metabolic genes were further analyzed by qRT-PCR. Overall, qRT-PCR results on day 1 indicated that AtWRI1 down-regulated TAGL and DAGK , and up-regulated PPDK , LPL , LPGAT1 , and PDH , resulting in enhanced lipid production in NsAtWRI1 transformants from early growth phase. AtWRI1 TF regulated several genes involved in lipid synthesis in N. salina , resulting in enhancement

  6. Osteoblast-specific transcription factor Osterix increases vitamin D receptor gene expression in osteoblasts.

    Directory of Open Access Journals (Sweden)

    Chi Zhang

    Full Text Available Osterix (Osx is an osteoblast-specific transcription factor required for osteoblast differentiation from mesenchymal stem cells. In Osx knock-out mice, no bone formation occurs. The vitamin D receptor (VDR is a member of the nuclear hormone receptor superfamily that regulates target gene transcription to ensure appropriate control of calcium homeostasis and bone development. Here, we provide several lines of evidence that show that the VDR gene is a target for transcriptional regulation by Osx in osteoblasts. For example, calvaria obtained from Osx-null embryos displayed dramatic reductions in VDR expression compared to wild-type calvaria. Stable overexpression of Osx stimulated VDR expression in C2C12 mesenchymal cells. Inhibition of Osx expression by siRNA led to downregulation of VDR. In contrast, Osx levels remained unchanged in osteoblasts in VDR-null mice. Mechanistic approaches using transient transfection assays showed that Osx directly activated a 1 kb fragment of the VDR promoter in a dose-dependent manner. To define the region of the VDR promoter that was responsive to Osx, a series of VDR promoter deletion mutants were examined and the minimal Osx-responsive region was refined to the proximal 120 bp of the VDR promoter. Additional point mutants were used to identify two GC-rich regions that were responsible for VDR promoter activation by Osx. Chromatin immunoprecipitation assays demonstrated that endogenous Osx was associated with the native VDR promoter in primary osteoblasts in vivo. Cumulatively, these data strongly support a direct regulatory role for Osx in VDR gene expression. They further provide new insight into potential mechanisms and pathways that Osx controls in osteoblasts and during the process of osteoblastic cell differentiation.

  7. Increasing the efficiency of bacterial transcription simulations: When to exclude the genome without loss of accuracy

    Directory of Open Access Journals (Sweden)

    McMillen David R

    2008-09-01

    Full Text Available Abstract Background Simulating the major molecular events inside an Escherichia coli cell can lead to a very large number of reactions that compose its overall behaviour. Not only should the model be accurate, but it is imperative for the experimenter to create an efficient model to obtain the results in a timely fashion. Here, we show that for many parameter regimes, the effect of the host cell genome on the transcription of a gene from a plasmid-borne promoter is negligible, allowing one to simulate the system more efficiently by removing the computational load associated with representing the presence of the rest of the genome. The key parameter is the on-rate of RNAP binding to the promoter (k_on, and we compare the total number of transcripts produced from a plasmid vector generated as a function of this rate constant, for two versions of our gene expression model, one incorporating the host cell genome and one excluding it. By sweeping parameters, we identify the k_on range for which the difference between the genome and no-genome models drops below 5%, over a wide range of doubling times, mRNA degradation rates, plasmid copy numbers, and gene lengths. Results We assess the effect of the simulating the presence of the genome over a four-dimensional parameter space, considering: 24 min Conclusion Exclusion of the genome is shown to yield less than 5% difference in transcript numbers over wide ranges of values, and computational speed is improved by two to 24 times by excluding explicit representation of the genome.

  8. An Increase of Abundance and Transcriptional Activity for Acinetobacter junii Post Wastewater Treatment

    Directory of Open Access Journals (Sweden)

    Muhammad Raihan Jumat

    2018-04-01

    Full Text Available A membrane bioreactor (MBR-based wastewater treatment plant (WWTP in Saudi Arabia is assessed over a five-month period in 2015 and once in 2017 for bacterial diversity and transcriptional activity using metagenomics, metatranscriptomics and real time quantitative polymerase chain reaction (RT-qPCR. Acinetobacter spp. are shown to be enriched in the chlorinated effluent. Members of the Acinetobacter genus are the most abundant in the effluent and chlorinated effluent. At the species level, Acinetobacter junii have higher relative abundances post MBR and chlorination. RNA-seq analysis show that, in A. junii, 288 genes and 378 genes are significantly upregulated in the effluent and chlorinated effluent, respectively, with 98 genes being upregulated in both. RT-qPCR of samples in 2015 and 2017 confirm the upregulation observed in RNA-seq. Analysis of the 98 genes show that majority of the upregulated genes are involved in cellular repair and metabolism followed by resistance, virulence, and signaling. Additionally, two different subpopulations of A. junii are observed in the effluent and chlorinated effluent. The upregulation of cellular repair and metabolism genes, and the formation of different subpopulations of A. junii in both effluents provide insights into the mechanisms employed by A. junii to persist in the conditions of a WWTP.

  9. Transcriptional Slippage and RNA Editing Increase the Diversity of Transcripts in Chloroplasts: Insight from Deep Sequencing of Vigna radiata Genome and Transcriptome.

    Directory of Open Access Journals (Sweden)

    Ching-Ping Lin

    Full Text Available We performed deep sequencing of the nuclear and organellar genomes of three mungbean genotypes: Vigna radiata ssp. sublobata TC1966, V. radiata var. radiata NM92 and the recombinant inbred line RIL59 derived from a cross between TC1966 and NM92. Moreover, we performed deep sequencing of the RIL59 transcriptome to investigate transcript variability. The mungbean chloroplast genome has a quadripartite structure including a pair of inverted repeats separated by two single copy regions. A total of 213 simple sequence repeats were identified in the chloroplast genomes of NM92 and RIL59; 78 single nucleotide variants and nine indels were discovered in comparing the chloroplast genomes of TC1966 and NM92. Analysis of the mungbean chloroplast transcriptome revealed mRNAs that were affected by transcriptional slippage and RNA editing. Transcriptional slippage frequency was positively correlated with the length of simple sequence repeats of the mungbean chloroplast genome (R2=0.9911. In total, 41 C-to-U editing sites were found in 23 chloroplast genes and in one intergenic spacer. No editing site that swapped U to C was found. A combination of bioinformatics and experimental methods revealed that the plastid-encoded RNA polymerase-transcribed genes psbF and ndhA are affected by transcriptional slippage in mungbean and in main lineages of land plants, including three dicots (Glycine max, Brassica rapa, and Nicotiana tabacum, two monocots (Oryza sativa and Zea mays, two gymnosperms (Pinus taeda and Ginkgo biloba and one moss (Physcomitrella patens. Transcript analysis of the rps2 gene showed that transcriptional slippage could affect transcripts at single sequence repeat regions with poly-A runs. It showed that transcriptional slippage together with incomplete RNA editing may cause sequence diversity of transcripts in chloroplasts of land plants.

  10. Geminin deletion increases the number of fetal hematopoietic stem cells by affecting the expression of key transcription factors.

    Science.gov (United States)

    Karamitros, Dimitris; Patmanidi, Alexandra L; Kotantaki, Panoraia; Potocnik, Alexandre J; Bähr-Ivacevic, Tomi; Benes, Vladimir; Lygerou, Zoi; Kioussis, Dimitris; Taraviras, Stavros

    2015-01-01

    Balancing stem cell self-renewal and initiation of lineage specification programs is essential for the development and homeostasis of the hematopoietic system. We have specifically ablated geminin in the developing murine hematopoietic system and observed profound defects in the generation of mature blood cells, leading to embryonic lethality. Hematopoietic stem cells (HSCs) accumulated in the fetal liver following geminin ablation, while committed progenitors were reduced. Genome-wide transcriptome analysis identified key HSC transcription factors as being upregulated upon geminin deletion, revealing a gene network linked with geminin that controls fetal hematopoiesis. In order to obtain mechanistic insight into the ability of geminin to regulate transcription, we examined Hoxa9 as an example of a key gene in definitive hematopoiesis. We demonstrate that in human K562 cells geminin is associated with HOXA9 regulatory elements and its absence increases HOXA9 transcription similarly to that observed in vivo. Moreover, silencing geminin reduced recruitment of the PRC2 component SUZ12 to the HOXA9 locus and resulted in an increase in RNA polymerase II recruitment and H3K4 trimethylation (H3K4me3), whereas the repressive marks H3K9me3 and H3K27me3 were reduced. The chromatin landscape was also modified at the regulatory regions of HOXA10 and GATA1. K562 cells showed a reduced ability to differentiate to erythrocytes and megakaryocytes upon geminin silencing. Our data suggest that geminin is indispensable for fetal hematopoiesis and regulates the generation of a physiological pool of stem and progenitor cells in the fetal hematopoietic system. © 2015. Published by The Company of Biologists Ltd.

  11. Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

    Science.gov (United States)

    Céspedes, Miguel Angel; Galindo, Maximo Ibo; Couso, Juan Pablo

    2010-01-01

    The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function. PMID:21079739

  12. Muscle and neural isoforms of agrin increase utrophin expression in cultured myotubes via a transcriptional regulatory mechanism.

    Science.gov (United States)

    Gramolini, A O; Burton, E A; Tinsley, J M; Ferns, M J; Cartaud, A; Cartaud, J; Davies, K E; Lunde, J A; Jasmin, B J

    1998-01-09

    Duchenne muscular dystrophy is a prevalent X-linked neuromuscular disease for which there is currently no cure. Recently, it was demonstrated in a transgenic mouse model that utrophin could functionally compensate for the lack of dystrophin and alleviate the muscle pathology (Tinsley, J. M., Potter, A. C., Phelps, S. R., Fisher, R., Trickett, J. I., and Davies, K. E. (1996) Nature 384, 349-353). In this context, it thus becomes essential to determine the cellular and molecular mechanisms presiding over utrophin expression in attempts to overexpress the endogenous gene product throughout skeletal muscle fibers. In a recent study, we showed that the nerve exerts a profound influence on utrophin gene expression and postulated that nerve-derived trophic factors mediate the local transcriptional activation of the utrophin gene within nuclei located in the postsynaptic sarcoplasm (Gramolini, A. O., Dennis, C. L., Tinsley, J. M., Robertson, G. S., Davies, K. E, Cartaud, J., and Jasmin, B. J. (1997) J. Biol. Chem. 272, 8117-8120). In the present study, we have therefore focused on the effect of agrin on utrophin expression in cultured C2 myotubes. In response to Torpedo-, muscle-, or nerve-derived agrin, we observed a significant 2-fold increase in utrophin mRNAs. By contrast, CGRP treatment failed to affect expression of utrophin transcripts. Western blotting experiments also revealed that the increase in utrophin mRNAs was accompanied by an increase in the levels of utrophin. To determine whether these changes were caused by parallel increases in the transcriptional activity of the utrophin gene, we transfected muscle cells with a 1. 3-kilobase pair utrophin promoter-reporter (nlsLacZ) gene construct and treated them with agrin for 24-48 h. Under these conditions, both muscle- and nerve-derived agrin increased the activity of beta-galactosidase, indicating that agrin treatment led, directly or indirectly, to the transcriptional activation of the utrophin gene

  13. Increased transcription of Glutathione S-transferases in acaricide exposed scabies mites

    OpenAIRE

    Currie Bart J; Holt Deborah C; Morgan Marjorie S; Arlian Larry G; Pasay Cielo J; Mounsey Kate E; Walton Shelley F; McCarthy James S

    2010-01-01

    Abstract Background Recent evidence suggests that Sarcoptes scabiei var. hominis mites collected from scabies endemic communities in northern Australia show increasing tolerance to 5% permethrin and oral ivermectin. Previous findings have implicated detoxification pathways in developing resistance to these acaricides. We investigated the contribution of Glutathione S-transferase (GST) enzymes to permethrin and ivermectin tolerance in scabies mites using biochemical and molecular approaches. R...

  14. Increasing Malonyl-CoA Derived Product through Controlling the Transcription Regulators of Phospholipid Synthesis in Saccharomyces cerevisiae.

    Science.gov (United States)

    Chen, Xiaoxu; Yang, Xiaoyu; Shen, Yu; Hou, Jin; Bao, Xiaoming

    2017-05-19

    Malonyl-CoA is a precursor of a variety of compounds such as polyketides and flavonoids. In Saccharomyces cerevisiae, malonyl-CoA concentration is tightly regulated and therefore maintained at a very low level, limiting the production of malonyl-CoA-derived chemicals. Here we manipulated the phospholipid synthesis transcriptional regulators to control the malonyl-CoA levels and increase the downstream product. Through manipulating different regulators including Ino2p, Ino4p, Opi1p, and a series of synthetic Ino2p variants, combining with studying the inositol and choline effect, the engineered strain achieved a 9-fold increase of the titer of malonyl-CoA-derived product 3-hydroxypropionic acid, which is among the highest improvement relative to previously reported strategies. Our study provides a new strategy to regulate malonyl-CoA availability and will contribute to the production of other highly valued malonyl-CoA-derived chemicals.

  15. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization.

    Directory of Open Access Journals (Sweden)

    Seung-Beom Hong

    2010-12-01

    Full Text Available Germline mutations in a tumor suppressor gene FLCN lead to development of fibrofolliculomas, lung cysts and renal cell carcinoma (RCC in Birt-Hogg-Dubé syndrome. TFE3 is a member of the MiTF/TFE transcription factor family and Xp11.2 translocations found in sporadic RCC involving TFE3 result in gene fusions and overexpression of chimeric fusion proteins that retain the C-terminal DNA binding domain of TFE3. We found that GPNMB expression, which is regulated by MiTF, was greatly elevated in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Since TFE3 is implicated in RCC, we hypothesized that elevated GPNMB expression was due to increased TFE3 activity resulting from the inactivation of FLCN.TFE3 knockdown reduced GPNMB expression in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Moreover, FLCN knockdown induced GPNMB expression in FLCN-restored renal cancer cells. Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization as revealed by elevated GPNMB mRNA and protein expression, and predominantly nuclear immunostaining of TFE3 in renal cancer cells, mouse embryo fibroblast cells, mouse kidneys and mouse and human renal tumors. Nuclear localization of TFE3 was associated with TFE3 post-translational modifications including decreased phosphorylation.Increased TFE3 activity is a downstream event induced by FLCN inactivation and is likely to be important for renal tumor development. This study provides an important novel mechanism for induction of TFE3 activity in addition to TFE3 overexpression resulting from Xp11.2 translocations, suggesting that TFE3 may be more broadly involved in tumorigenesis.

  16. The Transcriptional Heat Shock Response of Salmonella Typhimurium Shows Hysteresis and Heated Cells Show Increased Resistance to Heat and Acid Stress

    DEFF Research Database (Denmark)

    Pin, C.; Hansen, Trine; Munoz-Cuevas, M.

    2012-01-01

    We investigated if the transcriptional response of Salmonella Typhimurium to temperature and acid variations was hysteretic, i.e. whether the transcriptional regulation caused by environmental stimuli showed memory and remained after the stimuli ceased. The transcriptional activity of non.......e., they remained up-regulated after the environmental stress ceased. At 25uC the transcriptional regulation of genes encoding for heat shock proteins was determined by the previous environment. Gene networks constructed with up-regulated genes were significantly more modular than those of down-regulated genes......H 4.5 were not affected. The exposure to pH 5 only caused up-regulation of 12 genes and this response was neither hysteretic nor accompanied of increased resistance to inactivation conditions. Cellular memory at the transcriptional level may represent a mechanism of adaptation to the environment...

  17. Rhinovirus-bacteria coexposure synergistically induces CCL20 production from human bronchial epithelial cells.

    Science.gov (United States)

    Maciejewski, Barbara A; Jamieson, Kyla C; Arnason, Jason W; Kooi, Cora; Wiehler, Shahina; Traves, Suzanne L; Leigh, Richard; Proud, David

    2017-05-01

    Exacerbations of chronic obstructive pulmonary disease are triggered by viral or bacterial pathogens, with human rhinovirus (HRV) and nontypeable Hemophilus influenzae (NTHI) among the most commonly detected pathogens. Patients who suffer from concomitant viral and bacterial infection have more severe exacerbations. The airway epithelial cell is the initial site of viral and bacterial interactions, and CCL20 is an epithelial chemokine that attracts immature dendritic cells to the airways and can act as an antimicrobial. As such, it contributes to innate and adaptive immune responses to infection. We used primary cultures of human bronchial epithelial cells and the BEAS-2B cell line to examine the effects of bacterial-viral coexposure, as well as each stimulus alone, on epithelial expression of CXCL8 and, in particular, CCL20. HRV-bacterial coexposure induced synergistic production of CXCL8 and CCL20 compared with the sum of each stimulus alone. Synergistic induction of CCL20 did not require viral replication and occurred with two different HRV serotypes that use different viral receptors. Synergy was also seen with either NTHI or Pseudomonas aeruginosa Synergistic induction of CCL20 was transcriptionally regulated. Although NF-κB was required for transcription, it did not regulate synergy, but NF-IL-6 did appear to contribute. Among MAPK inhibitors studied, neither SB203580 nor PD98059 had any effect on synergy, whereas U0126 prevented synergistic induction of CCL20 by HRV and bacteria, apparently via "off-target" effects. Thus bacterial-viral coexposure synergistically increases innate immune responses compared with individual infections. We speculate that this increased inflammatory response leads to worse clinical outcomes. Copyright © 2017 the American Physiological Society.

  18. Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide

    Directory of Open Access Journals (Sweden)

    Li Zheng

    2010-10-01

    Full Text Available Abstract Background Hypoxia-inducible factor-1α (HIF-1α, a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α. Results Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide. Conclusions The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional

  19. Melanogenesis-Inducing Effect of Cirsimaritin through Increases in Microphthalmia-Associated Transcription Factor and Tyrosinase Expression

    Directory of Open Access Journals (Sweden)

    Hyo Jung Kim

    2015-04-01

    Full Text Available The melanin-inducing properties of cirsimaritin were investigated in murine B16F10 cells. Cirsimaritin is an active flavone with methoxy groups, which is isolated from the branches of Lithocarpus dealbatus. Tyrosinase activity and melanin content in murine B16F10 melanoma cells were increased by cirsimaritin in a dose-dependent manner. Western blot analysis revealed that tyrosinase, tyrosinase-related protein (TRP 1, TRP2 protein levels were enhanced after treatment with cirsimaritin for 48 h. Cirsimaritin also upregulated the expression of microphthalmia-associated transcription factor (MITF after 24 h of treatment. Furthermore, cirsimaritin induced phosphorylation of cyclic adenosine monophosphate (cAMP response element-binding protein (CREB in a dose-dependent manner after treatment for 15 min. The cirsimaritin-mediated increase of tyrosinase activity was significantly attenuated by H89, a cAMP-dependent protein kinase A inhibitor. These findings indicate that cirsimaritin stimulates melanogenesis in B16F10 cells by activation of CREB as well as upregulation of MITF and tyrosinase expression, which was activated by cAMP signaling. Finally, the melanogenic effect of cirsimaritin was confirmed in human epidermal melanocytes. These results support the putative application of cirsimaritin in ultraviolet photoprotection and hair coloration treatments.

  20. The Stepwise Increase in the Number of Transcription Factor Families in the Precambrian Predated the Diversification of Plants On Land.

    Science.gov (United States)

    Catarino, Bruno; Hetherington, Alexander J; Emms, David M; Kelly, Steven; Dolan, Liam

    2016-11-01

    The colonization of the land by streptophytes and their subsequent radiation is a major event in Earth history. We report a stepwise increase in the number of transcription factor (TF) families and subfamilies in Archaeplastida before the colonization of the land. The subsequent increase in TF number on land was through duplication within existing TF families and subfamilies. Almost all subfamilies of the Homeodomain (HD) and basic Helix-Loop-Helix (bHLH) had evolved before the radiation of extant land plant lineages from a common ancestor. We demonstrate that the evolution of these TF families independently followed similar trends in both plants and metazoans; almost all extant HD and bHLH subfamilies were present in the first land plants and in the last common ancestor of bilaterians. These findings reveal that the majority of innovation in plant and metazoan TF families occurred in the Precambrian before the Phanerozoic radiation of land plants and metazoans. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Coniferyl Aldehyde Reduces Radiation Damage Through Increased Protein Stability of Heat Shock Transcriptional Factor 1 by Phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seo-Young [Graduate School of Pharmaceutical Sciences, Ewha Women' s University, Seoul (Korea, Republic of); Lee, Hae-June [Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Nam, Joo-Won; Seo, Eun-Kyoung [Graduate School of Pharmaceutical Sciences, Ewha Women' s University, Seoul (Korea, Republic of); Lee, Yun-Sil, E-mail: yslee0425@ewha.ac.kr [Graduate School of Pharmaceutical Sciences, Ewha Women' s University, Seoul (Korea, Republic of)

    2015-03-15

    Purpose: We previously screened natural compounds and found that coniferyl aldehyde (CA) was identified as an inducer of HSF1. In this study, we further examined the protective effects of CA against ionizing radiation (IR) in normal cell system. Methods and Materials: Western blotting and reverse transcription-polymerase chain reaction tests were performed to evaluate expression of HSF1, HSP27, and HSP70 in response to CA. Cell death and cleavage of PARP and caspase-3 were analyzed to determine the protective effects of CA in the presence of IR or taxol. The protective effects of CA were also evaluated using animal models. Results: CA increased stability of the HSF1 protein by phosphorylation at Ser326, which was accompanied by increased expression of HSP27 and HSP70. HSF1 phosphorylation at Ser326 by CA was mediated by EKR1/2 activation. Cotreatment of CA with IR or taxol in normal cells induced protective effects with phosphorylation- dependent patterns at Ser326 of HSF1. The decrease in bone marrow (BM) cellularity and increase of terminal deoxynucleotidyl transferase dUTP nick end labeling–positive BM cells by IR were also significantly inhibited by CA in mice (30.6% and 56.0%, respectively). A549 lung orthotopic lung tumor model indicated that CA did not affect the IR-mediated reduction of lung tumor nodules, whereas CA protected normal lung tissues from the therapeutic irradiation. Conclusions: These results suggest that CA may be useful for inducing HSF1 to protect against normal cell damage after IR or chemotherapeutic agents.

  2. Post-fusion treatment with MG132 increases transcription factor expression in somatic cell nuclear transfer embryos in pigs.

    Science.gov (United States)

    You, Jinyoung; Lee, Joohyeong; Kim, Jinyoung; Park, Junhong; Lee, Eunsong

    2010-02-01

    The objective of this study was to examine the effect of post-fusion treatment of somatic cell nuclear transfer (SCNT) oocytes with the proteasomal inhibitor MG132 on maturation promoting factor (MPF) activity, nuclear remodeling, embryonic development, and gene expression of cloned pig embryos. Immediately after electrofusion, SCNT oocytes were treated with MG132 and/or caffeine for 2 hr, vanadate for 0.5 hr, or vanadate for 0.5 hr followed by MG132 for 1.5 hr. Of the MG132 concentrations tested (0-5 microM), the 1 microM concentration showed a higher rate of blastocyst formation (25.9%) than 0 (14.2%), 0.5 (16.9%), and 5 microM (16.9%). Post-fusion treatment with MG132, caffeine, and both MG132 and caffeine improved blastocyst formation (22.1%, 21.4%, and 24.4%, respectively), whereas vanadate treatment inhibited blastocyst formation (6.5%) compared to the control (11.1%). When examined 2 hr after fusion and 1 hr after activation, MPF activity remained at a higher (P fusion with caffeine and/or MG132, but it was decreased by vanadate. The rate of oocytes showing premature chromosome condensation was not altered by MG132 but was decreased by vanadate treatment. In addition, formation of single pronuclei was increased by MG132 compared to control and vanadate treatment. MG132-treated embryos showed increased expression of POU5F1, DPPA2, DPPA3, DPPA5, and NDP52l1 genes compared to control embryos. Our results demonstrate that post-fusion treatment of SCNT oocytes with MG132 prevents MPF degradation and increases expression of transcription factors in SCNT embryos, which are necessary for normal development of SCNT embryos. (c) 2009 Wiley-Liss, Inc.

  3. Tomato plants increase their tolerance to low temperature in a chilling acclimation process entailing comprehensive transcriptional and metabolic adjustments.

    Science.gov (United States)

    Barrero-Gil, Javier; Huertas, Raúl; Rambla, José Luís; Granell, Antonio; Salinas, Julio

    2016-10-01

    Low temperature is a major environmental stress that seriously compromises plant development, distribution and productivity. Most crops are from tropical origin and, consequently, chilling sensitive. Interestingly, however, some tropical plants, are able to augment their chilling tolerance when previously exposed to suboptimal growth temperatures. Yet, the molecular and physiological mechanisms underlying this adaptive process, termed chilling acclimation, still remain practically unknown. Here, we demonstrate that tomato plants can develop a chilling acclimation response, which includes comprehensive transcriptomic and metabolic adjustments leading to increased chilling tolerance. More important, our results reveal strong resemblances between this response and cold acclimation, the process whereby plants from temperate regions raise their freezing tolerance after exposure to low, non-freezing temperatures. Both chilling and cold acclimation are regulated by a similar set of transcription factors and hormones, and share common defence mechanisms, including the accumulation of compatible solutes, the mobilization of antioxidant systems and the rearrangement of the photosynthetic machinery. Nonetheless, we have found some important divergences that may account for the freezing sensitivity of tomato plants. The data reported in this manuscript should foster new research into the chilling acclimation response with the aim of improving tomato tolerance to low temperature. © 2016 John Wiley & Sons Ltd.

  4. Human Lysozyme Synergistically Enhances Bactericidal Dynamics and Lowers the Resistant Mutant Prevention Concentration for Metronidazole to Helicobacter pylori by Increasing Cell Permeability

    Directory of Open Access Journals (Sweden)

    Xiaolin Zhang

    2016-10-01

    Full Text Available Metronidazole (MNZ is an effective agent that has been employed to eradicate Helicobacter pylori (H. pylori. The emergence of broad MNZ resistance in H. pylori has affected the efficacy of this therapeutic agent. The concentration of MNZ, especially the mutant prevention concentration (MPC, plays an important role in selecting or enriching resistant mutants and regulating therapeutic effects. A strategy to reduce the MPC that can not only effectively treat H. pylori but also prevent resistance mutations is needed. H. pylori is highly resistant to lysozyme. Lysozyme possesses a hydrolytic bacterial cell wall peptidoglycan and a cationic dependent mode. These effects can increase the permeability of bacterial cells and promote antibiotic absorption into bacterial cells. In this study, human lysozyme (hLYS was used to probe its effects on the integrity of the H. pylori outer and inner membranes using as fluorescent probe hydrophobic 1-N-phenyl-naphthylamine (NPN and the release of aspartate aminotransferase. Further studies using a propidium iodide staining method assessed whether hLYS could increase cell permeability and promote cell absorption. Finally, we determined the effects of hLYS on the bactericidal dynamics and MPC of MNZ in H. pylori. Our findings indicate that hLYS could dramatically increase cell permeability, reduce the MPC of MNZ for H. pylori, and enhance its bactericidal dynamic activity, demonstrating that hLYS could reduce the probability of MNZ inducing resistance mutations.

  5. Dietary alleviation of maternal obesity and diabetes: increased resistance to diet-induced obesity transcriptional and epigenetic signatures.

    Directory of Open Access Journals (Sweden)

    Linda Attig

    Full Text Available According to the developmental origins of health and diseases (DOHaD, and in line with the findings of many studies, obesity during pregnancy is clearly a threat to the health and well-being of the offspring, later in adulthood. We previously showed that 20% of male and female inbred mice can cope with the obesogenic effects of a high-fat diet (HFD for 20 weeks after weaning, remaining lean. However the feeding of a control diet (CD to DIO mice during the periconceptional/gestation/lactation period led to a pronounced sex-specific shift (17% to 43% from susceptibility to resistance to HFD, in the female offspring only. Our aim in this study was to determine how, in the context of maternal obesity and T2D, a CD could increase resistance on female fetuses. Transcriptional analyses were carried out with a custom-built mouse liver microarray and by quantitative RT-PCR for muscle and adipose tissue. Both global DNA methylation and levels of pertinent histone marks were assessed by LUMA and western blotting, and the expression of 15 relevant genes encoding chromatin-modifying enzymes was analyzed in tissues presenting global epigenetic changes. Resistance was associated with an enhancement of hepatic pathways protecting against steatosis, the unexpected upregulation of neurotransmission-related genes and the modulation of a vast imprinted gene network. Adipose tissue displayed a pronounced dysregulation of gene expression, with an upregulation of genes involved in lipid storage and adipocyte hypertrophy or hyperplasia in obese mice born to lean and obese mothers, respectively. Global DNA methylation, several histone marks and key epigenetic regulators were also altered. Whether they were themselves lean (resistant or obese (sensitive, the offspring of lean and obese mice clearly differed in terms of several metabolic features and epigenetic marks suggesting that the effects of a HFD depend on the leanness or obesity of the mother.

  6. Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

    NARCIS (Netherlands)

    Loosdregt, J. van; Fleskens, V.; Fu, J.; Brenkman, A.B.; Bekker, C.P.J.; Pals, C.E.G.M.; Meerding, J.; Berkers, C.R.; Barbi, J.; Gröne, A.; Sijts, E.J.A.M.; Maurice, M.M.; Kalkhoven, E.; Prakken, B.J.; Ovaa, H.; Pan, F.; Zaiss, D.M.W.; Coffer, P.J

    2013-01-01

    Stable Foxp3 expression is required for the development of functional regulatory T (Treg) cells. Here, we demonstrate that the expression of the transcription factor Foxp3 can be regulated through the polyubiquitination of multiple lysine residues, resulting in proteasome-mediated degradation.

  7. Microsomal Triglyceride Transfer Protein Inhibition Induces Endoplasmic Reticulum Stress and Increases Gene Transcription via Ire1α/cJun to Enhance Plasma ALT/AST*

    Science.gov (United States)

    Josekutty, Joby; Iqbal, Jahangir; Iwawaki, Takao; Kohno, Kenji; Hussain, M. Mahmood

    2013-01-01

    Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival. PMID:23532846

  8. Microsomal triglyceride transfer protein inhibition induces endoplasmic reticulum stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST.

    Science.gov (United States)

    Josekutty, Joby; Iqbal, Jahangir; Iwawaki, Takao; Kohno, Kenji; Hussain, M Mahmood

    2013-05-17

    Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.

  9. Comparative Analysis of Muscle Hypertrophy Models Reveals Divergent Gene Transcription Profiles and Points to Translational Regulation of Muscle Growth through Increased mTOR Signaling

    Directory of Open Access Journals (Sweden)

    Marcelo G. Pereira

    2017-12-01

    Full Text Available Skeletal muscle mass is a result of the balance between protein breakdown and protein synthesis. It has been shown that multiple conditions of muscle atrophy are characterized by the common regulation of a specific set of genes, termed atrogenes. It is not known whether various models of muscle hypertrophy are similarly regulated by a common transcriptional program. Here, we characterized gene expression changes in three different conditions of muscle growth, examining each condition during acute and chronic phases. Specifically, we compared the transcriptome of Extensor Digitorum Longus (EDL muscles collected (1 during the rapid phase of postnatal growth at 2 and 4 weeks of age, (2 24 h or 3 weeks after constitutive activation of AKT, and (3 24 h or 3 weeks after overload hypertrophy caused by tenotomy of the Tibialis Anterior muscle. We observed an important overlap between significantly regulated genes when comparing each single condition at the two different timepoints. Furthermore, examining the transcriptional changes occurring 24 h after a hypertrophic stimulus, we identify an important role for genes linked to a stress response, despite the absence of muscle damage in the AKT model. However, when we compared all different growth conditions, we did not find a common transcriptional fingerprint. On the other hand, all conditions showed a marked increase in mTORC1 signaling and increased ribosome biogenesis, suggesting that muscle growth is characterized more by translational, than transcriptional regulation.

  10. Increased IL17A, IFNG, and FOXP3 Transcripts in Moderate-Severe Psoriasis: A Major Influence Exerted by IL17A in Disease Severity

    Directory of Open Access Journals (Sweden)

    Priscilla Stela Santana de Oliveira

    2016-01-01

    Full Text Available Psoriasis is a chronic and recurrent dermatitis, mediated by keratinocytes and T cells. Several proinflammatory cytokines contribute to formation and maintenance of psoriatic plaque. The Th1/Th17 pathways and some of IL-1 family members were involved in psoriasis pathogenesis and could contribute to disease activity. Therefore, we sought to analyse skin transcript levels of IL17A, IL22, RORC, IL8, IFNG, IL33, IL36A, FOXP3, and IL10 and correlate with clinic of patients with plaque-type psoriasis. In order to conduct that, we collected punch biopsies from lesional skin and obtained tissue RNA. After reverse transcription, qRT-PCR quantified the relative mRNA expression. The main results revealed increased transcripts levels of IL17A, IFNG, and FOXP3 in moderate-severe patients. Despite this, only IL17A can increase the chance to worsen disease severity. We also observed many significant positive correlations between each transcript. In conclusion, IL17A is elevated in lesional skin from psoriasis patients and plays crucial role in disease severity.

  11. Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation?

    Directory of Open Access Journals (Sweden)

    Schlumberger Martin

    2002-12-01

    Full Text Available Abstract Background Sodium/iodide symporter (NIS is a key protein in iodide transport by thyroid cells and this activity is a prerequisite for effective radioiodide treatment of thyroid cancer. In the majority of thyroid cancers, however, iodide uptake is reduced, probably as a result of decreased NIS protein expression. Methods To identify the mechanisms that negatively affect NIS expression in thyroid tumors, we performed electrophoresis mobility shift assays and immunoblot analysis of nuclear protein extracts from normal and tumoral thyroid tissues from 14 unrelated patients. Results Two proteins closely related to the transcription factors AP2 and Sp1 were identified in the nuclear extracts. Expression of both AP2 and Sp1 in nuclear extracts from thyroid tumors was significantly higher than that observed in corresponding normal tissues. Conclusion These observations raise the possibility that NIS expression, and subsequently iodide transport, are reduced in thyroid tumors at least in part owing to alterations in the binding activity of AP2 and Sp1 transcription factors to NIS promoter.

  12. The Vitamin E Analog Gamma-Tocotrienol (GT3 and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM

    Directory of Open Access Journals (Sweden)

    Rupak Pathak

    2016-11-01

    Full Text Available Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR and strongly induce endothelial thrombomodulin (TM; which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member gamma-tocotrienol (GT3 also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC generation assay. Expression of Kruppel-like factor 2 (KLF2, one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR. TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2 expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases.

  13. A Mutation in a Saccharomyces Cerevisiae Gene (Rad3) Required for Nucleotide Excision Repair and Transcription Increases the Efficiency of Mismatch Correction

    OpenAIRE

    Yang, Y.; Johnson, A. L.; Johnston, L. H.; Siede, W.; Friedberg, E. C.; Ramachandran, K.; Kunz, B. A.

    1996-01-01

    RAD3 functions in DNA repair and transcription in Saccharomyces cerevisiae and particular rad3 alleles confer a mutator phenotype, possibly as a consequence of defective mismatch correction. We assessed the potential involvement of the Rad3 protein in mismatch correction by comparing heteroduplex repair in isogenic rad3-1 and wild-type strains. The rad3-1 allele increased the spontaneous mutation rate but did not prevent heteroduplex repair or bias its directionality. Instead, the efficiency ...

  14. Brassinosteroids-Induced Systemic Stress Tolerance was Associated with Increased Transcripts of Several Defence-Related Genes in the Phloem in Cucumis sativus.

    Directory of Open Access Journals (Sweden)

    Pingfang Li

    Full Text Available Brassinosteroids (BRs, a group of naturally occurring plant steroidal compounds, are essential for plant growth, development and stress tolerance. Recent studies showed that BRs could induce systemic tolerance to biotic and abiotic stresses; however, the molecular mechanisms by which BRs signals lead to responses in the whole plant are largely unknown. In this study, 24-epibrassinosteroid (EBR-induced systemic tolerance in Cucumis sativus L. cv. Jinyan No. 4 was analyzed through the assessment of symptoms of photooxidative stress by chlorophyll fluorescence imaging pulse amplitude modulation. Expression of defense/stress related genes were induced in both treated local leaves and untreated systemic leaves by local EBR application. With the suppressive subtractive hybridization (SSH library using cDNA from the phloem sap of EBR-treated plants as the tester and distilled water (DW-treated plants as the driver, 14 transcripts out of 260 clones were identified. Quantitative Real Time-Polymerase Chain Reaction (RT-qPCR validated the specific up-regulation of these transcripts. Of the differentially expressed transcripts with known functions, transcripts for the selected four cDNAs, which encode an auxin-responsive protein (IAA14, a putative ankyrin-repeat protein, an F-box protein (PP2, and a major latex, pathogenesis-related (MLP-like protein, were induced in local leaves, systemic leaves and roots after foliar application of EBR onto mature leaves. Our results demonstrated that EBR-induced systemic tolerance is accompanied with increased transcript of genes in the defense response in other organs. The potential role of phloem mRNAs as signaling components in mediating BR-regulated systemic resistance is discussed.

  15. Transformation of SV40-immortalized human uroepithelial cells by 3-methylcholanthrene increases IFN- and Large T Antigen-induced transcripts

    Directory of Open Access Journals (Sweden)

    Easton Marilyn J

    2010-02-01

    Full Text Available Abstract Background Simian Virus 40 (SV40 immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC or SV40-immortalized and then 3-MC-transformed (HUC-TC. Results To characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag expression-related changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in IFP 9-27, 2'-5' OAS, IF 56, MxA and MxAB were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-γ and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in both cell types. We conclude that IFN-γ metabolic responses were functional in both cell lines, but IFN-γ anti-proliferative responses functioned only in tumor cells. Conclusions Synergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon.

  16. Curcumin synergistically increases effects of β-interferon and retinoic acid on breast cancer cells in vitro and in vivo by up-regulation of GRIM-19 through STAT3-dependent and STAT3-independent pathways.

    Science.gov (United States)

    Ren, Min; Wang, Ying; Wu, Xiaodong; Ge, Suxia; Wang, Benzhong

    2017-03-01

    The study aimed to investigate the effects of combination treatment of curcumin and β-interferon (IFN-β)/retinoic acid (RA) on breast cancer cells, including cell viability, apoptosis and migration, and to determine the mechanisms related to GRIM-19 through STAT3-dependent and STAT3-independent pathways. The following groups were used for the in vitro experiment: control siRNA, GRIM-19 siRNA, IFN-β/RA and IFN-β/RA + curcumin. Cell viability is by the MTT method, cell apoptosis by flow cytometry and cell migration by wound healing experiment; GRIM-19, STAT3, survivin, Bcl-2, GADD153 and COX-2 expression was measured by Western blot. In vivo experiment, MCF-7 cells were subcutaneously injected into nude mice. GRIM-19 siRNA promoted MCF-7 cell proliferation and migration; inhibited cell apoptosis; and promoted the expression of STAT3, survivin, Bcl-2 and MMP-9. IFN-β/RA inhibited cell proliferation and migration; promoted cell apoptosis; up-regulated GRIM-19; and inhibited the expression of STAT3, survivin, Bcl-2 and MMP-9. Combination treatment of curcumin and IFN-β/RA had a stronger effect than that of the IFN-β/RA group. In addition, curcumin and IFN-β/RA combination inhibited the expression of COX-2 and up-regulated GADD153. Curcumin synergistically increases the effects of IFN-β/RA on breast cancer cells. The mechanism may be related to the up-regulation of GRIM-19 through STAT3-dependent and STAT3-independent pathways.

  17. The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA.

    Science.gov (United States)

    Harford, Terri J; Kliment, Greg; Shukla, Girish C; Weyman, Crystal M

    2017-12-01

    The muscle regulatory transcription factor MyoD is a master regulator of skeletal myoblast differentiation. We have previously reported that MyoD is also necessary for the elevated expression of the pro-apoptotic Bcl2 family member PUMA, and the ensuing apoptosis, that occurs in a subset of myoblasts induced to differentiate. Herein, we report the identification of a functional MyoD binding site within the extended PUMA promoter. In silico analysis of the murine PUMA extended promoter revealed three potential MyoD binding sites within 2 kb of the transcription start site. Expression from a luciferase reporter construct containing this 2 kb fragment was enhanced by activation of MyoD in both myoblasts and fibroblasts and diminished by silencing of MyoD in myoblasts. Experiments utilizing truncated versions of this promoter region revealed that the potential binding site at position - 857 was necessary for expression. Chromatin immunoprecipitation (ChIP) analysis confirmed binding of MyoD to the DNA region encompassing position - 857. The increase in MyoD binding to the PUMA promoter as a consequence of culture in differentiation media (DM) was comparable to the increase in MyoD binding at the myogenin promoter and was diminished in myoblasts silenced for MyoD expression. Finally, ChIP analysis using an antibody specific for the transcription factor p53 demonstrated that, in myoblasts silenced for MyoD expression, p53 binding to the PUMA promoter was diminished in response to culture in DM. These data indicate that MyoD plays a direct role in regulating PUMA expression and reveal functional consequences of MyoD expression on p53 mediated transcription of PUMA.

  18. Stimulation of B-Raf increases c-Jun and c-Fos expression and upregulates AP-1-regulated gene transcription in insulinoma cells.

    Science.gov (United States)

    Langfermann, Daniel S; Rössler, Oliver G; Thiel, Gerald

    2017-12-08

    Stimulation of pancreatic β-cells with glucose activates the protein kinases B-Raf and extracellular signal-regulated protein kinase that participate in glucose sensing. Inhibition of both kinases results in impairment of glucose-regulated gene transcription. To analyze the signaling pathway controlled by B-Raf, we expressed a conditionally active form of B-Raf in INS-1 insulinoma cells. Here, we show that stimulation of B-Raf strongly activated the transcription factor AP-1 which is accompanied by increased c-Jun and c-Fos promoter activities, an upregulation of c-Jun and c-Fos biosynthesis, and elevated transcriptional activation potentials of c-Jun and c-Fos. Mutational analysis identified the AP-1 sites within the c-Jun promoter and the serum response element (SRE) within the c-Fos promoter as the essential genetic elements connecting B-Raf stimulation with AP-1 activation. In line with this, the transcriptional activation potential of the SRE-binding protein Elk-1 was increased following B-Raf activation. The signal pathway from B-Raf to AP-1 required the activation of c-Jun. We identified the cyclin D1 gene as a delayed response gene for AP-1 following stimulation of B-Raf in insulinoma cells. Moreover, MAP kinase phosphatase-1 and the Ca 2+ /calmodulin-dependent protein phosphatase calcineurin were identified to function as shut-off-devices for the signaling cascade connecting B-Raf stimulation with the activation of AP-1. The fact that stimulation with glucose, activation of L-type voltage-gated Ca 2+ channels, and stimulation of B-Raf all trigger an activation of AP-1 indicates that AP-1 is a point of convergence of signaling pathways in β-cell. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Isoxanthohumol, a constituent of hop (Humulus lupulus L.), increases stress resistance in Caenorhabditis elegans dependent on the transcription factor DAF-16.

    Science.gov (United States)

    Büchter, Christian; Havermann, Susannah; Koch, Karoline; Wätjen, Wim

    2016-02-01

    The flavanone isoxanthohumol (IX) has gained attention as antioxidative and chemopreventive agent, but the molecular mechanism of action remains unclear. We investigated effects of this secondary plant compound in vivo using the model organism Caenorhabditis elegans. Adult C. elegans nematodes were incubated with IX, and then, the stress resistance was analysed in the SYTOX assay; lifespan was monitored by touch-provoked movement method, the amount of reactive oxygen species (ROS) was measured in the DCF assay, and the nuclear localisation of the transcription factor DAF-16 was analysed by using a transgenic strain. By the use of a DAF-16 loss-of-function strain, we analysed whether the effects are dependent on DAF-16. IX increases the resistance of the nematode against thermal stress. Additionally, a reduction in ROS in vivo was caused by IX. Since the flavanone only has a marginal radical-scavenging capacity (TEAC assay), we suggest that IX mediates its antioxidative effects indirectly via activation of DAF-16 (homologue to mammalian FOXO proteins). The nuclear translocation of this transcription factor is increased by IX. In the DAF-16-mutated strain, the IX-mediated increase in stress resistance was completely abolished; furthermore, an increased formation of ROS and a reduced lifespan was mediated by IX. IX or a bacterial metabolite of IX causes antioxidative effects as well as an increased stress resistance in C. elegans via activation of DAF-16. The homologous pathway may have implications in the molecular mechanism of IX in mammals.

  20. NF1, Sp1 and HSF1 are synergistically involved in sulfide-induced sqr activation in echiuran worm Urechis unicinctus

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiaolong; Qin, Zhenkui; Li, Xueyu; Ma, Xiaoyu; Gao, Beibei; Zhang, Zhifeng, E-mail: zzfp107@ouc.edu.cn

    2016-06-15

    Highlights: • Sulfide activates sqr transcription against respiratory toxicity in Urechis unicinctus. • Sulfide increases expressions and activities of NF1, Sp1 and HSF1 in a time-dependent manner. • NF1 and Sp1 participate in both basal and early sulfide-induced sqr transcription. • HSF1 functions more significantly than NF1 and Sp1 in sulfide-induced sqr transcription. • Transcription factors NF1, Sp1 and HSF1 enhance sqr promoter activity synergistically. - Abstract: Background: Sulfide is a well-known environmental toxic substance. Mitochondrial sulfide oxidation is a main mechanism of sulfide detoxification in organisms, and sulfide: quinone oxidoreductase (SQR) is a key enzyme which is involved in transferring electrons from sulfide to ubiquinone and converting sulfide into thiosulfate. Previous studies have revealed the SQR-mediated mitochondrial sulfide oxidation exists in the echiuran worm Urechis unicinctus, and its sqr mRNA level increased significantly when the worm is exposed to sulfide. In this study, we attempt to reveal the synergistic regulation of transcription factors on sulfide-induced sqr transcription in U. unicinctus. Methods: ChIP and EMSA were used to identify the interactions between sqr proximal promoter (from −391 to +194 bp) and transcription factors NF1 (nuclear factor 1) and Sp1 (specificity protein 1). Site-directed mutation and transfection assays further revealed their binding sites and synergistic roles of HSF1, NF1 and Sp1 in the sqr transcription. When U. unicinctus were exposed to 150 μM sulfide, the expression levels and nuclear contents of NF1 and Sp1 were examined by Western blotting, and the binding contents between NF1 or Sp1 and the sqr promoter were also detected by ChIP. Results: Transcription factors NF1 and Sp1 were confirmed to interact with the sqr proximal promoter, and their binding sites were identified in −75 to −69 bp for NF1 and −210 to −201 bp for Sp1. Transfection assays showed mutation

  1. The Dietary Constituent Falcarindiol Promotes Cholesterol Efflux from THP-1 Macrophages by Increasing ABCA1 Gene Transcription and Protein Stability

    OpenAIRE

    Wang, Limei; Palme, Veronika; Schilcher, Nicole; Ladurner, Angela; Heiss, Elke H.; Stangl, Herbert; Bauer, Rudolf; Dirsch, Verena M.; Atanasov, Atanas G.

    2017-01-01

    We report increased cholesterol efflux from macrophages in the presence of falcarindiol, an important dietary constituent present in commonly used vegetables and medicinal plants. Falcarindiol (3–20 μM) increased cholesterol efflux from THP-1-derived macrophages. Western blot analysis showed an increased protein level of ABCA1 upon falcarindiol exposure. Quantitative real-time PCR revealed that also ABCA1 mRNA level rise with falcarindiol (10 μM) treatment. The effect of falcarindiol on ABCA1...

  2. The LIM Homeodomain Transcription Factor LHX6

    Science.gov (United States)

    Zhang, Zichao; Gutierrez, Diana; Li, Xiao; Bidlack, Felicitas; Cao, Huojun; Wang, Jianbo; Andrade, Kelsey; Margolis, Henry C.; Amendt, Brad A.

    2013-01-01

    LHX6 is a LIM-homeobox transcription factor expressed during embryogenesis; however, the molecular mechanisms regulating LHX6 transcriptional activities are unknown. LHX6 and the PITX2 homeodomain transcription factor have overlapping expression patterns during tooth and craniofacial development, and in this report, we demonstrate new transcriptional mechanisms for these factors. PITX2 and LHX6 are co-expressed in the oral and dental epithelium and epithelial cell lines. Lhx6 expression is increased in Pitx2c transgenic mice and decreased in Pitx2 null mice. PITX2 activates endogenous Lhx6 expression and the Lhx6 promoter, whereas LHX6 represses its promoter activity. Chromatin immunoprecipitation experiments reveal endogenous PITX2 binding to the Lhx6 promoter. LHX6 directly interacts with PITX2 to inhibit PITX2 transcriptional activities and activation of multiple promoters. Bimolecular fluorescence complementation assays reveal an LHX6·PITX2 nuclear interaction in living cells. LHX6 has a dominant repressive effect on the PITX2 synergistic activation with LEF-1 and β-catenin co-factors. Thus, LHX6 acts as a transcriptional repressor and represses the expression of several genes involved in odontogenesis. We have identified specific defects in incisor, molar, mandible, bone, and root development and late stage enamel formation in Lhx6 null mice. Amelogenin and ameloblastin expression is reduced and/or delayed in the Lhx6 null mice, potentially resulting from defects in dentin deposition and ameloblast differentiation. Our results demonstrate that LHX6 regulates cell proliferation in the cervical loop and promotes cell differentiation in the anterior region of the incisor. We demonstrate new molecular mechanisms for LHX6 and an interaction with PITX2 for normal craniofacial and tooth development. PMID:23229549

  3. Multiple circadian transcriptional elements cooperatively regulate cell-autonomous transcriptional oscillation ofPeriod3, a mammalian clock gene.

    Science.gov (United States)

    Matsumura, Ritsuko; Akashi, Makoto

    2017-09-29

    Cell-autonomous oscillation in clock gene expression drives circadian rhythms. The development of comprehensive analytical techniques, such as bioinformatics and ChIP-sequencing, has enabled the genome-wide identification of potential circadian transcriptional elements that regulate the transcriptional oscillation of clock genes. However, detailed analyses using traditional biochemical and molecular-biological approaches, such as binding and reporter assays, are still necessary to determine whether these potential circadian transcriptional elements are actually functional and how significantly they contribute to driving transcriptional oscillation. Here, we focused on the molecular mechanism of transcriptional oscillations in the mammalian clock gene Period3 ( Per3 ). The PER3 protein is essential for robust peripheral clocks and is a key component in circadian output processes. We found three E box-like elements located upstream of human Per3 transcription start sites that additively contributed to cell-autonomous transcriptional oscillation. However, we also found that Per3 is still expressed in a circadian manner when all three E box-like elements are functionally impaired. We noted that Per3 transcription was activated by the synergistic actions of two D box-like elements and the three E box-like elements, leading to a drastic increase in circadian amplitude. Interestingly, circadian expression of Per3 was completely disrupted only when all five transcriptional elements were functionally impaired. These results indicate that three E box-like and two D box-like elements cooperatively and redundantly regulate cell-autonomous transcriptional oscillation of Per3 . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. The Dietary Constituent Falcarindiol Promotes Cholesterol Efflux from THP-1 Macrophages by Increasing ABCA1 Gene Transcription and Protein Stability

    Directory of Open Access Journals (Sweden)

    Limei Wang

    2017-09-01

    Full Text Available We report increased cholesterol efflux from macrophages in the presence of falcarindiol, an important dietary constituent present in commonly used vegetables and medicinal plants. Falcarindiol (3–20 μM increased cholesterol efflux from THP-1-derived macrophages. Western blot analysis showed an increased protein level of ABCA1 upon falcarindiol exposure. Quantitative real-time PCR revealed that also ABCA1 mRNA level rise with falcarindiol (10 μM treatment. The effect of falcarindiol on ABCA1 protein as well as mRNA level were counteracted by co-treatment with BADGE, an antagonist of PPARγ. Furthermore, falcarindiol significantly inhibited ABCA1 protein degradation in the presence of cycloheximide. This post-translational regulation of ABCA1 by falcarindiol occurs most likely by inhibition of lysosomal cathepsins, resulting in decreased proteolysis and extended protein half-life of ABCA1. Taken together, falcarindiol increases ABCA1 protein level by two complementary mechanisms, i.e., promoting ABCA1 gene expression and inhibiting ABCA1 protein degradation, which lead to enhanced cholesterol efflux.

  5. The Dietary Constituent Falcarindiol Promotes Cholesterol Efflux from THP-1 Macrophages by Increasing ABCA1 Gene Transcription and Protein Stability.

    Science.gov (United States)

    Wang, Limei; Palme, Veronika; Schilcher, Nicole; Ladurner, Angela; Heiss, Elke H; Stangl, Herbert; Bauer, Rudolf; Dirsch, Verena M; Atanasov, Atanas G

    2017-01-01

    We report increased cholesterol efflux from macrophages in the presence of falcarindiol, an important dietary constituent present in commonly used vegetables and medicinal plants. Falcarindiol (3-20 μM) increased cholesterol efflux from THP-1-derived macrophages. Western blot analysis showed an increased protein level of ABCA1 upon falcarindiol exposure. Quantitative real-time PCR revealed that also ABCA1 mRNA level rise with falcarindiol (10 μM) treatment. The effect of falcarindiol on ABCA1 protein as well as mRNA level were counteracted by co-treatment with BADGE, an antagonist of PPARγ. Furthermore, falcarindiol significantly inhibited ABCA1 protein degradation in the presence of cycloheximide. This post-translational regulation of ABCA1 by falcarindiol occurs most likely by inhibition of lysosomal cathepsins, resulting in decreased proteolysis and extended protein half-life of ABCA1. Taken together, falcarindiol increases ABCA1 protein level by two complementary mechanisms, i.e., promoting ABCA1 gene expression and inhibiting ABCA1 protein degradation, which lead to enhanced cholesterol efflux.

  6. Decreased transcription-coupled nucleotide excision repair capacity is associated with increased p53- and MLH1-independent apoptosis in response to cisplatin

    International Nuclear Information System (INIS)

    Stubbert, Lawton J; Smith, Jennifer M; McKay, Bruce C

    2010-01-01

    One of the most commonly used classes of anti-cancer drugs presently in clinical practice is the platinum-based drugs, including cisplatin. The efficacy of cisplatin therapy is often limited by the emergence of resistant tumours following treatment. Cisplatin resistance is multi-factorial but can be associated with increased DNA repair capacity, mutations in p53 or loss of DNA mismatch repair capacity. RNA interference (RNAi) was used to reduce the transcription-coupled nucleotide excision repair (TC-NER) capacity of several prostate and colorectal carcinoma cell lines with specific defects in p53 and/or DNA mismatch repair. The effect of small inhibitory RNAs designed to target the CSB (Cockayne syndrome group B) transcript on TC-NER and the sensitivity of cells to cisplatin-induced apoptosis was determined. These prostate and colon cancer cell lines were initially TC-NER proficient and RNAi against CSB significantly reduced their DNA repair capacity. Decreased TC-NER capacity was associated with an increase in the sensitivity of tumour cells to cisplatin-induced apoptosis, even in p53 null and DNA mismatch repair-deficient cell lines. The present work indicates that CSB and TC-NER play a prominent role in determining the sensitivity of tumour cells to cisplatin even in the absence of p53 and DNA mismatch repair. These results further suggest that CSB represents a potential target for cancer therapy that may be important to overcome resistance to cisplatin in the clinic

  7. The Neurogenic Basic Helix-Loop-Helix Transcription Factor NeuroD6 Concomitantly Increases Mitochondrial mass and Regulates Cytoskeletal Organization in the Early Stages of Neuronal Differentiation

    Directory of Open Access Journals (Sweden)

    Kristin Kathleen Baxter

    2009-08-01

    Full Text Available Mitochondria play a central role during neurogenesis by providing energy in the form of ATP for cytoskeletal remodelling, outgrowth of neuronal processes, growth cone activity and synaptic activity. However, the fundamental question of how differentiating neurons control mitochondrial biogenesis remains vastly unexplored. Since our previous studies have shown that the neurogenic bHLH (basic helix–loop–helix transcription factor NeuroD6 is sufficient to induce differentiation of the neuronal progenitor-like PC12 cells and that it triggers expression of mitochondrial-related genes, we investigated whether NeuroD6 could modulate the mitochondrial biomass using our PC12-ND6 cellular paradigm. Using a combination of flow cytometry, confocal microscopy and mitochondrial fractionation, we demonstrate that NeuroD6 stimulates maximal mitochondrial mass at the lamellipodia stage, thus preceding axonal growth. NeuroD6 triggers remodelling of the actin and microtubule networks in conjunction with increased expression of the motor protein KIF5B, thus promoting mitochondrial movement in developing neurites with accumulation in growth cones. Maintenance of the NeuroD6-induced mitochondrial mass requires an intact cytoskeletal network, as its disruption severely reduces mitochondrial mass. The present study provides the first evidence that NeuroD6 plays an integrative role in co-ordinating increase in mitochondrial mass with cytoskeletal remodelling, suggestive of a role of this transcription factor as a co-regulator of neuronal differentiation and energy metabolism.

  8. Rice and Bean Targets for Biofortification Combined with High Carotenoid Content Crops Regulate Transcriptional Mechanisms Increasing Iron Bioavailability

    Directory of Open Access Journals (Sweden)

    Desirrê Morais Dias

    2015-11-01

    Full Text Available Iron deficiency affects thousands of people worldwide. Biofortification of staple food crops aims to support the reduction of this deficiency. This study evaluates the effect of combinations of common beans and rice, targets for biofortification, with high carotenoid content crops on the iron bioavailability, protein gene expression, and antioxidant effect. Iron bioavailability was measured by the depletion/repletion method. Seven groups were tested (n = 7: Pontal bean (PB; rice + Pontal bean (R + BP; Pontal bean + sweet potato (PB + SP; Pontal bean + pumpkin (PB + P; Pontal bean + rice + sweet potato (PB + R + P; Pontal bean + rice + sweet potato (PB + R + SP; positive control (Ferrous Sulfate. The evaluations included: hemoglobin gain, hemoglobin regeneration efficiency (HRE, gene expression of divalente metal transporter 1 (DMT-1, duodenal citocromo B (DcytB, ferroportin, hephaestin, transferrin and ferritin and total plasma antioxidant capacity (TAC. The test groups, except the PB, showed higher HRE (p < 0.05 than the control. Gene expression of DMT-1, DcytB and ferroportin increased (p < 0.05 in the groups fed with high content carotenoid crops (sweet potato or pumpkin. The PB group presented lower (p < 0.05 TAC than the other groups. The combination of rice and common beans, and those with high carotenoid content crops increased protein gene expression, increasing the iron bioavailability and antioxidant capacity.

  9. VrDREB2A, a DREB-binding transcription factor from Vigna radiata, increased drought and high-salt tolerance in transgenic Arabidopsis thaliana.

    Science.gov (United States)

    Chen, Honglin; Liu, Liping; Wang, Lixia; Wang, Suhua; Cheng, Xuzhen

    2016-03-01

    Mung bean (Vigna radiata L.) is commonly grown in Asia as an important nutritional dry grain legume, as it can survive better in arid conditions than other crops. Abiotic stresses, such as drought and high-salt contents, negatively impact its growth and production. The dehydration-responsive element-binding protein 2 (DREB2) transcription factors play a significant role in the response to these stress stimuli via transcriptional regulation of downstream genes containing the cis-element dehydration-responsive element (DRE). However, the molecular mechanisms involved in the drought tolerance of this species remain elusive, with very few reported candidate genes. No DREB2 ortholog has been reported for mung bean, and the function of mung bean DREB2 is not clear. In this study, a novel VrDREB2A gene with conserved AP2 domains and transactivation ability was isolated from mung bean. A modified VrDREB2A protein lacking the putative negative regulatory domain encoded by nucleotides 394-543 was shown to be localized in the nucleus. Expression of the VrDREB2A gene was induced by drought, high salt concentrations and abscisic acid treatment. Furthermore, comparing with the wild type Arabidopsis, the overexpression of VrDREB2A activated the expression of downstream genes in transgenic Arabidopsis, resulting in enhanced tolerance to drought and high-salt stresses and no growth retardation. The results from this study indicate that VrDREB2A functions as an important transcriptional activator and may help increase the abiotic stress tolerance of the mung bean plant.

  10. The Transcription Factor DAF-16 is Essential for Increased Longevity in C. elegans Exposed to Bifidobacterium longum BB68.

    Science.gov (United States)

    Zhao, Liang; Zhao, Yang; Liu, Ruihai; Zheng, Xiaonan; Zhang, Min; Guo, Huiyuan; Zhang, Hao; Ren, Fazheng

    2017-08-07

    The longevity-promoting benefits of lactobacilli were hypothesized as early as 1907. Although the anti-aging effects of lactic acid bacteria (LAB) have been observed in nematodes, rodents and humans for over a century, the mechanisms underlying the effects of probiotics on aging have rarely been assessed. Using the Caenorhabditis elegans (C. elegans) model, various studies have elucidated the role of different signaling cascades, especially the DAF-16 cascade, on lifespan extension by LAB. In this study, the mechanisms through which Bifidobacterium longum strain BB68 affects the longevity of C. elegans were assessed. The lifespan of nematodes increased by 28% after worms were fed BB68, and this extension of lifespan was completely lost in backgrounds containing a mutated DAF-16 gene. High levels of DAF-16 (in the daf-16 (mu86); muIs61 strain) nuclear accumulation and high expression of the SOD-3 gene (a DAF-16-specific target gene) were observed as a result of BB68 treatment. Immunofluorescence microscopy revealed that TIR-1 and JNK-1 are involved in the phosphorylation and activation of DAF-16. Thus, BB68 increased the longevity of nematodes by activating the TIR-1 - JNK-1 - DAF-16 signaling pathway, and the cell wall component of BB68 contributed to longevity.

  11. Rice and Bean Targets for Biofortification Combined with High Carotenoid Content Crops Regulate Transcriptional Mechanisms Increasing Iron Bioavailability.

    Science.gov (United States)

    Dias, Desirrê Morais; de Castro Moreira, Maria Eliza; Gomes, Mariana Juste Contin; Lopes Toledo, Renata Celi; Nutti, Marilia Regini; Pinheiro Sant'Ana, Helena Maria; Martino, Hércia Stampini Duarte

    2015-11-23

    Iron deficiency affects thousands of people worldwide. Biofortification of staple food crops aims to support the reduction of this deficiency. This study evaluates the effect of combinations of common beans and rice, targets for biofortification, with high carotenoid content crops on the iron bioavailability, protein gene expression, and antioxidant effect. Iron bioavailability was measured by the depletion/repletion method. Seven groups were tested (n = 7): Pontal bean (PB); rice + Pontal bean (R + BP); Pontal bean + sweet potato (PB + SP); Pontal bean + pumpkin (PB + P); Pontal bean + rice + sweet potato (PB + R + P); Pontal bean + rice + sweet potato (PB + R + SP); positive control (Ferrous Sulfate). The evaluations included: hemoglobin gain, hemoglobin regeneration efficiency (HRE), gene expression of divalente metal transporter 1 (DMT-1), duodenal citocromo B (DcytB), ferroportin, hephaestin, transferrin and ferritin and total plasma antioxidant capacity (TAC). The test groups, except the PB, showed higher HRE (p common beans, and those with high carotenoid content crops increased protein gene expression, increasing the iron bioavailability and antioxidant capacity.

  12. Batf3 and Id2 have a synergistic effect on Irf8-directed classical CD8α+ dendritic cell development

    KAUST Repository

    Jaiswal, Hemant

    2013-11-13

    Dendritic cells (DCs) are heterogeneous cell populations represented by different subtypes, each varying in terms of gene expression patterns and specific functions. Recent studies identified transcription factors essential for the development of different DC subtypes, yet molecular mechanisms for the developmental program and functions remain poorly understood. In this study, we developed and characterized a mouse DC progenitor-like cell line, designated DC9, from Irf8-/- bone marrow cells as a model for DC development and function. Expression of Irf8 in DC9 cells led to plasmacytoid DCs and CD8α+ DC-like cells, with a concomitant increase in plasmacytoid DC- and CD8α+ DC-specific gene transcripts and induction of type I IFNs and IL12p40 following TLR ligand stimulation. Irf8 expression in DC9 cells led to an increase in Id2 and Batf3 transcript levels, transcription factors shown to be important for the development of CD8α+ DCs. We show that, without Irf8 , expression of Id2 and Batf3 was not sufficient for directing classical CD8α+ DC development. When coexpressed with Irf8, Batf3 and Id2 had a synergistic effect on classical CD8α+ DC development. We demonstrate that Irf8 is upstream of Batf3 and Id2 in the classical CD8α+ DC developmental program and define the hierarchical relationship of transcription factors important for classical CD8α+ DC development.

  13. MYB and bHLH transcription factor transgenes increase anthocyanin pigmentation in petunia and lisianthus plants, and the petunia phenotypes are strongly enhanced under field conditions

    Directory of Open Access Journals (Sweden)

    Kathy E Schwinn

    2014-11-01

    Full Text Available Petunia line Mitchell [MP, Petunia axillaris × (P. axillaris × P. hybrida] and Eustoma grandiflorum (lisianthus plants were produced containing a transgene for over-expression of the R2R3-MYB transcription factor (ROSEA1 that up-regulates flavonoid biosynthesis in Antirrhinum majus. The petunia lines were also crossed with previously produced MP lines containing a Zea mays flavonoid-related bHLH transcription factor transgene (LEAF COLOR, LC, which induces strong vegetative pigmentation when these 35S:LC plants are exposed to high light levels. 35S:ROS1 lisianthus transgenics had limited changes in anthocyanin pigmentation, specifically, precocious pigmentation of flower petals and increased pigmentation of sepals. RNA transcript levels for two anthocyanin biosynthetic genes, chalcone synthase and anthocyanidin synthase, were increased in the 35S:ROS1 lisianthus petals compared to those of control lines. With MP, the 35S:ROS1 calli showed novel red pigmentation in culture, but this was generally not seen in tissue culture plantlets regenerated from the calli or young plants transferred to soil in the greenhouse. Anthocyanin pigmentation was enhanced in the stems of mature 35S:ROS1 MP plants, but the MP white-flower phenotype was not complemented. Progeny from a 35S:ROS1×35S:LC cross had novel pigmentation phenotypes that were not present in either parental line or MP. In particular, there was increased pigment accumulation in the petal throat region, and the anthers changed from yellow to purple colour. An outdoor field trial was conducted with the 35S:ROS1, 35S:LC, 35S:ROS1×35S:LC and control MP lines. Field conditions rapidly induced intense foliage pigmentation in 35S:LC plants, a phenotype not observed in control MP or equivalent 35S:LC plants maintained in a greenhouse. No difference in plant stature, seed germination, or plant survival was observed between transgenic and control plants.

  14. Toxoplasma gondii Inhibits Gamma Interferon (IFN-γ)- and IFN-β-Induced Host Cell STAT1 Transcriptional Activity by Increasing the Association of STAT1 with DNA

    Science.gov (United States)

    Rosowski, Emily E.; Nguyen, Quynh P.; Camejo, Ana; Spooner, Eric

    2014-01-01

    The gamma interferon (IFN-γ) response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogen Toxoplasma gondii, but prior infection with Toxoplasma can inhibit this response. Recently, it was reported that the Toxoplasma type II NTE strain prevents the recruitment of chromatin remodeling complexes containing Brahma-related gene 1 (BRG-1) to promoters of IFN-γ-induced secondary response genes such as Ciita and major histocompatibility complex class II genes in murine macrophages, thereby inhibiting their expression. We report here that a type I strain of Toxoplasma inhibits the expression of primary IFN-γ response genes such as IRF1 through a distinct mechanism not dependent on the activity of histone deacetylases. Instead, infection with a type I, II, or III strain of Toxoplasma inhibits the dissociation of STAT1 from DNA, preventing its recycling and further rounds of STAT1-mediated transcriptional activation. This leads to increased IFN-γ-induced binding of STAT1 at the IRF1 promoter in host cells and increased global IFN-γ-induced association of STAT1 with chromatin. Toxoplasma type I infection also inhibits IFN-β-induced interferon-stimulated gene factor 3-mediated gene expression, and this inhibition is also linked to increased association of STAT1 with chromatin. The secretion of proteins into the host cell by a type I strain of Toxoplasma without complete parasite invasion is not sufficient to block STAT1-mediated expression, suggesting that the effector protein responsible for this inhibition is not derived from the rhoptries. PMID:24478085

  15. Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2).

    Science.gov (United States)

    Schneider, Kevin; Valdez, Joshua; Nguyen, Janice; Vawter, Marquis; Galke, Brandi; Kurtz, Theodore W; Chan, Jefferson Y

    2016-04-01

    The NRF2 (also known as NFE2L2) transcription factor is a critical regulator of genes involved in defense against oxidative stress. Previous studies suggest thatNrf2plays a role in adipogenesisin vitro, and deletion of theNrf2gene protects against diet-induced obesity in mice. Here, we demonstrate that resistance to diet-induced obesity inNrf2(-/-)mice is associated with a 20-30% increase in energy expenditure. Analysis of bioenergetics revealed thatNrf2(-/-)white adipose tissues exhibit greater oxygen consumption. White adipose tissue showed a >2-fold increase inUcp1gene expression. Oxygen consumption is also increased nearly 2.5-fold inNrf2-deficient fibroblasts. Oxidative stress induced by glucose oxidase resulted in increasedUcp1expression. Conversely, antioxidant chemicals (such asN-acetylcysteine and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride) and SB203580 (a known suppressor ofUcp1expression) decreasedUcp1and oxygen consumption inNrf2-deficient fibroblasts. These findings suggest that increasing oxidative stress by limitingNrf2function in white adipocytes may be a novel means to modulate energy balance as a treatment of obesity and related clinical disorders. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Diammonium phosphate stimulates transcription of L-lactate dehydrogenase leading to increased L-lactate production in the thermotolerant Bacillus coagulans strain.

    Science.gov (United States)

    Sun, Lifan; Li, Yanfeng; Wang, Limin; Wang, Yanping; Yu, Bo

    2016-08-01

    Exploration of cost-effective fermentation substrates for efficient lactate production is an important economic objective. Although some organic nitrogen sources are also cheaper, inorganic nitrogen salts for lactate fermentation have additional advantages in facilitating downstream procedures and significantly improving the commercial competitiveness of lactate production. In this study, we first established an application of diammonium phosphate to replace yeast extract with a reduced 90 % nitrogen cost for a thermotolerant Bacillus coagulans strain. In vivo enzymatic and transcriptional analyses demonstrated that diammonium phosphate stimulates the gene expression of L-lactate dehydrogenase, thus providing higher specific enzyme activity in vivo and increasing L-lactic acid production. This new information provides a foundation for establishing a cost-effective process for polymer-grade L-lactic acid production in an industrial setting.

  17. Increased renal gene transcription of protein kinase C-beta in human diabetic nephropathy: relationship to long-term glycaemic control

    DEFF Research Database (Denmark)

    Langham, R.G.; Kelly, D.J.; Gow, R.M.

    2008-01-01

    are unknown. We sought to determine whether in addition to activation, diabetes may lead to increased transcription of two PKC isoforms that have been implicated in the pathogenesis of diabetic nephropathy, PKC-alpha and PKC-beta. METHODS: Recent advances in molecular biological techniques now permit...... quantitative analysis of mRNA from archival, formalin-fixed, paraffin-embedded tissue sections. RNA was extracted from scraped 6 microm sections of biopsy tissue, and PRKC-alpha and PRKC-beta (also known as PRKCA and PRKCB) mRNA measured using real-time PCR. Expression of genes encoding PKC isoforms...... was examined in renal biopsies (n=25) with classical histological features of diabetic nephropathy and compared with that in normal control tissue (n=6). Peptide localisation of PKC-alpha, PKC-beta and the activated forms phosphorylated PKC-alpha and -beta was also performed on matched paraffin...

  18. The transcription of MGAT4A glycosyl transferase is increased in white cells of peripheral blood of Type 2 Diabetes patients

    Directory of Open Access Journals (Sweden)

    Cruz Miguel

    2007-10-01

    Full Text Available Abstract Background Human glycosylase IV is involved in GLUT2 transporter regulation in pancreatic β cells. A KO of this gene along with a high fat diet in a mice model has been associated with the development of type 2 diabetes (T2D. The aims of this study were to measure and compare the MGAT4A mRNA levels in white blood cells (WBC from T2D subjects and healthy subjects (T2NB, and to measure the half-life of the MGAT4A mRNA. Results We studied a sample of 73 individuals, 40 T2D subjects and 33 T2NB subjects. Anthropometrical and biochemical profiles were registered. The MGAT4A mRNA levels in WBC and the transcript half-life in Jurkat T cells were determined by Real-Time PCR. A blood differential cell counting was made for each individual. Cell counting showed T2D subjects exhibited an increased number of WBC compared to T2NB subjects (P = 0.0001. Biochemical parameters such as fasting glucose (P = 0.0001, and triglycerides (P = 0.002 were statistically significant. T2D subjects had 4.2-fold more MGAT4A transcript compared to T2NB subjects (P = 0.002. The MGAT4A mRNA had a half-life of 2.04 h in Jurkat T cells. Conclusion The results of this work suggest that in T2D subjects, high levels of glucose and triglycerides are accompanied by an increase on MGAT4A mRNA levels and WBC count; condition that suggests a pro-inflammatory state due to a chronic metabolic stress.

  19. Pregnancy induces transcriptional activation of the peripheral innate immune system and increases oxidative DNA damage among healthy third trimester pregnant women.

    Directory of Open Access Journals (Sweden)

    Xinyin Jiang

    Full Text Available BACKGROUND: Pregnancy induces physiological adaptations that may involve, or contribute to, alterations in the genomic landscape. Pregnancy also increases the nutritional demand for choline, an essential nutrient that can modulate epigenomic and transcriptomic readouts secondary to its role as a methyl donor. Nevertheless, the interplay between human pregnancy, choline and the human genome is largely unexplored. METHODOLOGY/PRINCIPAL FINDINGS: As part of a controlled feeding study, we assessed the influence of pregnancy and choline intake on maternal genomic markers. Healthy third trimester pregnant (n = 26, wk 26-29 gestation and nonpregnant (n = 21 women were randomized to choline intakes of 480 mg/day, approximating the Adequate Intake level, or 930 mg/day for 12-weeks. Blood leukocytes were acquired at study week 0 and study week 12 for microarray, DNA damage and global DNA/histone methylation measurements. A main effect of pregnancy that was independent of choline intake was detected on several of the maternal leukocyte genomic markers. Compared to nonpregnant women, third trimester pregnant women exhibited higher (P<0.05 transcript abundance of defense response genes associated with the innate immune system including pattern recognition molecules, neutrophil granule proteins and oxidases, complement proteins, cytokines and chemokines. Pregnant women also exhibited higher (P<0.001 levels of DNA damage in blood leukocytes, a genomic marker of oxidative stress. No effect of choline intake was detected on the maternal leukocyte genomic markers with the exception of histone 3 lysine 4 di-methylation which was lower among pregnant women in the 930 versus 480 mg/d choline intake group. CONCLUSIONS: Pregnancy induces transcriptional activation of the peripheral innate immune system and increases oxidative DNA damage among healthy third trimester pregnant women.

  20. Increases in Expression of 14-3-3 Eta and 14–3–3 Zeta Transcripts during Neuroprotection Induced by Δ9-Tetrahydrocannabinol in AF5 Cells

    Science.gov (United States)

    Chen, Jia; Lee, Chun-Ting; Errico, Stacie L.; Becker, Kevin G.; Freed, William J.

    2008-01-01

    The molecular mechanisms involved in NMDA-induced cell death and Δ9-tetrahydrocannabinol (THC)-induced neuroprotection were investigated in vitro using an AF5 neural progenitor cell line model. By microarray analysis, Ywhah, CK1, Hsp60, Pdcd 4 and Pdcd 7 were identified as being strongly regulated by both NMDA toxicity and THC neuroprotection. The 14-3-3 eta (14–3–3η; gene symbol Ywhah) and 14-3- zeta (14–3–3ζ; gene symbol Ywhaz) transcripts were deceased by NMDA treatment, and increased by THC treatment prior to NMDA, as measured by cDNA microarray analysis and quantitative real-time RT-PCR. Other 14-3-3 isoforms were unchanged. While up-regulation of 14–3–3ζ expression was observed 30 min after treatment with THC plus NMDA, down-regulation by NMDA alone was not seen until 16 hr after treatment. By Western blotting, THC increased 14-3-3 protein only in cells that were also treated with NMDA. Over expression of 14-3-3η or 14-3-3ζ by transient plasmid transfection increased 14-3-3 protein levels, and decreased NMDA-induced cell death. These data suggest that increases in 14-3-3 proteins mediate THC-induced neuroprotection under conditions of NMDA-induced cellular stress. PMID:17455326

  1. miRNA-mediated post-transcriptional silencing of transgenes leads to increased adeno-associated viral vector yield and targeting specificity.

    Science.gov (United States)

    Reid, C A; Boye, S L; Hauswirth, W W; Lipinski, D M

    2017-08-01

    The production of high-titer recombinant adeno-associated virus (rAAV) vector is essential for treatment of genetic diseases affecting the retina and choroid, where anatomical constraints may limit injectable volumes. Problematically, cytotoxicity arising from overexpression of the transgene during vector production frequently leads to a reduction in vector yield. Herein, we evaluate the use of microRNA (miRNA)-mediated silencing to limit overexpression of cytotoxic transgenes during packaging as a method of increasing vector yield. We examined if post-transcriptional regulation of transgenes during packaging via miRNA technology would lead to increased rAAV yields. Our results demonstrate that silencing of cytotoxic transgenes during production resulted in up to a 22-fold increase in vector yield. The inclusion of organ-specific miRNA sequences improved biosafety by limiting off-target expression following systemic rAAV administration. The small size (22-23 bp) of the target site allows for the inclusion of multiple copies into the vector with minimal impact on coding capacity. Taken together, our results suggest that inclusion of miRNA target sites into the 3'-untranslated region of the AAV cassette allow for silencing of cytotoxic transgenes during vector production leading to improved vector yield, in addition to increasing targeting specificity without reliance on cell-specific promoters.

  2. Determining lower threshold concentrations for synergistic effects.

    Science.gov (United States)

    Bjergager, Maj-Britt Andersen; Dalhoff, Kristoffer; Kretschmann, Andreas; Nørgaard, Katrine Banke; Mayer, Philipp; Cedergreen, Nina

    2017-01-01

    Though only occurring rarely, synergistic interactions between chemicals in mixtures have long been a point of focus. Most studies analyzing synergistic interactions used unrealistically high chemical concentrations. The aim of the present study is to determine the threshold concentration below which proven synergists cease to act as synergists towards the aquatic crustacean Daphnia magna. To do this, we compared several approaches and test-setups to evaluate which approach gives the most conservative estimate for the lower threshold for synergy for three known azole synergists. We focus on synergistic interactions between the pyrethroid insecticide, alpha-cypermethrin, and one of the three azole fungicides prochloraz, propiconazole or epoxiconazole measured on Daphnia magna immobilization. Three different experimental setups were applied: A standard 48h acute toxicity test, an adapted 48h test using passive dosing for constant chemical exposure concentrations, and a 14-day test. Synergy was defined as occuring in mixtures where either EC 50 values decreased more than two-fold below what was predicted by concentration addition (horizontal assessment) or as mixtures where the fraction of immobile organisms increased more than two-fold above what was predicted by independent action (vertical assessment). All three tests confirmed the hypothesis of the existence of a lower azole threshold concentration below which no synergistic interaction was observed. The lower threshold concentration, however, decreased with increasing test duration from 0.026±0.013μM (9.794±4.897μgL -1 ), 0.425±0.089μM (145.435±30.46μgL -1 ) and 0.757±0.253μM (249.659±83.44μgL -1 ) for prochloraz, propiconazole and epoxiconazole in standard 48h toxicity tests to 0.015±0.004μM (5.651±1.507μgL -1 ), 0.145±0.025μM (49.619±8.555μgL -1 ) and 0.122±0.0417μM (40.236±13.75μgL -1 ), respectively, in the 14-days tests. Testing synergy in relation to concentration addition provided

  3. Increased expression of bHLH transcription factor E2A (TCF3) in prostate cancer promotes proliferation and confers resistance to doxorubicin induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Patel, Divya [Center for Cancer Research and Therapeutics Development, Clark Atlanta University, 223 James P. Brawley Dr. SW, Atlanta, GA 30314 (United States); Chaudhary, Jaideep, E-mail: jchaudhary@cau.edu [Center for Cancer Research and Therapeutics Development, Clark Atlanta University, 223 James P. Brawley Dr. SW, Atlanta, GA 30314 (United States); Dept. of Biological Sciences, Clark Atlanta University, 223 James P. Brawley Dr. SW, Atlanta, GA 30314 (United States)

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer E2A, considered as a tumor suppressor is highly expressed in prostate cancer. Black-Right-Pointing-Pointer Silencing of E2A attenuates cell proliferation and promotes apoptosis. Black-Right-Pointing-Pointer E2A regulates c-myc, Id1, Id3 and CDKN1A expression. Black-Right-Pointing-Pointer Loss of E2A promotes doxorubicin dependent apoptosis in prostate cancer cells. Black-Right-Pointing-Pointer Results suggest that E2A acts as a tumor promoter at least in prostate cancer. -- Abstract: E2A (TCF3) is a multifunctional basic helix loop helix (bHLH), transcription factor. E2A regulates transcription of target genes by homo- or heterodimerization with cell specific bHLH proteins. In general, E2A promotes cell differentiation, acts as a negative regulator of cell proliferation in normal cells and cancer cell lines and is required for normal B-cell development. Given the diverse biological pathways regulated/influenced by E2A little is known about its expression in cancer. In this study we investigated the expression of E2A in prostate cancer. Unexpectedly, E2A immuno-histochemistry demonstrated increased E2A expression in prostate cancer as compared to normal prostate. Silencing of E2A in prostate cancer cells DU145 and PC3 led to a significant reduction in proliferation due to G1 arrest that was in part mediated by increased CDKN1A(p21) and decreased Id1, Id3 and c-myc. E2A silencing in prostate cancer cell lines also resulted in increased apoptosis due to increased mitochondrial permeability and caspase 3/7 activation. Moreover, silencing of E2A increased sensitivity to doxorubicin induced apoptosis. Based on our results, we propose that E2A could be an upstream regulator of Id1 and c-Myc which are highly expressed in prostate cancer. These results for the first time demonstrate that E2A could in fact acts as a tumor promoter at least in prostate cancer.

  4. Transforming growth factor-β increases interleukin-13 synthesis via GATA-3 transcription factor in T-lymphocytes from patients with systemic sclerosis.

    Science.gov (United States)

    Baraut, Julie; Farge, Dominique; Jean-Louis, Francette; Masse, Ingrid; Grigore, Elena Ivan; Arruda, Lucas C M; Lamartine, Jérôme; Verrecchia, Franck; Michel, Laurence

    2015-07-31

    Transforming growth factor (TGF)-β and interleukin (IL)-13 play a crucial role in the pathogenesis of systemic sclerosis (SSc), partly through activation of collagen production that leads to fibrosis. The aim of the present study was to determine whether TFG-β alters IL-13 production in T lymphocytes from patients with SSc from that seen in those of healthy donors. IL-13 mRNA and protein synthesis under TFG-β exposure was measured in circulating T lymphocytes from healthy donors and patients with SSc and also in the Jurkat Th2 T-cell line, using quantitative real-time PCR and fluorescence-activated cell sorting analysis, respectively. The involvement of Smad and GATA-3 transcription factors was assessed by using specific inhibitors and small interfering RNA, and the binding capacity of GATA-3 to the IL-13 gene promoter was evaluated by chromatin immunoprecipitation assay. TGF-β induced a significant decrease in IL-13 mRNA and protein levels in lymphocytes from healthy donors (mean [±SD] inhibition of 30% ± 10% and 20% ± 7%, respectively; p T-cell subtypes from patients with SSc, with respective increases of 2.4 ± 0.3-fold, 1.6 ± 0.05-fold and 2.7 ± 0.02-fold. The involvement of the Smad signaling pathway and upregulation of GATA-3 binding capacity on the IL-13 promoter in lymphocytes from patients with SSc contributed to the effect of TGF-β on IL-13 production. These results demonstrate that TGF-β upregulates IL-13 synthesis through GATA-3 expression in the T lymphocytes of patients with SSc, confirming that the GATA-3 transcription factor can be regarded as a novel therapeutic target in patients with SSc.

  5. C-peptide increases Na,K-ATPase expression via PKC- and MAP kinase-dependent activation of transcription factor ZEB in human renal tubular cells.

    Directory of Open Access Journals (Sweden)

    Dana Galuska

    Full Text Available Replacement of proinsulin C-peptide in type 1 diabetes ameliorates nerve and kidney dysfunction, conditions which are associated with a decrease in Na,K-ATPase activity. We determined the molecular mechanism by which long term exposure to C-peptide stimulates Na,K-ATPase expression and activity in primary human renal tubular cells (HRTC in control and hyperglycemic conditions.HRTC were cultured from the outer cortex obtained from patients undergoing elective nephrectomy. Ouabain-sensitive rubidium ((86Rb(+ uptake and Na,K-ATPase activity were determined. Abundance of Na,K-ATPase was determined by Western blotting in intact cells or isolated basolateral membranes (BLM. DNA binding activity was determined by electrical mobility shift assay (EMSA. Culturing of HRTCs for 5 days with 1 nM, but not 10 nM of human C-peptide leads to increase in Na,K-ATPase α(1-subunit protein expression, accompanied with increase in (86Rb(+ uptake, both in normal- and hyperglycemic conditions. Na,K-ATPase α(1-subunit expression and Na,K-ATPase activity were reduced in BLM isolated from cells cultured in presence of high glucose. Exposure to1 nM, but not 10 nM of C-peptide increased PKCε phosphorylation as well as phosphorylation and abundance of nuclear ERK1/2 regardless of glucose concentration. Exposure to 1 nM of C-peptide increased DNA binding activity of transcription factor ZEB (AREB6, concomitant with Na,K-ATPase α(1-subunit mRNA expression. Effects of 1 nM C-peptide on Na,K-ATPase α(1-subunit expression and/or ZEB DNA binding activity in HRTC were abolished by incubation with PKC or MEK1/2 inhibitors and ZEB siRNA silencing.Despite activation of ERK1/2 and PKC by hyperglycemia, a distinct pool of PKCs and ERK1/2 is involved in regulation of Na,K-ATPase expression and activity by C-peptide. Most likely C-peptide stimulates sodium pump expression via activation of ZEB, a transcription factor that has not been previously implicated in C

  6. Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells

    International Nuclear Information System (INIS)

    Thewes, Verena; Orso, Francesca; Jäger, Richard; Eckert, Dawid; Schäfer, Sabine; Kirfel, Gregor; Garbe, Stephan; Taverna, Daniela; Schorle, Hubert

    2010-01-01

    Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2α and AP-2γ is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms. We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant. We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed Cell Death and Cell Adhesion and Migration as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. Ctgf, Nrp1, Tnfaip3, Gsta3) and AP-2 and other main apoptosis players and to create a unique network. Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference

  7. Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation- sensitivity in breast cancer cells

    LENUS (Irish Health Repository)

    Thewes, Verena

    2010-05-11

    Abstract Background Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2α and AP-2γ is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms. Methods We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant. Results We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed Cell Death and Cell Adhesion and Migration as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. Ctgf, Nrp1, Tnfaip3, Gsta3) and AP-2 and other main apoptosis players and to create a unique network. Conclusions Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the

  8. A sigmoidal transcriptional response: cooperativity, synergy and dosage effects.

    Science.gov (United States)

    Veitia, Reiner A

    2003-02-01

    A sigmoidal transcriptional response (STR) is thought to act as a molecular switch to control gene expression. This nonlinear behaviour arises as a result of the cooperative recognition of a promoter/enhancer by transcription factors (TFs) and/or their synergy to attract the basal transcriptional machinery (BTM). Although this cooperation between TFs is additive in terms of energy, it leads to an exponential increase in affinity between the BTM and the pre-initiation complexes. This exponential increase in the strength of interactions is the principle that governs synergistic systems. Here, I propose a minimalist quasi-equilibrium model to explore qualitatively the STR taking into account cooperative recognition of the promoter/enhancer and synergy. Although the focus is on the effect of activators, a similar treatment can be applied to inhibitors. One of the main insights obtained from the model is that generation of a sigmoidal threshold is possible even in the absence of cooperative DNA binding provided the TFs synergistically interact with the BTM. On the contrary, when there is cooperative binding, the impact of synergy diminishes. It will also be shown that a sigmoidal response to a morphogenetic gradient can be used to generate a nested gradient of another morphogen. Previously, I had proposed that halving the amounts of TFs involved in sigmoidal transcriptional switches could account for the abnormal dominant phenotypes associated with some of these genes. This phenomenon, called haploinsufficiency (HI), has been recognised as the basis of many human diseases. Although a formal proof linking HI and a sigmoidal response is lacking, it is tempting to explore the model from the perspective of dosage effects.

  9. Increased abundance of ADAM9 transcripts in the blood is associated with tissue damage [version 2; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Darawan Rinchai

    2016-10-01

    Full Text Available Background: Members of the ADAM (a disintegrin and metalloprotease domain family have emerged as critical regulators of cell-cell signaling during development and homeostasis. ADAM9 is consistently overexpressed in various human cancers, and has been shown to play an important role in tumorigenesis. However, little is known about the involvement of ADAM9 during immune-mediated processes. Results: Mining of an extensive compendium of transcriptomic datasets identified important gaps in knowledge regarding the possible role of ADAM9 in immunological homeostasis and inflammation: 1 The abundance of ADAM9 transcripts in the blood was increased in patients with acute infection but, 2 changed very little after in vitro exposure to a wide range of pathogen-associated molecular patterns (PAMPs. 3 Furthermore it was found to increase significantly in subjects as a result of tissue injury or tissue remodeling, in absence of infectious processes. Conclusions: Our findings indicate that ADAM9 may constitute a valuable biomarker for the assessment of tissue damage, especially in clinical situations where other inflammatory markers are confounded by infectious processes.

  10. Restraint stress increases prolactin-mediated phosphorylation of signal transducer and activator of transcription 5 in the hypothalamus and adrenal cortex in the male mouse.

    Science.gov (United States)

    Kirk, S E; Xie, T Y; Steyn, F J; Grattan, D R; Bunn, S J

    2017-06-01

    Prolactin is a pleiotropic peptide hormone produced by the lactotrophs in the anterior pituitary. Its rate of secretion is primarily regulated by a negative-feedback mechanism where prolactin stimulates the activity of the tuberoinfundibular dopaminergic (TIDA) neurones, increasing their release of dopamine, which accesses the pituitary via the median eminence to suppress further prolactin secretion. In addition to its well established role in lactation, circulating prolactin is secreted in response to stress, although the mechanism by which this is achieved or its cellular targets remains unknown. In the present study, we show that 15 minutes of restraint stress causes an approximately seven-fold increase in circulating prolactin concentration in male mice. Monitoring prolactin receptor activation, using immunohistochemistry to determine the level and distribution of tyrosine phosphorylated signal transducer and activator of transcription 5 (pSTAT5), we show that this stress-induced increase in prolactin interacts with both central and peripheral targets. Restraint stress for 15 minutes significantly increased pSTAT5 staining in the arcuate nucleus, median eminence and the zona fasciculata of the adrenal cortex. In each case, this response was prevented by pretreating the animals with bromocriptine to block prolactin secretion from the pituitary. Interestingly, in contrast to many cells in the arcuate nucleus, stress reduced pSTAT5 staining of the TIDA neurones (identified by dual-labelling for tyrosine hydroxylase). This suggests that there is reduced prolactin signalling in these cells and thus potentially a decline in their inhibitory influence on prolactin secretion. These results provide evidence that prolactin secreted in response to acute stress is sufficient to activate prolactin receptors in selected target tissues known to be involved in the physiological adaptation to stress. © 2017 British Society for Neuroendocrinology.

  11. Antisense transcription-dependent chromatin signature modulates sense transcript dynamics.

    Science.gov (United States)

    Brown, Thomas; Howe, Françoise S; Murray, Struan C; Wouters, Meredith; Lorenz, Philipp; Seward, Emily; Rata, Scott; Angel, Andrew; Mellor, Jane

    2018-02-12

    Antisense transcription is widespread in genomes. Despite large differences in gene size and architecture, we find that yeast and human genes share a unique, antisense transcription-associated chromatin signature. We asked whether this signature is related to a biological function for antisense transcription. Using quantitative RNA-FISH, we observed changes in sense transcript distributions in nuclei and cytoplasm as antisense transcript levels were altered. To determine the mechanistic differences underlying these distributions, we developed a mathematical framework describing transcription from initiation to transcript degradation. At GAL1 , high levels of antisense transcription alter sense transcription dynamics, reducing rates of transcript production and processing, while increasing transcript stability. This relationship with transcript stability is also observed as a genome-wide association. Establishing the antisense transcription-associated chromatin signature through disruption of the Set3C histone deacetylase activity is sufficient to similarly change these rates even in the absence of antisense transcription. Thus, antisense transcription alters sense transcription dynamics in a chromatin-dependent manner. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

  12. The neurotoxicant PCB-95 by increasing the neuronal transcriptional repressor REST down-regulates caspase-8 and increases Ripk1, Ripk3 and MLKL expression determining necroptotic neuronal death.

    Science.gov (United States)

    Guida, Natascia; Laudati, Giusy; Serani, Angelo; Mascolo, Luigi; Molinaro, Pasquale; Montuori, Paolo; Di Renzo, Gianfranco; Canzoniero, Lorella M T; Formisano, Luigi

    2017-10-15

    Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases RE1-silencing transcription factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation. Our results demonstrated that in cortical neurons PCB-95 increased RIPK1, RIPK3, and MLKL expression and decreased caspase-8 at the gene and protein level. Furthermore, the RIPK1 inhibitor necrostatin-1 or siRNA-mediated RIPK1, RIPK3 and MLKL expression knockdown significantly reduced PCB-95-induced neuronal death. Intriguingly, PCB-95-induced increases in RIPK1, RIPK3, MLKL expression and decreases in caspase-8 expression were reversed by knockdown of REST expression with a REST-specific siRNA (siREST). Notably, in silico analysis of the rat genome identified a REST consensus sequence in the caspase-8 gene promoter (Casp8-RE1), but not the RIPK1, RIPK3 and MLKL promoters. Interestingly, in PCB-95-treated neurons, REST binding to the Casp8-RE1 sequence increased in parallel with a reduction in its promoter activity, whereas under the same experimental conditions, transfection of siREST or mutation of the Casp8-RE1 sequence blocked PCB-95-induced caspase-8 reduction. Since RIPK1, RIPK3 and MLKL rat genes showed no putative REST binding site, we assessed whether the transcription factor cAMP Responsive Element Binding Protein (CREB), which has a consensus sequence in all three genes, affected neuronal death. In neurons treated with PCB-95, CREB protein expression decreased in parallel with a reduction in binding to the RIPK1, RIPK3 and MLKL gene promoter sequence. Furthermore, CREB overexpression was

  13. Silica ecosystem for synergistic biotransformation

    OpenAIRE

    Mutlu, Baris R.; Sakkos, Jonathan K.; Yeom, Sujin; Wackett, Lawrence P.; Aksan, Alptekin

    2016-01-01

    Synergistical bacterial species can perform more varied and complex transformations of chemical substances than either species alone, but this is rarely used commercially because of technical difficulties in maintaining mixed cultures. Typical problems with mixed cultures on scale are unrestrained growth of one bacterium, which leads to suboptimal population ratios, and lack of control over bacterial spatial distribution, which leads to inefficient substrate transport. To address these issues...

  14. Synergistic drug combinations improve therapeutic selectivity

    Science.gov (United States)

    Lehàr, Joseph; Krueger, Andrew S.; Avery, William; Heilbut, Adrian M.; Johansen, Lisa M.; Price, E. Roydon; Rickles, Richard J.; Short, Glenn F.; Staunton, Jane E.; Jin, Xiaowei; Lee, Margaret S.; Zimmermann, Grant R.; Borisy, Alexis A.

    2009-01-01

    Prevailing drug discovery approaches focus on compounds with molecular selectivity, inhibiting disease-relevant targets over others in vitro. However in vivo, many such agents are not therapeutically selective, either because of undesirable activity at effective doses or because the biological system responds to compensate. In theory, drug combinations should permit increased control of such complex biology, but there is a common concern that therapeutic synergy will generally be mirrored by synergistic side-effects. Here we provide evidence, from 94,110 multi-dose combination experiments representing diverse disease areas and large scale flux balance simulations of inhibited bacterial metabolism, that multi-target synergies are more specific than single agent activities to particular cellular contexts. Using an anti-inflammatory combination, we show how multi-target synergy can achieve therapeutic selectivity in animals through differential target expression. Synergistic combinations can increase the number of selective therapies using the current pharmacopeia, and offer opportunities for more precise control of biological systems. PMID:19581876

  15. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection.

    Directory of Open Access Journals (Sweden)

    Sophie Reuse

    2009-06-01

    Full Text Available The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs combined with prostratin, a non-tumor-promoting nuclear factor (NF- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+ T

  16. Protein Inhibitors of Activated STAT (Pias1 and Piasy) Differentially Regulate Pituitary Homeobox 2 (PITX2) Transcriptional Activity*

    Science.gov (United States)

    Wang, Jianbo; Sun, Zhao; Zhang, Zichao; Saadi, Irfan; Wang, Jun; Li, Xiao; Gao, Shan; Engle, Jamison J.; Kuburas, Adisa; Fu, Xueyao; Yu, Wenjie; Klein, William H.; Russo, Andrew F.; Amendt, Brad A.

    2013-01-01

    Protein inhibitors of activated STAT (Pias) proteins can act independent of sumoylation to modulate the activity of transcription factors and Pias proteins interacting with transcription factors can either activate or repress their activity. Pias proteins are expressed in many tissues and cells during development and we asked if Pias proteins regulated the pituitary homeobox 2 (PITX2) homeodomain protein, which modulates developmental gene expression. Piasy and Pias1 proteins are expressed during craniofacial/tooth development and directly interact and differentially regulate PITX2 transcriptional activity. Piasy and Pias1 are co-expressed in craniofacial tissues with PITX2. Yeast two-hybrid, co-immunoprecipitation and pulldown experiments demonstrate Piasy and Pias1 interactions with the PITX2 protein. Piasy interacts with the PITX2 C-terminal tail to attenuate its transcriptional activity. In contrast, Pias1 interacts with the PITX2 C-terminal tail to increase PITX2 transcriptional activity. The E3 ligase activity associated with the RING domain in Piasy is not required for the attenuation of PITX2 activity, however, the RING domain of Pias1 is required for enhanced PITX2 transcriptional activity. Bimolecular fluorescence complementation assays reveal PITX2 interactions with Piasy and Pias1 in the nucleus. Piasy represses the synergistic activation of PITX2 with interacting co-factors and Piasy represses Pias1 activation of PITX2 transcriptional activity. In contrast, Pias1 did not affect the synergistic interaction of PITX2 with transcriptional co-factors. Last, we demonstrate that Pias proteins form a complex with PITX2 and Lef-1, and PITX2 and β-catenin. Lef-1, β-catenin, and Pias interactions with PITX2 provide new molecular mechanisms for the regulation of PITX2 transcriptional activity and the activity of Pias proteins. PMID:23515314

  17. Protein inhibitors of activated STAT (Pias1 and Piasy) differentially regulate pituitary homeobox 2 (PITX2) transcriptional activity.

    Science.gov (United States)

    Wang, Jianbo; Sun, Zhao; Zhang, Zichao; Saadi, Irfan; Wang, Jun; Li, Xiao; Gao, Shan; Engle, Jamison J; Kuburas, Adisa; Fu, Xueyao; Yu, Wenjie; Klein, William H; Russo, Andrew F; Amendt, Brad A

    2013-05-03

    Protein inhibitors of activated STAT (Pias) proteins can act independent of sumoylation to modulate the activity of transcription factors and Pias proteins interacting with transcription factors can either activate or repress their activity. Pias proteins are expressed in many tissues and cells during development and we asked if Pias proteins regulated the pituitary homeobox 2 (PITX2) homeodomain protein, which modulates developmental gene expression. Piasy and Pias1 proteins are expressed during craniofacial/tooth development and directly interact and differentially regulate PITX2 transcriptional activity. Piasy and Pias1 are co-expressed in craniofacial tissues with PITX2. Yeast two-hybrid, co-immunoprecipitation and pulldown experiments demonstrate Piasy and Pias1 interactions with the PITX2 protein. Piasy interacts with the PITX2 C-terminal tail to attenuate its transcriptional activity. In contrast, Pias1 interacts with the PITX2 C-terminal tail to increase PITX2 transcriptional activity. The E3 ligase activity associated with the RING domain in Piasy is not required for the attenuation of PITX2 activity, however, the RING domain of Pias1 is required for enhanced PITX2 transcriptional activity. Bimolecular fluorescence complementation assays reveal PITX2 interactions with Piasy and Pias1 in the nucleus. Piasy represses the synergistic activation of PITX2 with interacting co-factors and Piasy represses Pias1 activation of PITX2 transcriptional activity. In contrast, Pias1 did not affect the synergistic interaction of PITX2 with transcriptional co-factors. Last, we demonstrate that Pias proteins form a complex with PITX2 and Lef-1, and PITX2 and β-catenin. Lef-1, β-catenin, and Pias interactions with PITX2 provide new molecular mechanisms for the regulation of PITX2 transcriptional activity and the activity of Pias proteins.

  18. Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling.

    Science.gov (United States)

    Pansters, N A; Langen, R C; Wouters, E F; Schols, A M

    2013-05-01

    Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.

  19. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.

    Science.gov (United States)

    Preston, R S; Philp, A; Claessens, T; Gijezen, L; Dydensborg, A B; Dunlop, E A; Harper, K T; Brinkhuizen, T; Menko, F H; Davies, D M; Land, S C; Pause, A; Baar, K; van Steensel, M A M; Tee, A R

    2011-03-10

    Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel-Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt-Hogg-Dubé syndrome. For this, we analysed a Birt-Hogg-Dubé patient-derived renal tumour cell line (UOK257) that is devoid of the Birt-Hogg-Dubé protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1α or HIF2α protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1α and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt-Hogg-Dubé patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the 'Warburg effect'). UOK257 cells also possessed a higher expression level of the L-lactate influx monocarboxylate transporter 1 and consequently utilized L-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt-Hogg-Dubé-associated renal lesions.

  20. Culture and neuroscience: additive or synergistic?

    Science.gov (United States)

    Dapretto, Mirella; Iacoboni, Marco

    2010-01-01

    The investigation of cultural phenomena using neuroscientific methods—cultural neuroscience (CN)—is receiving increasing attention. Yet it is unclear whether the integration of cultural study and neuroscience is merely additive, providing additional evidence of neural plasticity in the human brain, or truly synergistic, yielding discoveries that neither discipline could have achieved alone. We discuss how the parent fields to CN: cross-cultural psychology, psychological anthropology and cognitive neuroscience inform the investigation of the role of cultural experience in shaping the brain. Drawing on well-established methodologies from cross-cultural psychology and cognitive neuroscience, we outline a set of guidelines for CN, evaluate 17 CN studies in terms of these guidelines, and provide a summary table of our results. We conclude that the combination of culture and neuroscience is both additive and synergistic; while some CN methodologies and findings will represent the direct union of information from parent fields, CN studies employing the methodological rigor required by this logistically challenging new field have the potential to transform existing methodologies and produce unique findings. PMID:20083533

  1. Synergistic energy conversion process using nuclear energy and fossil fuels

    International Nuclear Information System (INIS)

    Hori, Masao

    2007-01-01

    Because primary energies such as fossil fuels, nuclear energy and renewable energy are limited in quantity of supply, it is necessary to use available energies effectively for the increase of energy demand that is inevitable this century while keeping environment in good condition. For this purpose, an efficient synergistic energy conversion process using nuclear energy and fossil fuels together converted to energy carriers such are electricity, hydrogen, and synthetic fuels seems to be effective. Synergistic energy conversion processes containing nuclear energy were surveyed and effects of these processes on resource saving and the CO 2 emission reduction were discussed. (T.T.)

  2. Antioxidant, antimicrobial and synergistic activities of tea polyphenols

    African Journals Online (AJOL)

    Microbial resistance to antibiotics has become an increasing global problem and there is a need to find out novel potent antimicrobial agents with alternative modes of action as accessories to antibiotic therapy. This study investigated the antioxidant, antimicrobial and synergistic properties of tea polyphenols. The tea ...

  3. Synergistic Effect of Poultry Manure and Sawdust on Changes in ...

    African Journals Online (AJOL)

    Synergistic Effect of Poultry Manure and Sawdust on Changes in Soil Structural Indices of a Sandy-Clay Loam Ultisol. ... Decreases in bulk density occurred as a result of increase in amendment applied, the trend was 8t>4t>2t for all the amendments. However, only the application of 8t/ha of poultry manure decrease bulk ...

  4. Contrast-induced nephrotoxicity: possible synergistic effect of stress hyperglycemia.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Oxidative stress on the renal tubules has been implicated as a mechanism of injury in both stress hyperglycemia and contrast-induced nephrotoxicity. The purpose of this study was to determine whether the combination of these effects has a synergistic effect on accentuating renal tubular apoptosis and therefore increasing the risk of contrast-induced nephrotoxicity.

  5. MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.

    Science.gov (United States)

    Burgos, Jonathan R; Iresjö, Britt-Marie; Smedh, Ulrika

    2016-04-01

    The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor per se. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid P component (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation.

  6. Synergistic effects of irradiation of waste-water

    International Nuclear Information System (INIS)

    Woodbridge, D.D.

    1975-01-01

    Water is an absolute necessity for all forms of animal and plant life. As man's requirements for water increase, the need for better methods of purification also increase. Technology has been slow to develop new methods of water treatment for the direct utilization of waste-water. Many new construction projects are at a standstill because waste-water treatment methods have not been developed to handle adequately the ever-increasing flow of sewage. Theoretical considerations of the use of high-level radiation in the treatment of waste-water have failed to consider the effects of the hydrated electron, and the potential of the possible synergistic effects of combining chlorine, oxygen and irradiation. An extensive testing programme at the University Center for Pollution Research of the Florida Institute of Technology over the past four years has shown that irradiation of waste-water samples immersed in an aqueous environment provide bacterial kill and reduction in organic pollution far greater than that obtained from theoretical considerations of G values and earlier experiments where the waste samples were not immersed in an aqueous environment. These testing programmes have investigated the synergistic effects of combining oxygen and irradiation. Each of these combined treatments resulted in an increased bacterial kill factor. Tests on Staphylococcus aureus bacteria and faecal streptococcus bacteria indicate that the synergistic effects observed for faecal coliform bacteria also apply to the pathogenic bacteria. A statistical analysis of the data obtained shows the relationships between the various effects on the bacteria. A definite shielding factor from the turbidity of the waste-water has been shown to exist. Synergistic effects have been shown to offset significantly the shielding effects. Optimization of these synergistic effects can greatly increase the effectiveness of irradiation in the treatment of waste-water. (author)

  7. Auxins increase expression of the brassinosteroid receptor and brassinosteroid-responsive genes in Arabidopsis

    OpenAIRE

    Sakamoto, Tomoaki; Fujioka, Shozo

    2013-01-01

    Auxins and brassinosteroids are essential phytohormones that synergistically regulate physiological and developmental processes in plants. Previously, we demonstrated that auxins stimulate brassinosteroid perception by regulating the level of brassinosteroid receptor in rice. Here we showed that auxin treatment increased expression of the Arabidopsis brassinosteroid receptor gene BRI1. The promoter of BRI1 has an auxin-response element that is targeted by auxin-response factor transcription f...

  8. Changes in transcription of cytokinin metabolism and signalling genes in grape (Vitis vinifera L.) berries are associated with the ripening-related increase in isopentenyladenine.

    Science.gov (United States)

    Böttcher, Christine; Burbidge, Crista A; Boss, Paul K; Davies, Christopher

    2015-09-16

    Cytokinins are known to play an important role in fruit set and early fruit growth, but their involvement in later stages of fruit development is less well understood. Recent reports of greatly increased cytokinin concentrations in the flesh of ripening kiwifruit (Actinidia deliciosa (A. Chev.) C.F. Liang & A.R. Ferguson) and grapes (Vitis vinifera L.) have suggested that these hormones are implicated in the control of ripening-related processes. A similar pattern of isopentenyladenine (iP) accumulation was observed in the ripening fruit of several grapevine cultivars, strawberry (Fragaria ananassa Duch.) and tomato (Solanum lycopersicum Mill.), suggesting a common, ripening-related role for this cytokinin. Significant differences in maximal iP concentrations between grapevine cultivars and between fruit species might reflect varying degrees of relevance or functional adaptations of this hormone in the ripening process. Grapevine orthologues of five Arabidopsis (Arabidopsis thaliana L.) gene families involved in cytokinin metabolism and signalling were identified and analysed for their expression in developing grape berries and a range of other grapevine tissues. Members of each gene family were characterised by distinct expression profiles during berry development and in different grapevine organs, suggesting a complex regulation of cellular cytokinin activities throughout the plant. The post-veraison-specific expression of a set of biosynthesis, activation, perception and signalling genes together with a lack of expression of degradation-related genes during the ripening phase were indicative of a local control of berry iP concentrations leading to the observed accumulation of iP in ripening grapes. The transcriptional analysis of grapevine genes involved in cytokinin production, degradation and response has provided a possible explanation for the ripening-associated accumulation of iP in grapes and other fruit. The pre- and post-veraison-specific expression of

  9. Mechanisms of synergistic skin penetration by sonophoresis and iontophoresis.

    Science.gov (United States)

    Hikima, Tomohiro; Ohsumi, Shinya; Shirouzu, Kenta; Tojo, Kakuji

    2009-05-01

    The mechanism of skin penetration enhancement by ultrasound under sonophoresis (US) or by an electrical field under iontophoresis (IP) was investigated using hairless mouse skin in vitro. The seven model chemicals with different molecular weights (122-1485) were dissolved in a hydrophilic gel. Donor gel with the chemicals was loaded on the skin surface and then the skin was treated with US (300 kHz, 5.2 W/cm(2), 5.4% duty-cycle) and IP (0.32+/-0.03 mA/cm(2)) individually or with US and IP in combination (US+IP). The penetration profiles of the chemicals with a molecular weight of less than 500 were influenced by the presence of an electric charge, the profiles of ionized chemicals for US+IP were the same as profiles for IP, while the penetration flux of a non-ionized chemical synergistically increased with US+IP compared with the individual flux of US and IP. The chemicals with molecular weight of more than 1000 showed synergistic effects with US+IP. The mathematical simulation assuming a bilayer skin model revealed that the synergistic effects were mainly influenced by electroosmosis in the stratum corneum (SC). Therefore the synergistic effects of US+IP was mainly caused by the SC diffusivity of chemicals increased by US and the electroosmotic water flow by IP application.

  10. Synergistic Interactions in Multispecies Biofilms

    DEFF Research Database (Denmark)

    Ren, Dawei

    that the plasmid host range can be greatly affected by the surrounding bacterial community. This needs to be taken into account as many antibiotic resistance and virulence determinants are plasmid-encoded, which can spread further and raise antibiotic-resistant bacteria in soil....... bacterial species, the study to elucidate the impact of interaction networks on the multispecies biofilms in natural ecosystems, especially in soil, is still at an early stage. The diverse patterns of interactions within the mixed communities as well as the predatorprey relationship between protozoa...... interactions in this four-species biofilm model community. Manuscript 2 presents the further application of this developed approach on evaluating the synergistic/antagonistic interactions in multispecies biofilms composed of seven soil isolates. 63% of the four-species biofilms were found to interact...

  11. Synergistic Interactions in Multispecies Biofilms

    DEFF Research Database (Denmark)

    Ren, Dawei

    structured aggregation consisting of multiple species of bacteria whose function relies on a complex web of cooperative and/or competitive interactions between community members, indicating that research in “whole-entity” should not be based on the assembled results from “mono pieces”. As one of the best...... bacterial species, the study to elucidate the impact of interaction networks on the multispecies biofilms in natural ecosystems, especially in soil, is still at an early stage. The diverse patterns of interactions within the mixed communities as well as the predatorprey relationship between protozoa...... interactions in this four-species biofilm model community. Manuscript 2 presents the further application of this developed approach on evaluating the synergistic/antagonistic interactions in multispecies biofilms composed of seven soil isolates. 63% of the four-species biofilms were found to interact...

  12. DNA, cell wall and general oxidative damage underlie the tellurite/cefotaxime synergistic effect in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Roberto C Molina-Quiroz

    Full Text Available The constant emergence of antibiotic multi-resistant pathogens is a concern worldwide. An alternative for bacterial treatment using nM concentrations of tellurite was recently proposed to boost antibiotic-toxicity and a synergistic effect of tellurite/cefotaxime (CTX was described. In this work, the molecular mechanism underlying this phenomenon is proposed. Global changes of the transcriptional profile of Escherichia coli exposed to tellurite/CTX were determined by DNA microarrays. Induction of a number of stress regulators (as SoxS, genes related to oxidative damage and membrane transporters was observed. Accordingly, increased tellurite adsorption/uptake and oxidative injuries to proteins and DNA were determined in cells exposed to the mixture of toxicants, suggesting that the tellurite-mediated CTX-potentiating effect is dependent, at least in part, on oxidative stress. Thus, the synergistic tellurite-mediated CTX-potentiating effect depends on increased tellurite uptake/adsorption which results in damage to proteins, DNA and probably other macromolecules. Our findings represent a contribution to the current knowledge of bacterial physiology under antibiotic stress and can be of great interest in the development of new antibiotic-potentiating strategies.

  13. Nanotechnology for Multimodal Synergistic Cancer Therapy.

    Science.gov (United States)

    Fan, Wenpei; Yung, Bryant; Huang, Peng; Chen, Xiaoyuan

    2017-11-22

    The complexity, diversity, and heterogeneity of tumors seriously undermine the therapeutic potential of treatment. Therefore, the current trend in clinical research has gradually shifted from a focus on monotherapy to combination therapy for enhanced treatment efficacy. More importantly, the cooperative enhancement interactions between several types of monotherapy contribute to the naissance of multimodal synergistic therapy, which results in remarkable superadditive (namely "1 + 1 > 2") effects, stronger than any single therapy or their theoretical combination. In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergistic therapy as well as the intensive exploration of the underlying synergistic mechanisms for explaining the significant improvements in synergistic therapeutic outcome. Furthermore, the featured applications of multimodal synergistic therapy in overcoming tumor multidrug resistance, hypoxia, and metastasis will also be discussed in detail, which may provide new ways for the efficient regression and even elimination of drug resistant, hypoxic solid, or distant metastatic tumors. Finally, some design tips for multifunctional nanomaterials and an outlook on the future development of multimodal synergistic therapy will be provided, highlighting key scientific issues and technical challenges and requiring remediation to accelerate clinical translation.

  14. Silica ecosystem for synergistic biotransformation

    Science.gov (United States)

    Mutlu, Baris R.; Sakkos, Jonathan K.; Yeom, Sujin; Wackett, Lawrence P.; Aksan, Alptekin

    2016-06-01

    Synergistical bacterial species can perform more varied and complex transformations of chemical substances than either species alone, but this is rarely used commercially because of technical difficulties in maintaining mixed cultures. Typical problems with mixed cultures on scale are unrestrained growth of one bacterium, which leads to suboptimal population ratios, and lack of control over bacterial spatial distribution, which leads to inefficient substrate transport. To address these issues, we designed and produced a synthetic ecosystem by co-encapsulation in a silica gel matrix, which enabled precise control of the microbial populations and their microenvironment. As a case study, two greatly different microorganisms: Pseudomonas sp. NCIB 9816 and Synechococcus elongatus PCC 7942 were encapsulated. NCIB 9816 can aerobically biotransform over 100 aromatic hydrocarbons, a feat useful for synthesis of higher value commodity chemicals or environmental remediation. In our system, NCIB 9816 was used for biotransformation of naphthalene (a model substrate) into CO2 and the cyanobacterium PCC 7942 was used to provide the necessary oxygen for the biotransformation reactions via photosynthesis. A mathematical model was constructed to determine the critical cell density parameter to maximize oxygen production, and was then used to maximize the biotransformation rate of the system.

  15. Overexpression of a Novel NAC Domain-Containing Transcription Factor Gene (AaNAC1) Enhances the Content of Artemisinin and Increases Tolerance to Drought and Botrytis cinerea in Artemisia annua.

    Science.gov (United States)

    Lv, Zongyou; Wang, Shu; Zhang, Fangyuan; Chen, Lingxian; Hao, Xiaolong; Pan, Qifang; Fu, Xueqing; Li, Ling; Sun, Xiaofen; Tang, Kexuan

    2016-09-01

    The NAC (NAM, ATAF and CUC) superfamily is one of the largest plant-specific transcription factor families. NAC transcription factors always play important roles in response to various abiotic stresses. A NAC transcription factor gene AaNAC1 containing a complete open reading frame (ORF) of 864 bp was cloned from Artemisia annua. The expression of AaNAC1 could be induced by dehydration, cold, salicylic acid (SA) and methyl jasmonate (MJ), suggesting that it might be a key regulator of stress signaling pathways in A. annua. AaNAC1 was shown to be localized to the nuclei by transforming tobacco leaf epidermal cells. When AaNAC1 was overexpressed in A. annua, the content of artemisinin and dihydroartemisinic acid was increased by 79% and 150%, respectively. The expression levels of artemisinin biosynthetic pathway genes, i.e. amorpha-4,11-diene synthase (ADS), artemisinic aldehyde Δ11(13) reductase (DBR2) and aldehyde dehydrogenase 1 (ALDH1), were increased. Dual luciferase (dual-LUC) assays showed that AaNAC1 could activate the transcription of ADS in vivo. The transgenic A. annua exhibited increased tolerance to drought and resistance to Botrytis cinerea. When AaNAC1 was overexpressed in Arabidopsis, the transgenic Arabidopsis were markedly more tolerant to drought. The transgenic Arabidopsis showed increased resistance to B. cinerea. These results indicate that AaNAC1 can potentially be used in transgenic breeding for improving the content of artemisinin and drought tolerance in A. annua. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  16. Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell apoptosis in C. elegans.

    Science.gov (United States)

    Lee, C-C; Tsai, Y-T; Kao, C-W; Lee, L-W; Lai, H-J; Ma, T-H; Chang, Y-S; Yeh, N-H; Lo, S J

    2014-04-10

    Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis or loss of ribosomal components are collectively described as 'ribosomopathies'. Treacher Collins syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in the early embryo. Here, we established a C. elegans model for studying Nopp140-associated ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4 (H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C. elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5 mutant of C. elegans can be a valuable model for studying human Nopp140-associated ribosomopathy at the cellular and molecular levels.

  17. Statistical metamodeling for revealing synergistic antimicrobial interactions.

    Directory of Open Access Journals (Sweden)

    Hsiang Chia Chen

    2010-11-01

    Full Text Available Many bacterial pathogens are becoming drug resistant faster than we can develop new antimicrobials. To address this threat in public health, a metamodel antimicrobial cocktail optimization (MACO scheme is demonstrated for rapid screening of potent antibiotic cocktails using uropathogenic clinical isolates as model systems. With the MACO scheme, only 18 parallel trials were required to determine a potent antimicrobial cocktail out of hundreds of possible combinations. In particular, trimethoprim and gentamicin were identified to work synergistically for inhibiting the bacterial growth. Sensitivity analysis indicated gentamicin functions as a synergist for trimethoprim, and reduces its minimum inhibitory concentration for 40-fold. Validation study also confirmed that the trimethoprim-gentamicin synergistic cocktail effectively inhibited the growths of multiple strains of uropathogenic clinical isolates. With its effectiveness and simplicity, the MACO scheme possesses the potential to serve as a generic platform for identifying synergistic antimicrobial cocktails toward management of bacterial infection in the future.

  18. SYNERGISTIC WOOD PRESERVATIVES FOR REPLACEMENT OF CCA

    Science.gov (United States)

    The objective of this project was to evaluate the potential synergistic combinations of environmentally-safe biocides as wood preservatives. These wood preservatives could be potential replacements for the heavy-metal based CCA.Didecyldimethylammonium chloride [DDAC] was...

  19. Intrinsic synergistic-topological mechanism versus synergistic-topological matrix in microtubule self-organization

    Directory of Open Access Journals (Sweden)

    Buljan Vlado A

    2014-12-01

    Overall our data indicate that under crowded conditions in vitro, the self-organization of a microtubule fiber is governed by an intrinsic synergistic-topological mechanism, which in conjunction with the topological changes, GTP-tubulin depletion, and cooperative motion of fiber constituting microtubules, may generate and maintain a ‘synergistic-topological matrix’. Failure of the mechanism to form biologically feasible microtubule synergistic-topological matrix may, per se, precondition tumorigenesis.

  20. Oxidative stress reduced by a green tea concentrate and Capsicum combination: synergistic effects.

    Science.gov (United States)

    Forney, Greg B; Morré, D James; Morré, Dorothy M

    2013-12-01

    Reactive oxygen species that are produced by aerobic metabolism and signaling cascades have the potential to play important roles in maintaining homeostatic redox and cell proliferation. When the balance between the production and elimination of reactive oxygen species is perturbed toward production, the result is oxidative stress. High levels of oxidative stress are a general characteristic of cancer. The altered redox state within a tumor microenvironment confers a growth advantage through increased proliferation rates, evasion of apoptosis, and increased resistance to therapeutic compounds. We have tested a synergistic combination of green tea-Camellia sinensis-concentrate and powdered Capsicum powder (TeaFense™/Capsol-T™) as a dietary supplement to reduce oxidative stress as an approach to elimination of malignant cells. Here, we demonstrate that the green tea-powdered Capsicum mixture effectively reduces levels of oxidative stress in both cancer (HeLa) and noncancer (MCF-10A) cells as determined from measurements of levels of the oxidative stress indicator Nrf-2 by western blot analysis. Nrf-2 is a transcription factor that controls an antioxidant response element. Increased expression of Nrf-2 is linked to high levels of oxidative stress and vice versa. Based on levels of Nrf-2, the mixture of green tea concentrate plus powdered Capsicum reduced oxidative stress by more than 50% compared with 15% by the green tea concentrate alone.

  1. Effects of immune synergist of Chinese medicinal herbs on the ...

    African Journals Online (AJOL)

    AJL

    2012-01-19

    Jan 19, 2012 ... Two-month-old piglets were fed with 1, 1.5 and 2% immune synergist of Chinese medicinal herbs together with vaccination against classic swine fever. Serum IgG and IgM levels increased more than the control group on day. 30 (P<0.05). B and T lymphocyte proliferation in piglets fed with 1.5 and 2% ...

  2. Comprehension of synergistic mechanisms for uranium extraction from phosphate ores

    International Nuclear Information System (INIS)

    Pecheur, Olivia

    2014-01-01

    Uranium VI is commonly extracted from phosphoric ores by a well-known process exploiting the synergistic mixture of two extractant molecules: HDEHP and TOPO. In the field of liquid-liquid extraction, synergistic combinations are common but the mechanisms at the origin of the synergy are not well understood. A multi-scale approach has been used to describe these mechanisms, combining two different descriptions: the molecular scale focuses on the ion point of view, while the supramolecular scale focuses on extractants' aggregation. These two approaches have been rationalized by molecular dynamics computations. The results allow describing the synergy through the structure of the complexes and aggregates. With the same approach, some bifunctional compounds, combining the two extracting sites in one molecule, have been studied and compared to the HDEHP/TOPO system in order to identify the origin of their increased capacities in extraction and selectivity. (author) [fr

  3. Coordinate enhancement of transgene transcription and translation in a lentiviral vector

    Directory of Open Access Journals (Sweden)

    Fernandez Soledad

    2006-02-01

    Full Text Available Abstract Background Coordinate enhancement of transgene transcription and translation would be a potent approach to significantly improve protein output in a broad array of viral vectors and nonviral expression systems. Many vector transgenes are complementary DNA (cDNA. The lack of splicing can significantly reduce the efficiency of their translation. Some retroviruses contain a 5' terminal post-transcriptional control element (PCE that facilitates translation of unspliced mRNA. Here we evaluated the potential for spleen necrosis virus PCE to stimulate protein production from HIV-1 based lentiviral vector by: 1 improving translation of the internal transgene transcript; and 2 functionally synergizing with a transcriptional enhancer to achieve coordinate increases in RNA synthesis and translation. Results Derivatives of HIV-1 SIN self-inactivating lentiviral vector were created that contain PCE and cytomegalovirus immediate early enhancer (CMV IE. Results from transfected cells and four different transduced cell types indicate that: 1 PCE enhanced transgene protein synthesis; 2 transcription from the internal promoter is enhanced by CMV IE; 3 PCE and CMV IE functioned synergistically to significantly increase transgene protein yield; 4 the magnitude of translation enhancement by PCE was similar in transfected and transduced cells; 5 differences were observed in steady state level of PCE vector RNA in transfected and transduced cells; 6 the lower steady state was not attributable to reduced RNA stability, but to lower cytoplasmic accumulation in transduced cells. Conclusion PCE is a useful tool to improve post-transcriptional expression of lentiviral vector transgene. Coordinate enhancement of transcription and translation is conferred by the combination of PCE with CMV IE transcriptional enhancer and increased protein yield up to 11 to 17-fold in transfected cells. The incorporation of the vector provirus into chromatin correlated with reduced

  4. Pooled screening for synergistic interactions subject to blocking and noise.

    Directory of Open Access Journals (Sweden)

    Kyle Li

    Full Text Available The complex molecular networks in the cell can give rise to surprising interactions: gene deletions that are synthetically lethal, gene overexpressions that promote stemness or differentiation, synergistic drug interactions that heighten potency. Yet, the number of actual interactions is dwarfed by the number of potential interactions, and discovering them remains a major problem. Pooled screening, in which multiple factors are simultaneously tested for possible interactions, has the potential to increase the efficiency of searching for interactions among a large set of factors. However, pooling also carries with it the risk of masking genuine interactions due to antagonistic influence from other factors in the pool. Here, we explore several theoretical models of pooled screening, allowing for synergy and antagonism between factors, noisy measurements, and other forms of uncertainty. We investigate randomized sequential designs, deriving formulae for the expected number of tests that need to be performed to discover a synergistic interaction, and the optimal size of pools to test. We find that even in the presence of significant antagonistic interactions and testing noise, randomized pooled designs can significantly outperform exhaustive testing of all possible combinations. We also find that testing noise does not affect optimal pool size, and that mitigating noise by a selective approach to retesting outperforms naive replication of all tests. Finally, we show that a Bayesian approach can be used to handle uncertainty in problem parameters, such as the extent of synergistic and antagonistic interactions, resulting in schedules for adapting pool size during the course of testing.

  5. Synergistic effects in plasma surface interactions

    International Nuclear Information System (INIS)

    Roberto, J.B.; Behrisch, R.

    1984-01-01

    The possible synergistic effects which can contribute to plasma surface interaction phenomena in fusion devices are reviewed. These effects include the influence of reactive ions, surface modification, temperature, radiation damage, and external forces and fields on erosion yields, hydrogen retention and release, and other surface processes. The important synergistic effects are described in terms of surface and edge conditions encountered in present fusion devices and expected in future reactors. Priority data needs include the chemical erosion of graphite at high particle fluxes, melt-layer stability under disruption-induced eddy current forces, the influence of bulk neutron damage on hydrogen retention, and an in-situ evaluation of synergistic effects in operating fusion devices

  6. Glycophenotypic alterations induced by Pteridium aquilinum in mice gastric mucosa: synergistic effect with Helicobacter pylori infection.

    Directory of Open Access Journals (Sweden)

    Joana Gomes

    Full Text Available The bracken fern Pteridium aquilinum is a plant known to be carcinogenic to animals. Epidemiological studies have shown an association between bracken fern exposure and gastric cancer development in humans. The biological effects of exposure to this plant within the gastric carcinogenesis process are not fully understood. In the present work, effects in the gastric mucosa of mice treated with Pteridium aquilinum were evaluated, as well as molecular mechanisms underlying the synergistic role with Helicobacter pylori infection. Our results showed that exposure to Pteridium aquilinum induces histomorphological modifications including increased expression of acidic glycoconjugates in the gastric mucosa. The transcriptome analysis of gastric mucosa showed that upon exposure to Pteridium aquilinum several glycosyltransferase genes were differently expressed, including Galntl4, C1galt1 and St3gal2, that are mainly involved in the biosynthesis of simple mucin-type carbohydrate antigens. Concomitant treatment with Pteridium aquilinum and infection with Helicobacter pylori also resulted in differently expressed glycosyltransferase genes underlying the biosynthesis of terminal sialylated Lewis antigens, including Sialyl-Lewis(x. These results disclose the molecular basis for the altered pattern of glycan structures observed in the mice gastric mucosa. The gene transcription alterations and the induced glycophenotypic changes observed in the gastric mucosa contribute for the understanding of the molecular mechanisms underlying the role of Pteridium aquilinum in the gastric carcinogenesis process.

  7. Glycophenotypic alterations induced by Pteridium aquilinum in mice gastric mucosa: synergistic effect with Helicobacter pylori infection.

    Science.gov (United States)

    Gomes, Joana; Magalhães, Ana; Carvalho, Ana S; Hernandez, Gilberto E; Papp, Suzanne L; Head, Steven R; Michel, Valérie; David, Leonor; Gärtner, Fátima; Touati, Eliette; Reis, Celso A

    2012-01-01

    The bracken fern Pteridium aquilinum is a plant known to be carcinogenic to animals. Epidemiological studies have shown an association between bracken fern exposure and gastric cancer development in humans. The biological effects of exposure to this plant within the gastric carcinogenesis process are not fully understood. In the present work, effects in the gastric mucosa of mice treated with Pteridium aquilinum were evaluated, as well as molecular mechanisms underlying the synergistic role with Helicobacter pylori infection. Our results showed that exposure to Pteridium aquilinum induces histomorphological modifications including increased expression of acidic glycoconjugates in the gastric mucosa. The transcriptome analysis of gastric mucosa showed that upon exposure to Pteridium aquilinum several glycosyltransferase genes were differently expressed, including Galntl4, C1galt1 and St3gal2, that are mainly involved in the biosynthesis of simple mucin-type carbohydrate antigens. Concomitant treatment with Pteridium aquilinum and infection with Helicobacter pylori also resulted in differently expressed glycosyltransferase genes underlying the biosynthesis of terminal sialylated Lewis antigens, including Sialyl-Lewis(x). These results disclose the molecular basis for the altered pattern of glycan structures observed in the mice gastric mucosa. The gene transcription alterations and the induced glycophenotypic changes observed in the gastric mucosa contribute for the understanding of the molecular mechanisms underlying the role of Pteridium aquilinum in the gastric carcinogenesis process.

  8. Comment on mRNA-Sequencing Analysis Reveals Transcriptional Changes in Root of Maize Seedlings Treated with Two Increasing Concentrations of a New Biostimulant.

    Science.gov (United States)

    da Silva, Ronivaldo Rodrigues

    2018-02-28

    Overpopulation is already a reality, and the need for alternative technologies to meet a continuously increasing food demand has been much discussed around the world. In addition, soil decreasing fertility and desertification are obstacles that we will need to be overcome to increase crop productivity with a much-reduced dependence upon inorganic fertilizers. In this context, protein hydrolysates has emerged as an important strategy to reduce the use of inorganic fertilizers, whose applications as biostimulants for plant growth have shown very promising results.

  9. Increased neurovirulence and reactivation of the herpes simplex virus type 1 latency associated transcript (LAT) negative mutant dLAT2903 with a disrupted LAT miR-H2

    Science.gov (United States)

    Jiang, Xianzhi; Brown, Don; Osorio, Nelson; Hsiang, Chinhui; BenMohamed, Lbachir; Wechsler, Steven L.

    2015-01-01

    At least six microRNAs (miRNAs) appear to be encoded by the latency associated transcript (LAT) of herpes simplex virus type 1 (HSV-1). The gene for ICP0, an important immediate early (IE) viral protein, is antisense to, and overlaps with, the region of LAT from which miRNA H2 (miR-H2) is derived. We recently reported that a mutant (McK-ΔH2) disrupted for miR-H2 on the wild type HSV-1 strain McKrae genomic background has increased ICP0 expression, increased neurovirulence, and slightly more rapid reactivation. We report here that HSV-1 mutants deleted for the LAT promoter nonetheless make significant amounts of miR-H2 during lytic tissue culture infection, presumably via readthrough transcription from an upstream promoter. To determine if miR-H2 might also play a role in the HSV-1 latency-reactivation cycle of a LAT negative mutant, we constructed dLAT-ΔH2, in which miR-H2 is disrupted in dLAT2903 without altering the predicted amino acid sequence of the overlapping ICP0 open reading frame. Similar to McK-ΔH2, dLAT-ΔH2 expressed more ICP0, was more neurovirulent, and had increased reactivation in the mouse TG explant induced reactivation model of HSV-1 compared to its parental virus. Interestingly, although the increased reactivation of McK-ΔH2 compared to its parental wt virus was subtle and only detected at very early times after explant TG induced reactivation, the increased reactivation of dLAT-ΔH2 compared to its dLAT2903 parental virus appeared more robust and was significantly increased even at late times after induction. These results confirm that miR-H2 plays a role in modulating the HSV-1 reactivation phenotype. PMID:26069184

  10. The LIM homeodomain transcription factor LHX6: a transcriptional repressor that interacts with pituitary homeobox 2 (PITX2) to regulate odontogenesis.

    Science.gov (United States)

    Zhang, Zichao; Gutierrez, Diana; Li, Xiao; Bidlack, Felicitas; Cao, Huojun; Wang, Jianbo; Andrade, Kelsey; Margolis, Henry C; Amendt, Brad A

    2013-01-25

    LHX6 is a LIM-homeobox transcription factor expressed during embryogenesis; however, the molecular mechanisms regulating LHX6 transcriptional activities are unknown. LHX6 and the PITX2 homeodomain transcription factor have overlapping expression patterns during tooth and craniofacial development, and in this report, we demonstrate new transcriptional mechanisms for these factors. PITX2 and LHX6 are co-expressed in the oral and dental epithelium and epithelial cell lines. Lhx6 expression is increased in Pitx2c transgenic mice and decreased in Pitx2 null mice. PITX2 activates endogenous Lhx6 expression and the Lhx6 promoter, whereas LHX6 represses its promoter activity. Chromatin immunoprecipitation experiments reveal endogenous PITX2 binding to the Lhx6 promoter. LHX6 directly interacts with PITX2 to inhibit PITX2 transcriptional activities and activation of multiple promoters. Bimolecular fluorescence complementation assays reveal an LHX6·PITX2 nuclear interaction in living cells. LHX6 has a dominant repressive effect on the PITX2 synergistic activation with LEF-1 and β-catenin co-factors. Thus, LHX6 acts as a transcriptional repressor and represses the expression of several genes involved in odontogenesis. We have identified specific defects in incisor, molar, mandible, bone, and root development and late stage enamel formation in Lhx6 null mice. Amelogenin and ameloblastin expression is reduced and/or delayed in the Lhx6 null mice, potentially resulting from defects in dentin deposition and ameloblast differentiation. Our results demonstrate that LHX6 regulates cell proliferation in the cervical loop and promotes cell differentiation in the anterior region of the incisor. We demonstrate new molecular mechanisms for LHX6 and an interaction with PITX2 for normal craniofacial and tooth development.

  11. The effect of insecticide synergists on the response of scabies mites to pyrethroid acaricides.

    Science.gov (United States)

    Pasay, Cielo; Arlian, Larry; Morgan, Marjorie; Gunning, Robin; Rossiter, Louise; Holt, Deborah; Walton, Shelley; Beckham, Simone; McCarthy, James

    2009-01-01

    Permethrin is the active component of topical creams widely used to treat human scabies. Recent evidence has demonstrated that scabies mites are becoming increasingly tolerant to topical permethrin and oral ivermectin. An effective approach to manage pesticide resistance is the addition of synergists to counteract metabolic resistance. Synergists are also useful for laboratory investigation of resistance mechanisms through their ability to inhibit specific metabolic pathways. To determine the role of metabolic degradation as a mechanism for acaricide resistance in scabies mites, PBO (piperonyl butoxide), DEF (S,S,S-tributyl phosphorotrithioate) and DEM (diethyl maleate) were first tested for synergistic activity with permethrin in a bioassay of mite killing. Then, to investigate the relative role of specific metabolic pathways inhibited by these synergists, enzyme assays were developed to measure esterase, glutathione S-transferase (GST) and cytochrome P450 monooxygenase (cytochrome P450) activity in mite extracts. A statistically significant difference in median survival time of permethrin-resistant Sarcoptes scabiei variety canis was noted when any of the three synergists were used in combination with permethrin compared to median survival time of mites exposed to permethrin alone (presistant mites compared to sensitive mites. These findings indicate the potential utility of synergists in reversing resistance to pyrethroid-based acaricides and suggest a significant role of metabolic mechanisms in mediating pyrethroid resistance in scabies mites.

  12. Focal cerebral ischemia induces increased myelin basic protein and growth-associated protein-43 gene transcription in peri-infarct areas in the rat brain

    DEFF Research Database (Denmark)

    Gregersen, R; Christensen, Thomas; Lehrmann, E

    2001-01-01

    Although oligodendrocytes are vulnerable to focal cerebral ischemia, remyelination of denuded or regenerating axons in the peri-infarct area has been observed in the central nervous system. We studied the expression of myelin basic protein (MBP), a major component of central nervous system myelin...... messenger RNA (mRNA) had disappeared by 24 h, whereas myelin protein, identified by MBP and myelin oligodendrocyte glycoprotein (MOG) immunohistochemistry, appeared structurally intact until day 3. Peri-infarct oligodendrocytes increased their expression of MBP mRNA from 24 h to maximal levels at day 7...... showed that increased expression of GAP-43 mRNA in neurons was concomitant to MBP mRNA upregulation in oligodendrocytes. While the mechanisms regulating oligodendrocyte survival and myelination signals are not clear at this point, axonal sprouting could putatively serve as a stimulus for the upregulation...

  13. Synergistic Effect of Caffeine and Glucocorticoids on Expression of Surfactant Protein B (SP-B) mRNA

    Science.gov (United States)

    Fehrholz, Markus; Bersani, Iliana; Kramer, Boris W.; Speer, Christian P.; Kunzmann, Steffen

    2012-01-01

    Administration of glucocorticoids and caffeine is a common therapeutic intervention in the neonatal period, but possible interactions between these substances are still unclear. The present study investigated the effect of caffeine and different glucocorticoids on expression of surfactant protein (SP)-B, crucial for the physiological function of pulmonary surfactant. We measured expression levels of SP-B, various SP-B transcription factors including erythroblastic leukemia viral oncogene homolog 4 (ErbB4) and thyroid transcription factor-1 (TTF-1), as well as the glucocorticoid receptor (GR) after administering different doses of glucocorticoids, caffeine, cAMP, or the phosphodiesterase-4 inhibitor rolipram in the human airway epithelial cell line NCI-H441. Administration of dexamethasone (1 µM) or caffeine (5 mM) stimulated SP-B mRNA expression with a maximal of 38.8±11.1-fold and 5.2±1.4-fold increase, respectively. Synergistic induction was achieved after co-administration of dexamethasone (1 mM) in combination with caffeine (10 mM) (206±59.7-fold increase, pglucocorticoids and caffeine, achieved by accumulation of intracellular cAMP. This effect was mediated by a caffeine-dependent phosphodiesterase inhibition and by upregulation of both ErbB4 and the GR. These results suggested that caffeine is able to induce the expression of SP-transcription factors and affects the signaling pathways of glucocorticoids, amplifying their effects. Co-administration of caffeine and corticosteroids may therefore be of benefit in surfactant homeostasis. PMID:23272120

  14. SYNERGISTIC ANTIBACTERIAL EFFECT OF STEM BARK ...

    African Journals Online (AJOL)

    userpc

    ABSTRACT. The study was aimed at screening the stem bark extracts of Faidherbia albida and Psidium guajava for synergistic antibacterial effect against methicillin resistant Staphylococcus aureus (MRSA). The powdered plant materials were extracted with methanol using cold maceration technique and the extracts were ...

  15. Modelling synergistic effects of appetite regulating hormones

    DEFF Research Database (Denmark)

    Schmidt, Julie Berg; Ritz, Christian

    2016-01-01

    We briefly reviewed one definition of dose addition, which is applicable within the framework of generalized linear models. We established how this definition of dose addition corresponds to effect addition in case only two doses per compound are considered for evaluating synergistic effects...

  16. Synergistic Antimicrobial Activities Of Phytoestrogens In Crude ...

    African Journals Online (AJOL)

    Ethanolic, methanolic and aqueous extracts of both leaves were studied for their in-vitro synergistic antimicrobial activity against both Gram positive and Gram negative micro-organisms, and Yeast using Agar diffusion method. The GC-MS phytochemical screening of methanolic extract showed that the major compounds in ...

  17. Vitex Agnus Castus Extract Improves Learning and Memory and Increases the Transcription of Estrogen Receptor α in Hippocampus of Ovariectomized Rats.

    Science.gov (United States)

    Allahtavakoli, Mohammad; Honari, Najmeh; Pourabolli, Iran; Kazemi Arababadi, Mohammad; Ghafarian, Hossein; Roohbakhsh, Ali; Esmaeili Nadimi, Ali; Shamsizadeh, Ali

    2015-07-01

    Lower level of estrogen hormone is considered as an important factor for loss of learning and memory in postmenopausal women. Although estrogen replacement therapy is used for compensation, but long-term usage of estrogen is associated with a higher risk of hormone-dependent cancers. Phytoestrogens, due to fewer side effects, have been proposed to prevent menopause-related cognitive decline. 24 female Wistar rats weighing 180-220 g were used in this study. The animals were ovariectomized and randomly divided into four groups including, control and two groups which received 8 and 80 mg/kg Vitex agnus castus (VAC) ethanolic extract orally. The last groups were treated with 40 μg/kg of estradiol valerat. Step-through passive avoidance (STPA) test was used for the evaluation of learning and memory. The hippocampal estrogen receptor α (ERα) expression was measured using Real-Time PCR. The results demonstrated that VAC extract or estradiol had better performance on step-through passive avoidance test than control group (all P<0.05). Moreover, administration of either estradiol or VAC extract increased the hippocampal mRNA level of ERα and prevented the decrease in uterine weight of ovariectomized rats. Based on our data, VAC extract improves learning and memory in ovariectomized rats. The positive effect of VAC extract on learning and memory is possibly associated with an increase in ERα gene expression in the hippocampal formation.

  18. Non-lethal heat shock increased Hsp70 and immune protein transcripts but not Vibrio tolerance in the white-leg shrimp.

    Directory of Open Access Journals (Sweden)

    Nguyen Hong Loc

    Full Text Available Non-lethal heat shock boosts bacterial and viral disease tolerance in shrimp, possibly due to increases in endogenous heat shock protein 70 (Hsp70 and/or immune proteins. To further understand the mechanisms protecting shrimp against infection, Hsp70 and the mRNAs encoding the immune-related proteins prophenoloxidase (proPO, peroxinectin, penaeidin, crustin and hemocyanin were studied in post-larvae of the white-leg shrimp Litopenaeus vannamei, following a non-lethal heat shock. As indicated by RT-qPCR, a 30 min abrupt heat shock increased Hsp70 mRNA in comparison to non-heated animals. Immunoprobing of western blots and quantification by ELISA revealed that Hsp70 production after heat shock was correlated with enhanced Hsp70 mRNA. proPO and hemocyanin mRNA levels were augmented, whereas peroxinectin and crustin mRNA levels were unchanged following non-lethal heat shock. Penaeidin mRNA was decreased by all heat shock treatments. Thirty min abrupt heat shock failed to improve survival of post-larvae in a standardized challenge test with Vibrio harveyi, indicating that under the conditions of this study, L. vannamei tolerance to Vibrio infection was influenced neither by Hsp70 accumulation nor the changes in the immune-related proteins, observations dissimilar to other shrimp species examined.

  19. [Synergistion mechanism of exogenous Ca2+ to SA-induced resistance to Botrytis cinerea in tomato].

    Science.gov (United States)

    Li, Lin-lin; Li, Tian-lai; Jiang, Guo-bin; Jin, Hua; Zou, Ji-xiang

    2015-11-01

    In this study, we investigated the effect of exogenous calcium and salicylic acid (SA) on Botrytis cinerea resistance in tomato seedlings. We treated a tomato strain susceptible to Botrytis cinerea with foliar spraying of water, SA, SA+CaCl2 and SA+EGTA (Ca2+ chelating agent) for one to five days. During the treatment, leaves were collected to analyze the reactive oxygen species (ROS) content, phenylalanine ammonia lyase (PAL) activity, chintase and β-1,3-glucanase levels, and the expression of pathogenesis related protein 1, 2, 3 (PR1, PR2, PR3). Three days after infection, the disease index was 74.8 in control plants, and 46.9, 38.5 and 70.3 in SA, SA+Ca and SA+ EGTA treated plants, respectively. SA treatment significantly increased ROS leaf accumulation, and activities of PAL, chintase and β-1,3-glucanase. These values were further enhanced in SA+Ca treated plants, but decreased in SA+EGTA treated plants. Application of SA significantly increased the expression levels of PR1, PR2a and PR3b, which were further elevated by the combination treatment with Ca2+. These effects were counteracted by the combination treatment of SA and EGTA. The transcription levels of PR2b and PR3a were up-regulated by 1-2 folds, and PR1, 2a and 3b by 2-5 folds in SA- and SA+Ca-treated plants relative to control. These data suggested that application of Ca2+ could synergistically increase SA-induced resistance to B. cinerea. The resistance was associated with ROS accumulation, therefore the increase in resistance might be through ROS ability to increase the activity of defense-related enzymes and expression levels of PR1, PR2a and PR3b.

  20. FOXO3a reactivation mediates the synergistic cytotoxic effects of rapamycin and cisplatin in oral squamous cell carcinoma cells

    International Nuclear Information System (INIS)

    Fang Liang; Wang Huiming; Zhou Lin; Yu Da

    2011-01-01

    FOXO3a, a well-known transcriptional regulator, controls a wide spectrum of biological processes. The Phosphoinositide-3-kinase (PI3K)/Akt signaling pathway inactivates FOXO3a via phosphorylation-induced nuclear exclusion and degradation. A loss or gain of FOXO3a activity has been correlated with efficiency of chemotherapies in various cancers including oral squamous cell carcinoma (OSCC). Therefore, in the current study, we have investigated the FOXO3a activity modulating and antitumor effects of rapamycin and cisplatin in OSCC cells. Cisplatin inhibited proliferation and induced apoptosis in a dose-dependent way in OSCC Tca8113 cells. Rapamycin alone had no effect on cell proliferation and apoptosis. Rapamycin downregulated the expression of S-phase kinase associated protein-2 (Skp2) and increased the FOXO3a protein stability but induced the upregulation of feedback Akt activation-mediated FOXO3a phosphorylation. Cisplatin decreased the phosphorylation of FOXO3a via Akt inhibition. Rapamycin combined with cisplatin as its feedback Akt activation inhibitor revealed the most dramatic FOXO3a nuclear localization and reactivation with the prevention of its feedback loop and exposed significant synergistic effects of decreased cell proliferation and increased apoptosis in vitro and decreased tumor size in vivo. Furthermore, the downstream effects of FOXO3a reactivation were found to be accumulation of p27 and Bim. In conclusion, rapamycin/cisplatin combination therapy boosts synergistic antitumor effects through the significant FOXO3a reactivation in OSCC cells. These results may represent a novel mechanism by which rapamycin/cisplatin combination therapy proves to be a potent molecular-targeted strategy for OSCC.

  1. The Translation Initiation Factor 1A (TheIF1A) fromTamarix hispidaIs Regulated by a Dof Transcription Factor and Increased Abiotic Stress Tolerance.

    Science.gov (United States)

    Yang, Guiyan; Yu, Lili; Wang, Yucheng; Wang, Chao; Gao, Caiqiu

    2017-01-01

    Eukaryotic translation initiation factor 1A ( eIF1A ) functions as an mRNA scanner and AUG initiation codon locator. However, few studies have clarified the role of eIF1A in abiotic stress. In this study, we cloned eIF1A ( TheIF1A ) from Tamarix hispida and found its expression to be induced by NaCl and polyethylene glycol (PEG) in roots, stems, and leaves. Compared to control, TheIF1A root expression was increased 187.63-fold when exposed to NaCl for 6 h, suggesting a potential abiotic stress response for this gene. Furthermore, transgenic tobacco plants overexpressing TheIF1A exhibited enhanced seed germination and a higher total chlorophyll content under salt and mannitol stresses. Increased superoxide dismutase, peroxidase, glutathione transferase and glutathione peroxidase activities, as well as decreased electrolyte leakage rates and malondialdehyde contents, were observed in TheIF1A -transgenic tobacco and T. hispida seedlings under salt and mannitol stresses. Histochemical staining suggested that TheIF1A improves reactive oxygen species (ROS) scavenging in plants. Moreover, TheIF1A may regulate expression of stress-related genes, including TOBLTP , GST , MnSOD , NtMPK9 , poxN1 , and CDPK15 . Moreover, a 1352-bp promoter fragment of TheIF1A was isolated, and cis -elements were identified. Yeast one-hybrid assays showed that ThDof can specifically bind to the Dof motif present in the promoter. In addition, ThDof showed expression patterns similar to those of TheIF1A under NaCl and PEG stresses. These findings suggest the potential mechanism and physiological roles of TheIF1A . ThDof may be an upstream regulator of TheIF1A , and TheIF1A may function as a stress response regulator to improve plant salt and osmotic stress tolerance via regulation of associated enzymes and ROS scavenging, thereby reducing cell damage under stress conditions.

  2. Exposure to static magnetic fields increases insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.

    Science.gov (United States)

    Mao, Libin; Wang, Huiqin; Ma, Fenghui; Guo, Zhixia; He, Hongpeng; Zhou, Hao; Wang, Nan

    2017-08-01

    To evaluate the effect of static magnetic fields (SMFs) on insulin secretion and explore the mechanisms underlying exposure to SMF-induced insulin secretion in rat insulinoma INS-1 cells. INS-1 cells were exposed to a 400 mT SMF for 72 h, and the proliferation of INS-1 cells was detected by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The secretion of insulin was measured with an enzyme linked immunosorbent assays (ELISA), the expression of genes was detected by real-time PCR, and the expression of proteins was measured by Western blotting. Exposure to an SMF increased the expression and secretion of insulin by INS-1 cells but did not affect cell proliferation. Moreover, SMF exposure up-regulated the expression of several pancreas-specific transcriptional factors. Specifically, the activity of the rat insulin promoter was enhanced in INS-1 cells exposed to an SMF, and the expression levels of synaptosomal-associated protein 25 (SNAP-25) and syntaxin-1A were up-regulated after exposure to an SMF. SMF exposure can promote insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.

  3. Extracellular matrix and hormones transcriptionally regulate bovine. beta. -casein 5 prime sequences in stably transfected mouse mammary cells

    Energy Technology Data Exchange (ETDEWEB)

    Schmidhauser, C. Bissell, M.J. (Univ. of California, Berkeley (United States)); Myers, C.A.; Casperson, G.F. (Monsanto Corporate Research, St. Louis, MO (United States))

    1990-12-01

    Milk protein regulation involves synergistic action of lactogenic hormones and extracellular matrix (ECM). It is well established that substratum has a dramatic effect on morphology and function of mammary cells. The molecular mechanisms that regulate the ECM- and hormone-dependent gene expression, however, have not been resolved. To address this question, a subpopulation (designated CID 9) of the mouse mammary epithelial cell strain COMMA-2D has been developed in which more than 35% of the cells express {beta}-casein, form alveoli-like structures when plated onto a reconstituted basement membrane, and secrete {beta}-casein undirectionally into a lumen. These cells were stably transfected with a series of chloramphenicol acetyltransferase (CAT) fusion genes to study transcriptional regulation of the bovine {beta}-casein gene. The expression of CAT in these lines demonstrated a striking matrix and hormone dependency. This regulation occurered primarily at the transcriptional level and was dependent on the length of the 5{prime} flanking region of the {beta}-casein promotor. Both matrix and hormonal control of transcription occurred within at least the first 1790 base pairs upstream and/or 42 base pairs downstream of the transcriptional initiation site. The ECM effect was independent of glucocorticoid stimulation. However, prolactin was essential and hydrocortisone further increased CAT expression. Endogenous {beta}-casein expression in these lines was similar to that of the parent CID 9 cells. Our data indicate the existence of matrix-dependent elements that regulate transcription.

  4. Synergistic effects in mixed Escherichia coli biofilms

    DEFF Research Database (Denmark)

    Reisner, A.; Holler, B.M.; Molin, Søren

    2006-01-01

    the pathways governing development of more complex heterogeneous communities. In this study, we established a laboratory model where biofilm-stimulating effects due to interactions between genetically diverse strains of Escherichia coli were monitored. Synergistic induction of biofilm formation resulting from...... the cocultivation of 403 undomesticated E. coli strains with a characterized E. coli K-12 strain was detected at a significant frequency. The survey suggests that different mechanisms underlie the observed stimulation, yet synergistic development of biofilm within the subset of E. coli isolates (n = 56) exhibiting...... the strongest effects was most often linked to conjugative transmission of natural plasmids carried by the E. coli isolates (70%). Thus, the capacity of an isolate to promote the biofilm through cocultivation was (i) transferable to the K-12 strain, (ii) was linked with the acquisition of conjugation genes...

  5. [Synergistic divergence--case report].

    Science.gov (United States)

    Boricean, Ioana Daniela

    2013-01-01

    This 12-year old girl was diagnosed with congenital exotropia (XT) on left eye (OS) when she was 16 month-old and she was subjected to five surgical interventions on OS. She is now with face turn to the right. Visual acuity is 1 cc. Anterior segment is normal on right eye (OD) and multiple scars under bulbar conjunctiva are present on OS. Posterior segment is normal on both eyes. Ocular motility: at cover-test XT is present on OS in primary position measuring 60 PD at distance and near (and left hypertropia) which decreases at 40 on levoversion but increases at over 80 PD on dextroversion. Ductions: OS abolished adduction, limitation of depression, OD normal. Versions: in dextroversion OD abduction is associated with OS abduction. Binocular single vision is absent. Surgery has been done on both eyes (large recessions on lateral recti). Postoperatively orthotropia was present in primary position with persisting simultaneous abduction, but the patient and family are very satisfied about the esthetic aspect.

  6. Synergistic failure of BWR internals

    International Nuclear Information System (INIS)

    Ware, A. G.; Chang, T.Y.

    1999-01-01

    Boiling Water Reactor (BWR) core shrouds and other reactor internals important to safety are experiencing intergranular stress corrosion cracking (IGSCC). The United States Nuclear Regulatory Commission has followed the problem, and as part of its investigations, contracted with the Idaho National Engineering and Environmental Laboratory to conduct a risk assessment. The overall project objective is to assess the potential consequences and risks associated with the failure of IGSCC-susceptible BWR vessel internals, with specific consideration given to potential cascading and common mode effects. An initial phase has been completed in which background material was gathered and evaluated, and potential accident sequences were identified. A second phase is underway to perform a simplified, quantitative probabilistic risk assessment on a representative high-power BWR/4. Results of the initial study conducted on the jet pumps show that any cascading failures would not result in a significant increase in the core damage frequency. The methodology is currently being extended to other major reactor internals components

  7. Synergistic effects in threshold models on networks

    Science.gov (United States)

    Juul, Jonas S.; Porter, Mason A.

    2018-01-01

    Network structure can have a significant impact on the propagation of diseases, memes, and information on social networks. Different types of spreading processes (and other dynamical processes) are affected by network architecture in different ways, and it is important to develop tractable models of spreading processes on networks to explore such issues. In this paper, we incorporate the idea of synergy into a two-state ("active" or "passive") threshold model of social influence on networks. Our model's update rule is deterministic, and the influence of each meme-carrying (i.e., active) neighbor can—depending on a parameter—either be enhanced or inhibited by an amount that depends on the number of active neighbors of a node. Such a synergistic system models social behavior in which the willingness to adopt either accelerates or saturates in a way that depends on the number of neighbors who have adopted that behavior. We illustrate that our model's synergy parameter has a crucial effect on system dynamics, as it determines whether degree-k nodes are possible or impossible to activate. We simulate synergistic meme spreading on both random-graph models and networks constructed from empirical data. Using a heterogeneous mean-field approximation, which we derive under the assumption that a network is locally tree-like, we are able to determine which synergy-parameter values allow degree-k nodes to be activated for many networks and for a broad family of synergistic models.

  8. Determining lower threshold concentrations for synergistic effects

    DEFF Research Database (Denmark)

    Bjergager, Maj-Britt Andersen; Dalhoff, Kristoffer; Kretschmann, Andreas

    2017-01-01

    which proven synergists cease to act as synergists towards the aquatic crustacean Daphnia magna. To do this, we compared several approaches and test-setups to evaluate which approach gives the most conservative estimate for the lower threshold for synergy for three known azole synergists. We focus.......619±8.555μgL(-1)) and 0.122±0.0417μM (40.236±13.75μgL(-1)), respectively, in the 14-days tests. Testing synergy in relation to concentration addition provided the most conservative values. The threshold values for the vertical assessments in tests where the two could be compared were in general 1.2 to 4.......7 fold higher than the horizontal assessments. Using passive dosing rather than dilution series or spiking did not lower the threshold significantly. Below the threshold for synergy, slight antagony could often be observed. This is most likely due to induction of enzymes active in metabolization of alpha...

  9. Synergistic Synthetic Biology: Units in Concert

    Science.gov (United States)

    Trosset, Jean-Yves; Carbonell, Pablo

    2013-01-01

    Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through in silico modeling by choosing the right complement of genetic parts and by experimental tuning through directed evolution and craftsmanship. In this review, we consider an additional and complementary tool available to the synthetic biologist for innovative design and successful construction of desired circuit functionalities: biological synergies. Synergy is a prevalent emergent property in biological systems that arises from the concerted action of multiple factors producing an amplification or cancelation effect compared with individual actions alone. Synergies appear in domains as diverse as those involved in chemical and protein activity, polypharmacology, and metabolic pathway complementarity. In conventional synthetic biology designs, synergistic cross-talk between parts and modules is generally attenuated in order to verify their orthogonality. Synergistic interactions, however, can induce emergent behavior that might prove useful for synthetic biology applications, like in functional circuit design, multi-drug treatment, or in sensing and delivery devices. Synergistic design principles are therefore complementary to those coming from orthogonal design and may provide added value to synthetic biology applications. The appropriate modeling, characterization, and design of synergies between biological parts and units will allow the discovery of yet unforeseeable, novel synthetic biology applications. PMID:25022769

  10. Synergistic Synthetic Biology: Units in Concert

    International Nuclear Information System (INIS)

    Trosset, Jean-Yves; Carbonell, Pablo

    2013-01-01

    Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through in silico modeling by choosing the right complement of genetic parts and by experimental tuning through directed evolution and craftsmanship. In this review, we consider an additional and complementary tool available to the synthetic biologist for innovative design and successful construction of desired circuit functionalities: biological synergies. Synergy is a prevalent emergent property in biological systems that arises from the concerted action of multiple factors producing an amplification or cancelation effect compared with individual actions alone. Synergies appear in domains as diverse as those involved in chemical and protein activity, polypharmacology, and metabolic pathway complementarity. In conventional synthetic biology designs, synergistic cross-talk between parts and modules is generally attenuated in order to verify their orthogonality. Synergistic interactions, however, can induce emergent behavior that might prove useful for synthetic biology applications, like in functional circuit design, multi-drug treatment, or in sensing and delivery devices. Synergistic design principles are therefore complementary to those coming from orthogonal design and may provide added value to synthetic biology applications. The appropriate modeling, characterization, and design of synergies between biological parts and units will allow the discovery of yet unforeseeable, novel synthetic biology applications.

  11. Multiple levels of synergistic collaboration in termite lignocellulose digestion.

    Directory of Open Access Journals (Sweden)

    Michael E Scharf

    Full Text Available In addition to evolving eusocial lifestyles, two equally fascinating aspects of termite biology are their mutualistic relationships with gut symbionts and their use of lignocellulose as a primary nutrition source. Termites are also considered excellent model systems for studying the production of bioethanol and renewable bioenergy from 2nd generation (non-food feedstocks. While the idea that gut symbionts are the sole contributors to termite lignocellulose digestion has remained popular and compelling, in recent years host contributions to the digestion process have become increasingly apparent. However, the degree to which host and symbiont, and host enzymes, collaborate in lignocellulose digestion remain poorly understood. Also, how digestive enzymes specifically collaborate (i.e., in additive or synergistic ways is largely unknown. In the present study we undertook translational-genomic studies to gain unprecedented insights into digestion by the lower termite Reticulitermes flavipes and its symbiotic gut flora. We used a combination of native gut tissue preparations and recombinant enzymes derived from the host gut transcriptome to identify synergistic collaborations between host and symbiont, and also among enzymes produced exclusively by the host termite. Our findings provide important new evidence of synergistic collaboration among enzymes in the release of fermentable monosaccharides from wood lignocellulose. These monosaccharides (glucose and pentoses are highly relevant to 2(nd-generation bioethanol production. We also show that, although significant digestion capabilities occur in host termite tissues, catalytic tradeoffs exist that apparently favor mutualism with symbiotic lignocellulose-digesting microbes. These findings contribute important new insights towards the development of termite-derived biofuel processing biotechnologies and shed new light on selective forces that likely favored symbiosis and, subsequently, group living in

  12. Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition.

    Science.gov (United States)

    Kosic, Milica; Arsikin-Csordas, Katarina; Paunovic, Verica; Firestone, Raymond A; Ristic, Biljana; Mircic, Aleksandar; Petricevic, Sasa; Bosnjak, Mihajlo; Zogovic, Nevena; Mandic, Milos; Bumbasirevic, Vladimir; Trajkovic, Vladimir; Harhaji-Trajkovic, Ljubica

    2016-10-28

    We investigated the in vitro and in vivo anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-d-glucose (2DG). NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial damage, and reactive oxygen species production, eventually leading to necrotic death of U251 glioma cells but not primary astrocytes. NDI/2DG-induced death of glioma cells was partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, suggesting the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agent chloroquine also displayed a synergistic anticancer effect with 2DG, whereas glucose deprivation or glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus further indicating that the anticancer effect of NDI/2DG combination was indeed due to LMP and glycolysis block. The two agents synergistically induced ATP depletion, mitochondrial depolarization, oxidative stress, and necrotic death also in B16 mouse melanoma cells. Moreover, the combined oral administration of NDI and 2DG reduced in vivo melanoma growth in C57BL/6 mice by inducing necrotic death of tumor cells, without causing liver, spleen, or kidney toxicity. Based on these results, we propose that NDI-triggered LMP causes initial mitochondrial damage that is further increased by 2DG due to the lack of glycolytic ATP required to maintain mitochondrial health. This leads to a positive feedback cycle of mitochondrial dysfunction, ATP loss, and reactive oxygen species production, culminating in necrotic cell death. Therefore, the combination of LMP-inducing agents and glycolysis inhibitors seems worthy of further exploration as an anticancer strategy. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Using gene transcription to assess ecological and anthropological stressors in brown bears

    Science.gov (United States)

    Bowen, Lizabeth; Miles, A. Keith; Waters, Shannon C.; Gustine, Dave; Joly, Kyle; Hilderbrand, Grant

    2017-01-01

    Increasingly, population- and ecosystem-level health assessments are performed using sophisticated molecular tools. Advances in molecular technology enable the identification of synergistic effects of multiple stressors on the individual physiology of different species. Brown bears (Ursus arctos) are an apex predator; thus, they are ideal candidates for detecting potentially ecosystem-level systemic perturbations using molecular-based tools. We used gene transcription to analyze 130 brown bear samples from three National Parks and Preserves in Alaska. Although the populations we studied are apparently stable in abundance and exist within protected and intact environments, differences in transcript profiles were noted. The most prevalent differences were among locations. The transcript patterns among groups reflect the influence of environmental factors, such as nutritional status, disease, and xenobiotic exposure. However, these profiles also likely represent baselines for each unique environment by which future measures can be made to identify early indication of population-level changes due to, for example, increasing Arctic temperatures. Some of those environmental changes are predicted to be potentially positive for brown bears, but other effects such as the manifestation of disease or indirect effects of oceanic acidification may produce negative impacts.

  14. The effect of insecticide synergists on the response of scabies mites to pyrethroid acaricides.

    Directory of Open Access Journals (Sweden)

    Cielo Pasay

    Full Text Available Permethrin is the active component of topical creams widely used to treat human scabies. Recent evidence has demonstrated that scabies mites are becoming increasingly tolerant to topical permethrin and oral ivermectin. An effective approach to manage pesticide resistance is the addition of synergists to counteract metabolic resistance. Synergists are also useful for laboratory investigation of resistance mechanisms through their ability to inhibit specific metabolic pathways.To determine the role of metabolic degradation as a mechanism for acaricide resistance in scabies mites, PBO (piperonyl butoxide, DEF (S,S,S-tributyl phosphorotrithioate and DEM (diethyl maleate were first tested for synergistic activity with permethrin in a bioassay of mite killing. Then, to investigate the relative role of specific metabolic pathways inhibited by these synergists, enzyme assays were developed to measure esterase, glutathione S-transferase (GST and cytochrome P450 monooxygenase (cytochrome P450 activity in mite extracts. A statistically significant difference in median survival time of permethrin-resistant Sarcoptes scabiei variety canis was noted when any of the three synergists were used in combination with permethrin compared to median survival time of mites exposed to permethrin alone (p<0.0001. Incubation of mite homogenates with DEF showed inhibition of esterase activity (37%; inhibition of GST activity (73% with DEM and inhibition of cytochrome P450 monooxygenase activity (81% with PBO. A 7-fold increase in esterase activity, a 4-fold increase in GST activity and a 2-fold increase in cytochrome P450 monooxygenase activity were observed in resistant mites compared to sensitive mites.These findings indicate the potential utility of synergists in reversing resistance to pyrethroid-based acaricides and suggest a significant role of metabolic mechanisms in mediating pyrethroid resistance in scabies mites.

  15. An AP-2 element acts synergistically with the cyclic AMP- and Phorbol ester-inducible enhancer of the human proenkephalin gene

    Energy Technology Data Exchange (ETDEWEB)

    Hyman, S.E.; Comb, M.; Pearlberg, J.; Goodman, H.M.

    1989-01-01

    An enhancer with two DNA elements, one containing the sequence CGTCA, is required for cyclic AMP-and phorbol ester-inducible transcription of the human proenkephalin gene. The authors report that an AP-2 element located adjacent to the enhancer acts synergistically with it to confer maximal response to cyclic AMP and phorbol esters.

  16. Human harvest, climate change and their synergistic effects drove the Chinese Crested Tern to the brink of extinction

    Directory of Open Access Journals (Sweden)

    Shuihua Chen

    2015-07-01

    Full Text Available Synergistic effect refers to simultaneous actions of separate factors which have a greater total effect than the sum of the individual factor effects. However, there has been a limited knowledge on how synergistic effects occur and individual roles of different drivers are not often considered. Therefore, it becomes quite challenging to manage multiple threatening processes simultaneously in order to mitigate biodiversity loss. In this regard, our hypothesis is, if the traits actually play different roles in the synergistic interaction, conservation efforts could be made more effectively. To understand the synergistic effect and test our hypothesis, we examined the processes associated with the endangerment of critically endangered Chinese Crested Tern (Thalasseus bernsteini, whose total population number was estimated no more than 50. Through monitoring of breeding colonies and investigations into causative factors, combined with other data on human activities, we found that widespread human harvest of seabird eggs and increasing frequency of typhoons are the major factors that threatened the Chinese Crested Tern. Furthermore, 28 percent of breeding failures were due to the synergistic effects in which egg harvest-induced renestings suffered the higher frequent typhoons. In such combined interactions, the egg harvest has clearly served as a proximal factor for the population decline, and the superimposition of enhanced typhoon activity further accelerated the species toward imminent extinction. Our findings suggest that species endangerment, on one hand, should be treated as a synergistic process, while conservation efforts, on the other hand, should focus principally on combatting the threat that triggers synergistic effects.

  17. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Melanie C., E-mail: melanie.mann@viro.med.uni-erlangen.de; Strobel, Sarah, E-mail: sarah.strobel@viro.med.uni-erlangen.de; Fleckenstein, Bernhard, E-mail: bernhard.fleckenstein@viro.med.uni-erlangen.de; Kress, Andrea K., E-mail: andrea.kress@viro.med.uni-erlangen.de

    2014-09-15

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. - Highlights: • ELL2, a transcription elongation factor, is upregulated in HTLV-1-positive T-cells. • Tax transactivates the ELL2 promoter. • Tax and ELL2 synergistically activate the HTLV-1 promoter. • Tax and ELL2 interact in vivo.

  18. The dietary biogenic amines tyramine and histamine show synergistic toxicity towards intestinal cells in culture.

    Science.gov (United States)

    Del Rio, Beatriz; Redruello, Begoña; Linares, Daniel M; Ladero, Victor; Fernandez, Maria; Martin, Maria Cruz; Ruas-Madiedo, Patricia; Alvarez, Miguel A

    2017-03-01

    Tyramine and histamine are the biogenic amines (BA) most commonly found at high concentrations in food; they may even appear together at toxic concentrations. The present work examines, via real-time cell analysis, whether histamine and tyramine show synergistic toxicity towards intestinal cell cultures. Employing a constant equipotency ratio, their interaction was examined via the combination index (CI) method of Chou & Talalay. Co-treatment with tyramine and histamine was associated with a stronger cytotoxic effect than was treatment with either BA or on its own. Indeed, a synergistic interaction (CIhistamine, at concentrations below the legal limit, increases the cytotoxicity of tyramine at concentrations frequently reached in some foods. The synergistic cytotoxicity of tyramine and histamine should be taken into account when establishing legal limits designed to ensure consumer safety. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. TNF-α contributes to postmenopausal osteoporosis by synergistically promoting RANKL-induced osteoclast formation.

    Science.gov (United States)

    Zha, Li; He, Li; Liang, Yijian; Qin, Hui; Yu, Bin; Chang, Linli; Xue, Li

    2018-03-20

    Previous studies showed that inflammatory cytokines promote osteoclast formation, characterized by the function of bone resorption. However, it remains unclear whether inflammatory factors contribute to osteoporosis syndrome in postmenopausal women. Here, we found that postmenopausal women with osteoporosis (PO) had increased levels of TNF-α, compared with those without osteoporosis. TNF-α is highly correlated with the RANK and estrogen levels in PO patients. in vitro, TNF-α synergistically promotes RANKL-induced osteoclast formation by activation of NF-κB and PI3K/Akt signaling. Moreover, inhibition of PI3K/Akt totally blocked the synergistic effects of TNF-α on NF-κB activation as well as osteoclast formation. Together, these results demonstrate that TNF-α synergistically promotes RANKL-induced osteoclasts formation through activation of PI3K/Akt signaling, which ultimately contributes to osteoporosis syndrome in postmenopausal women. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  20. Synergistic effects of iron powder on intumescent flame retardant polypropylene system

    Directory of Open Access Journals (Sweden)

    2009-06-01

    Full Text Available The effects of iron powder as a synergistic agent on the flame retardancy of intumescent flame retardant polypropylene composites (IFR-PP were studied. The thermogravimetric analysis (TGA and cone calorimeter (CONE were used to evaluate the synergistic effects of iron powder (Fe. The TGA data showed that Fe could enhance the thermal stability of the IFR-PP systems at high temperature and effectively increase the char residue formation. The CONE results revealed that Fe and IFR could clearly change the decomposition behavior of PP and form a char layer on the surface of the composites, consequently resulting in efficient reduction of the flammability parameters, such as heat release rate (HRR, mass loss (ML, Mass loss rate (MLR, total heat release (THR, carbon monoxide and so on. Thus, a suitable amount of Fe plays a synergistic effect in the flame retardancy of IFR composites.

  1. Antibacterial synergistic effect of chlorhexidine and hydrogen peroxide against Streptococcus sobrinus, Streptococcus faecalis and Staphylococcus aureus.

    Science.gov (United States)

    Steinberg, D; Heling, I; Daniel, I; Ginsburg, I

    1999-02-01

    Chlorhexidine (CHX) and Hydrogen peroxide (HP) are potent antibacterial agents that are used in controlling dental plaque. However, both agents bear undesired side-effects. We have tested the hypothesis that an antibacterial synergistic effect can occur between the two agents against Streptococcus sobrinus, Streptococcus faecalis and Staphylococcus aureus. We have found that at several combinations of HP and CHX an antibacterial synergistic effect does occur, while at other combinations a on-significant synergism was noticed. No antagonism between the two agents was found in our experimental system. It can be postulated that the mechanism of this synergistic effect is via alteration of the bacterial cell-surface by CHX thereby allowing for an increased amount of HP to penetrate and to react with the intercellular organelles of the bacteria. These results suggest that CHX and HP can be of use in controlling the dental plaque in the oral cavity.

  2. DNA damage in human lymphocytes due to synergistic interaction between ionizing radiation and pesticide

    International Nuclear Information System (INIS)

    Kim, J. K.; Lee, K. H.; Lee, B. H.; Chun, K. J.

    2001-01-01

    Biological risks may arise from the possibility of the synergistic interaction between harmful factors such as ionizing radiation and pesticide. The effect of pesticide on radiation-induced DNA damage in human in human blood lymphocytes was evaluated by the single cell gel electrophoresis (SCGE) assay. The lymphocytes, with or without pretreatment of the pesticide, were exposed to 2.0 Gy of gamma ray. Significantly increased tail moment, which was a marker of DNA strand breaks in SCGE assay, showed an excellent dose-response relationship. The present study confirms that the pesticide has the cytotoxic effect on lymphocytes and that it interacts synergistically with ionizing radiationon DNA damage, as well

  3. Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis.

    Science.gov (United States)

    Jin, Junfei; Lu, Zhongyang; Li, Yanchun; Cowart, L Ashley; Lopes-Virella, Maria F; Huang, Yan

    2018-01-01

    It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFκB)-dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA-stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFκB-dependent transcription and CER de novo synthesis in macrophages.

  4. Co-pyrolysis of waste newspaper with high-density polyethylene: Synergistic effect and oil characterization

    International Nuclear Information System (INIS)

    Chen, Weimin; Shi, Shukai; Zhang, Jun; Chen, Minzhi; Zhou, Xiaoyan

    2016-01-01

    Highlights: • Synergistic effect during co-pyrolysis occurred at 400–500 °C. • Oil yield from co-pyrolysis was increased by 31.59% compared to theoretical data. • Viscosity and T.A.N. of co-pyrolysis oil were decreased by 75.96% and 216.04%. • Synergistic effect was determined by altering the compounds content in derived oil. - Abstract: Biomass from waste newspaper (WP) was first co-pyrolyzed with high-density polyethylene (HDPE) in order to enhance the oil yield and its fuel properties. The synergistic effects during co-pyrolysis were investigated in terms of entire pyrolysis process, products yield and properties of liquid products (aqueous phase and oil phase) using thermogravimetric analysis coupled with infrared spectroscopy (TG-FTIR), physical properties analysis, elemental analysis, Fourier transform infrared spectroscopy (FT-IR), and gas chromatography/mass spectrometry (GC/MS). The results showed that synergistic effect occurred at 400–500 °C resulting in an obviously increase in oil phase by 31.59% as compared to theoretical data. Positive synergistic effects on fuel properties of co-pyrolysis oil were observed, especially demonstrating dramatically decrease in viscosity and total acid number by 75.96% and 216.04% in comparison to theoretical data. WP pyrolyzed alone gives mainly oxygenated compounds in its derived oil, while HDPE give hydrocarbons. No cross reaction products appeared in co-pyrolysis oil, implying that the synergistic effects were determined by altering its compounds content rather than generating cross reaction products. Unfortunately, aqueous phase and oil phase exhibit similar composition.

  5. Trihelix transcription factor GT-4 mediates salt tolerance via interaction with TEM2 in Arabidopsis.

    Science.gov (United States)

    Wang, Xiao-Hong; Li, Qing-Tian; Chen, Hao-Wei; Zhang, Wan-Ke; Ma, Biao; Chen, Shou-Yi; Zhang, Jin-Song

    2014-12-03

    Trihelix transcription factor family is plant-specific and plays important roles in developmental processes. However, their function in abiotic stress response is largely unclear. We studied one member GT-4 from Arabidopsis in relation to salt stress response. GT-4 expression is induced by salt stress and GT-4 protein is localized in nucleus and cytoplasm. GT-4 acts as a transcriptional activator and its C-terminal end is the activation domain. The protein can bind to the cis-elements GT-3 box, GT-3b box and MRE4. GT-4 confers enhanced salt tolerance in Arabidopsis likely through direct binding to the promoter and activation of Cor15A, in addition to possible regulation of other relevant genes. The gt-4 mutant shows salt sensitivity. TEM2, a member of AP2/ERF family was identified to interact with GT-4 in yeast two-hybrid, BiFC and Co-IP assays. Loss-of-function of TEM2 exerts no significant difference on salt tolerance or Cor15A expression in Arabidopsis. However, double mutant gt-4/tem2 shows greater sensitivity to salt stress and lower transcript level of Cor15A than gt-4 single mutant. GT-4 plus TEM2 can synergistically increase the promoter activity of Cor15A. GT-4 interacts with TEM2 and then co-regulates the salt responsive gene Cor15A to improve salt stress tolerance.

  6. A rank-based statistical test for measuring synergistic effects between two gene sets.

    Science.gov (United States)

    Shiraishi, Yuichi; Okada-Hatakeyama, Mariko; Miyano, Satoru

    2011-09-01

    Due to recent advances in high-throughput technologies, data on various types of genomic annotation have accumulated. These data will be crucially helpful for elucidating the combinatorial logic of transcription. Although several approaches have been proposed for inferring cooperativity among multiple factors, most approaches are haunted by the issues of normalization and threshold values. In this article, we propose a rank-based non-parametric statistical test for measuring the effects between two gene sets. This method is free from the issues of normalization and threshold value determination for gene expression values. Furthermore, we have proposed an efficient Markov chain Monte Carlo method for calculating an approximate significance value of synergy. We have applied this approach for detecting synergistic combinations of transcription factor binding motifs and histone modifications. C implementation of the method is available from http://www.hgc.jp/~yshira/software/rankSynergy.zip. yshira@hgc.jp Supplementary data are available at Bioinformatics online.

  7. Synergistic anti-Campylobacter jejuni activity of fluoroquinolone and macrolide antibiotics with phenolic compounds

    Directory of Open Access Journals (Sweden)

    Euna eOh

    2015-10-01

    Full Text Available The increasing resistance of Campylobacter to clinically-important antibiotics, such as fluoroquinolones and macrolides, is a serious public health problem. The objective of this study is to investigate synergistic anti-Campylobacter jejuni activity of fluoroquinolones and macrolides in combination with phenolic compounds. Synergistic antimicrobial activity was measured by performing a checkerboard assay with ciprofloxacin and erythromycin in the presence of 21 phenolic compounds. Membrane permeability changes in C. jejuni by phenolic compounds were determined by measuring the level of intracellular uptake of 1-N-phenylnaphthylamine (NPN. Antibiotic accumulation assays were performed to evaluate the level of ciprofloxacin accumulation in C. jejuni. Six phenolic compounds, including p-coumaric acid, sinapic acid, caffeic acid, vanillic acid, gallic acid, and taxifolin, significantly increased the susceptibility to ciprofloxacin and erythromycin in several human and poultry isolates. The synergistic antimicrobial effect was also observed in ciprofloxacin- and erythromycin-resistant C. jejuni strains. The phenolic compounds also substantially increased membrane permeability and antibiotic accumulation in C. jejuni. Interestingly, some phenolic compounds, such as gallic acid and taxifolin, significantly reduced the expression of the CmeABC multidrug efflux pump. Phenolic compounds increased the NPN accumulation in the cmeB mutant, indicating phenolic compounds may affect the membrane permeability. In this study, we successfully demonstrated that combinational treatment of C. jejuni with antibiotics and phenolic compounds synergistically inhibits C. jejuni by impacting both antimicrobial influx and efflux.

  8. White piedra: further evidence of a synergistic infection.

    Science.gov (United States)

    Youker, Summer R; Andreozzi, Robert J; Appelbaum, Peter C; Credito, Kim; Miller, Jeffrey J

    2003-10-01

    White piedra is a fungal infection of the hair shaft caused by Trichosporon beigelii. A synergistic coryneform bacterial infection is often present with T beigelii. White piedra, although not commonly reported to infect scalp hair in North America, is an important consideration in the differential diagnosis of scalp hair concretions. We report a case of white piedra of scalp hair with synergistic coryneform bacterial infection in two sisters, both US natives. Culture and light and electronmicroscopic evidence of the synergistic infection are presented.

  9. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain

    DEFF Research Database (Denmark)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie

    2016-01-01

    dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations in total) were evaluated in the rat...... plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response...... surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response...

  10. Response surface analysis of synergistic interactions of morphine and gabapentin in a rat model of postoperative pain

    DEFF Research Database (Denmark)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie

    on the AIC criterion. Result The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58...... % for the synergistic doses. Conclusions The finding of dose-dependent synergistic interactions might indicate that there is a high potential for gabapentin and morphine to be used in combination in the clinic, in order to optimize postoperative pain management and minimize side effects of morphine. 1. Brennan TJ......, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain [Internet]. 1996 Mar;64(3):493–501. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8783314 2. Greco W, Bravo G, Parsons J. The search for synergy: A critical review from a responce surface perspective. Pharmacol Rev...

  11. A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone

    Directory of Open Access Journals (Sweden)

    Jo Davisson V

    2011-04-01

    Full Text Available Abstract Background Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA and curcumin (CCM are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone. Methods Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED50. Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC. Results CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER- PR- Her2+ relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and

  12. A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone

    International Nuclear Information System (INIS)

    Altenburg, Jeffrey D; Bieberich, Andrew A; Terry, Colin; Harvey, Kevin A; VanHorn, Justin F; Xu, Zhidong; Jo Davisson, V; Siddiqui, Rafat A

    2011-01-01

    Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone. Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED 50 . Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC. CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER - PR - Her2 + ) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes

  13. Increased Placental Glucose Transport Rates in Pregnant Mice Carrying Fetuses with Targeted Disruption of Their Placental-Specific Igf2 Transcripts Are Not Associated with Raised Circulating Glucose Concentrations

    Directory of Open Access Journals (Sweden)

    Clive J. Petry

    2011-01-01

    Full Text Available At the beginning of the third week of pregnancy, mouse fetuses with targeted disruption of their paternally-transmitted insulin-like growth factor 2 gene placental-specific transcripts have growth-restricted placentas but normal body weights due to upregulated placental nutrient transport. We assessed whether increased placental glucose transport rates were associated with raised maternal glucose concentrations by performing intraperitoneal glucose tolerance tests (ipGTT in pregnant mice carrying knockout pups and comparing them with mice carrying genotype-matched phenotypically wild type pups. Mean ± SD body weights of affected pups were 95 ± 8% of control values at e16 and 73 ± 7% at e18. There were no differences in areas under the maternal ipGTT curves at either e16 (mean ± SD being 99.0 ± 9.1% of control values; P=.9 or e18 (91.4 ± 13.4%; P=.3, suggesting that effects on transplacental glucose transport in these mice are not mediated through changes in maternal glucose concentrations.

  14. CD74-ROS1 G2032R mutation transcriptionally up-regulates Twist1 in non-small cell lung cancer cells leading to increased migration, invasion, and resistance to crizotinib.

    Science.gov (United States)

    Gou, Wenfeng; Zhou, Xuejiao; Liu, Zi; Wang, Lijing; Shen, Jiwei; Xu, Xiaobo; Li, Zengqiang; Zhai, Xin; Zuo, Daiying; Wu, Yingliang

    2018-02-23

    The c-ros oncogene 1 (ROS1) is a receptor tyrosine kinase, which has been identified as an oncogene driver of non-small-cell lung cancer (NSCLC). Although crizotinib has a prominent effect on ROS1, resistance is inevitable. Development of the acquired ROS1 G2032R mutation has been reported as a resistant mechanism to ROS1 inhibitors in ROS1-rearranged (ROS1 + ) NSCLC patients. To explore the mechanism of drug resistance, we constructed the crizotinib resistance cell line, A549-CD74-ROS1 G2032R mutation cells, by the methods of fusion polymerase chain reaction (PCR), plasmid construction and cell transfection in vitro. The results showed that the expression of CD74-ROS1 or CD74-ROS1 G2032R mutation in A549 cells induced epithelial-mesenchymal transition (EMT), dramatically enhanced the ability of invasion and migration, and increased expression of matrix metalloproteinase (MMP)-9 and Twist1 transcription factor. Moreover, we found that inhibition of Twist1 could reverse EMT induced by CD74-ROS1 G2032R mutation. Combination of Twist1 siRNA and crizotinib significantly reduced cell vitality, inhibited cell invasion and migration, and promoted apoptosis in A549-CD74-ROS1 G2032R mutation cells. Taken together, these results suggested that CD74-ROS1 G2032R mutation mediated EMT phenotype by increasing the expression of Twist1, resulting in drug resistance. Combination of Twist1 silence and ROS1 inhibitor may provide a potent strategy to treat the ROS1 + NSCLC patients with crizotinib resistance. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Overexpression of Grain Amaranth (Amaranthus hypochondriacus) AhERF or AhDOF Transcription Factors in Arabidopsis thaliana Increases Water Deficit- and Salt-Stress Tolerance, Respectively, via Contrasting Stress-Amelioration Mechanisms

    Science.gov (United States)

    Massange-Sánchez, Julio A.; Palmeros-Suárez, Paola A.; Espitia-Rangel, Eduardo; Rodríguez-Arévalo, Isaac; Sánchez-Segura, Lino; Martínez-Gallardo, Norma A.; Alatorre-Cobos, Fulgencio; Tiessen, Axel; Délano-Frier, John P.

    2016-01-01

    Two grain amaranth transcription factor (TF) genes were overexpressed in Arabidopsis plants. The first, coding for a group VII ethylene response factor TF (i.e., AhERF-VII) conferred tolerance to water-deficit stress (WS) in transgenic Arabidopsis without affecting vegetative or reproductive growth. A significantly lower water-loss rate in detached leaves coupled to a reduced stomatal opening in leaves of plants subjected to WS was associated with this trait. WS tolerance was also associated with an increased antioxidant enzyme activity and the accumulation of putative stress-related secondary metabolites. However, microarray and GO data did not indicate an obvious correlation between WS tolerance, stomatal closure, and abscisic acid (ABA)-related signaling. This scenario suggested that stomatal closure during WS in these plants involved ABA-independent mechanisms, possibly involving reactive oxygen species (ROS). WS tolerance may have also involved other protective processes, such as those employed for methyl glyoxal detoxification. The second, coding for a class A and cluster I DNA binding with one finger TF (i.e., AhDof-AI) provided salt-stress (SS) tolerance with no evident fitness penalties. The lack of an obvious development-related phenotype contrasted with microarray and GO data showing an enrichment of categories and genes related to developmental processes, particularly flowering. SS tolerance also correlated with increased superoxide dismutase activity but not with augmented stomatal closure. Additionally, microarray and GO data indicated that, contrary to AhERF-VII, SS tolerance conferred by AhDof-AI in Arabidopsis involved ABA-dependent and ABA-independent stress amelioration mechanisms. PMID:27749893

  16. Overexpression of Grain Amaranth (Amaranthus hypochondriacus AhERF or AhDOF Transcription Factors in Arabidopsis thaliana Increases Water Deficit- and Salt-Stress Tolerance, Respectively, via Contrasting Stress-Amelioration Mechanisms.

    Directory of Open Access Journals (Sweden)

    Julio A Massange-Sánchez

    Full Text Available Two grain amaranth transcription factor (TF genes were overexpressed in Arabidopsis plants. The first, coding for a group VII ethylene response factor TF (i.e., AhERF-VII conferred tolerance to water-deficit stress (WS in transgenic Arabidopsis without affecting vegetative or reproductive growth. A significantly lower water-loss rate in detached leaves coupled to a reduced stomatal opening in leaves of plants subjected to WS was associated with this trait. WS tolerance was also associated with an increased antioxidant enzyme activity and the accumulation of putative stress-related secondary metabolites. However, microarray and GO data did not indicate an obvious correlation between WS tolerance, stomatal closure, and abscisic acid (ABA-related signaling. This scenario suggested that stomatal closure during WS in these plants involved ABA-independent mechanisms, possibly involving reactive oxygen species (ROS. WS tolerance may have also involved other protective processes, such as those employed for methyl glyoxal detoxification. The second, coding for a class A and cluster I DNA binding with one finger TF (i.e., AhDof-AI provided salt-stress (SS tolerance with no evident fitness penalties. The lack of an obvious development-related phenotype contrasted with microarray and GO data showing an enrichment of categories and genes related to developmental processes, particularly flowering. SS tolerance also correlated with increased superoxide dismutase activity but not with augmented stomatal closure. Additionally, microarray and GO data indicated that, contrary to AhERF-VII, SS tolerance conferred by AhDof-AI in Arabidopsis involved ABA-dependent and ABA-independent stress amelioration mechanisms.

  17. Positive autoregulation of the transcription factor Pax6 in response to increased levels of either of its major isoforms, Pax6 or Pax6(5a, in cultured cells

    Directory of Open Access Journals (Sweden)

    Mason John O

    2006-05-01

    Full Text Available Abstract Background Pax6 is a transcription factor essential for normal development of the eyes and nervous system. It has two major isoforms, Pax6 and Pax6(5a, and the ratios between their expression levels vary within narrow limits. We tested the effects of overexpressing either one or other isoform on endogenous Pax6 expression levels in Neuro2A and NIH3T3 cells. Results We found that both isoforms caused an up-regulation of endogenous Pax6 expression in cells with (Neuro2A or without (NIH3T3 constitutive Pax6 expression. Western blots showed that cells stably transfected with constructs expressing either Pax6 or Pax6(5a contained raised levels of both Pax6 and Pax6(5a. Quantitative RT-PCR confirmed an increase in levels of Pax6(5a mRNA in cells containing Pax6-expressing constructs and an increase in levels of Pax6 mRNA in cells containing Pax6(5a-expressing constructs. The fact that the introduction of constructs expressing only one isoform increased the cellular levels of not only that isoform but also the other indicates that activation of the endogenous Pax6 locus occurred. The ratio between the levels of the two isoforms was maintained close to physiological values. The overexpression of either isoform in neuroblastoma (Neuro2A cell lines also promoted morphological change and an increase in β-III-tubulin expression, indicating an increase in neurogenesis. Conclusion Our results demonstrate that Pax6 can up-regulate production of Pax6 protein from an entire intact endogenous Pax6 locus in its genomic environment. This adds to previous studies showing that Pax6 can up-regulate reporter expression driven by isolated Pax6 regulatory elements. Furthermore, our results suggest that an important function of positive feedback might be to stabilise the relative levels of Pax6 and Pax6(5a.

  18. Obesity and bipolar disorder: synergistic neurotoxic effects?

    Science.gov (United States)

    Liu, Celina S; Carvalho, André F; Mansur, Rodrigo B; McIntyre, Roger S

    2013-11-01

    Bipolar disorder (BD) is a disabling and chronic neuropsychiatric disorder that is typified by a complex illness presentation, episode recurrence and by its frequent association with psychiatric and medical comorbidities. Over the past decade, obesity has emerged as one of many comorbidities generating substantial concern in the BD population due to important prognostic implications. This comprehensive review details the bidirectional relationship between obesity and BD as evidenced by alterations in the structure and function of the central nervous system, in addition to greater depressive recurrence, cognitive dysfunction and risk of suicidality. Drawing on current research results, this article presents several putative mechanisms underlying the synergistic toxic effects and provides a framework for future treatment options for the obesity-BD comorbidity. There is a need for more large-scale prospective studies to investigate the bidirectional relationships between obesity and BD.

  19. HIV-1 reverse transcription.

    Science.gov (United States)

    Hu, Wei-Shau; Hughes, Stephen H

    2012-10-01

    Reverse transcription and integration are the defining features of the Retroviridae; the common name "retrovirus" derives from the fact that these viruses use a virally encoded enzyme, reverse transcriptase (RT), to convert their RNA genomes into DNA. Reverse transcription is an essential step in retroviral replication. This article presents an overview of reverse transcription, briefly describes the structure and function of RT, provides an introduction to some of the cellular and viral factors that can affect reverse transcription, and discusses fidelity and recombination, two processes in which reverse transcription plays an important role. In keeping with the theme of the collection, the emphasis is on HIV-1 and HIV-1 RT.

  20. LEF-1 Regulates Tyrosinase Gene Transcription In Vitro.

    Directory of Open Access Journals (Sweden)

    Xueping Wang

    Full Text Available TYR, DCT and MITF are three important genes involved in maintaining the mature phenotype and producing melanin; they therefore participate in neural crest cell development into melanocytes. Previous studies have revealed that the Wnt signaling factor lymphoid enhancer-binding factor (LEF-1 can enhance DCT and MITF gene expression. However, whether LEF-1 also affects TYR gene expression remains unclear. In the present study, we found that LEF-1 regulated TYR transcription in vitro. LEF-1 overexpression increased TYR gene promoter activity, whereas LEF-1 knockdown by RNA interference significantly decreased TYR expression. Moreover, the core GTTTGAT sequence (-56 to -50 within the TYR promoter is essential for the effect of LEF-1 on TYR expression, and chromatin immunoprecipitation (ChIP assay indicated that endogenous LEF-1 interacts with the TYR promoter. In addition, we observed a synergistic transactivation of the TYR promoter by LEF-1 and MITF. These data suggest that Wnt signaling plays an important role in regulating melanocyte development and differentiation.

  1. Synergistic activity of letrozole and sorafenib on breast cancer cells.

    Science.gov (United States)

    Bonelli, Mara A; Fumarola, Claudia; Alfieri, Roberta R; La Monica, Silvia; Cavazzoni, Andrea; Galetti, Maricla; Gatti, Rita; Belletti, Silvana; Harris, Adrian L; Fox, Stephen B; Evans, Dean B; Dowsett, Mitch; Martin, Lesley-Ann; Bottini, Alberto; Generali, Daniele; Petronini, Pier Giorgio

    2010-11-01

    Estrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-expressing breast cancer cell lines. Treatment with letrozole reduced testosterone-driven cell proliferation, by inhibiting the synthesis of estrogens. Sorafenib inhibited cell proliferation in a concentration-dependent manner; this effect was not dependent on sorafenib-mediated inhibition of Raf1, but involved the down-regulation of mTORC1 and its targets p70S6K and 4E-binding protein 1 (4E-BP1). At concentrations of 5-10 μM the growth-inhibitory effect of sorafenib was associated with the induction of apoptosis, as indicated by release of cytochrome c and Apoptosis-Inducing Factor into the cytosol, activation of caspase-9 and caspase-7, and PARP-1 cleavage. Combination of letrozole and sorafenib produced a synergistic inhibition of cell proliferation associated with an enhanced accumulation of cells in the G(0)/G(1) phase of the cell cycle and with a down-regulation of the cell cycle regulatory proteins c-myc, cyclin D1, and phospho-Rb. In addition, longer experiments (12 weeks) demonstrated that sorafenib may be effective in preventing the acquisition of resistance towards letrozole. Together, these results indicate that combination of letrozole and sorafenib might constitute a promising approach to the treatment of hormone-dependent breast cancer.

  2. Biomolecular Network-Based Synergistic Drug Combination Discovery

    Directory of Open Access Journals (Sweden)

    Xiangyi Li

    2016-01-01

    Full Text Available Drug combination is a powerful and promising approach for complex disease therapy such as cancer and cardiovascular disease. However, the number of synergistic drug combinations approved by the Food and Drug Administration is very small. To bridge the gap between urgent need and low yield, researchers have constructed various models to identify synergistic drug combinations. Among these models, biomolecular network-based model is outstanding because of its ability to reflect and illustrate the relationships among drugs, disease-related genes, therapeutic targets, and disease-specific signaling pathways as a system. In this review, we analyzed and classified models for synergistic drug combination prediction in recent decade according to their respective algorithms. Besides, we collected useful resources including databases and analysis tools for synergistic drug combination prediction. It should provide a quick resource for computational biologists who work with network medicine or synergistic drug combination designing.

  3. Revisiting the functional anatomy of the palmaris longus as a thenar synergist.

    Science.gov (United States)

    Moore, Colin W; Fanous, Jacob; Rice, Charles L

    2017-11-27

    Surgical studies describe the palmaris longus (PL) as a synergist in thumb abduction, which may facilitate its use in restoring thumb function using opponensplasty. However, beyond morphological descriptions and isometric thenar abduction strength measures, the evidence supporting the PL as a thenar synergist in-vivo is limited. The purpose here was to determine whether the PL provides synergistic contributions to thenar musculature by: (1) recording PL muscle activity using indwelling electromyography (EMG) during thumb movements; and (2) quantifying changes in PL muscle architecture using ultrasonography. In 10 healthy males, PL muscle activity was recorded during maximal thenar muscle contractions (abduction, flexion, opposition, adduction, and extension) with the wrist secured in a neutral position. The PL EMG was normalized to its maximal EMG recorded during isometric wrist flexion. Dynamic changes in PL muscle thickness (M T ) were determined during abduction and adduction using ultrasound imaging. The results indicate that the PL is activated during thenar movements with greatest relative PL EMG recorded during thenar abduction (46%), flexion (35%) and opposition (37%). Compared to rest, PL M T significantly increased (21%) during maximal thenar abduction. With direct measures in vivo, this study supports morphological and surgical observations indicating the PL acts as an extrinsic hand muscle in enhancing thenar muscle actions. Knowledge of the synergistic relationship between the PL and thenar musculature may allow for further development of surgical opponensplasty approaches using the abductor pollicis brevis and PL as a functional digastric unit. Clin. Anat, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Towards enhancing photocatalytic hydrogen generation: Which is more important, alloy synergistic effect or plasmonic effect?

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhenhe; Kibria, Md Golam; AlOtaibi, Bandar; Duchesne, Paul N.; Besteiro, Lucas V.; Gao, Yu; Zhang, Qingzhe; Mi, Zetian; Zhang, Peng; Govorov, Alexander O.; Mai, Liqiang; Chaker, Mohamed; Ma, Dongling

    2018-02-01

    Synergistic effect in alloys and plasmonic effect have both been explored for increasing the efficiency of water splitting. In depth understanding and comparison of their respective contributions in certain promising systems is highly desired for catalyst development, yet rarely investigated so far. We report herein our thorough investigations on a series of highly interesting nanocomposites composed of Pt, Au and C3N4 nanocomponents, which are designed to benefit from both synergistic and plasmonic effects. Detailed analyses led to an important conclusion that the contribution from the synergistic effect was at least 3.5 times that from the plasmonic effect in the best performing sample, Pt50Au50 alloy decorated C3N4. It showed remarkable turnover frequency of >1.6 mmol h-1 g-1 at room temperature. Our work provides physical insights for catalyst development by rationally designing samples to compare long-known synergistic effect with recently emerging, attractive plasmonic effect and represents the first case study in the field.

  5. Esterase inhibition by synergists in the western flower thrips Frankliniella occidentalis.

    Science.gov (United States)

    López-Soler, Neus; Cervera, Amelia; Quinto, Vicente; Abellán, Jaime; Bielza, Pablo; Martínez-Pardo, Rafael; Garcerá, Maria Dolores

    2011-12-01

    Western flower thrips (WFT), Frankliniella occidentalis (Pergande), is among the most important crop pests in the south-eastern region of Spain. Its increasing resistance to insecticides constitutes a serious problem, and understanding the mechanisms involved is therefore of great interest. Use of synergists to inhibit the enzymes involved in insecticide detoxification is widely used to determine their responsibility for insecticide resistance. However, they do not always act as intended or expected, and caution must be exercised when interpreting synergist results. Laboratory-selected strains of WFT were used to analyse the effects of the synergists piperonyl butoxide (PBO), S,S,S-tributyl phosphorotrithioate (DEF) and methiocarb on total esterase activity. Significant differences were found, indicating esterase activity inhibition by DEF, a lower effect for methiocarb and a small inhibition of the activity by PBO. Esterase isoenzyme inhibition by these compounds showed a similar result; this assay revealed an extreme sensitivity of Triplet A (resistance-associated esterases) to DEF. In an in vivo assay carried out with these compounds at different incubation times, only DEF caused posterior in vitro esterase activity inhibition, with a maximum effect 1 h after treatment. In this work, only DEF shows true synergistic inhibition of WFT esterases. Copyright © 2011 Society of Chemical Industry.

  6. Synergistic electrocatalytic effect of nanostructured mixed films formed by functionalised gold nanoparticles and bisphthalocyanines

    Energy Technology Data Exchange (ETDEWEB)

    Medina-Plaza, C. [Universidad de Valladolid, Department of Inorganic Chemistry, Engineers School (Spain); Furini, L.N. [Universidad de Valladolid, Department of Inorganic Chemistry, Engineers School (Spain); Faculdade de Ciências e Tecnologia, UNESP Univ Estadual Paulista, 19060-900 Presidente Prudente, SP (Brazil); Constantino, C.J.L. [Faculdade de Ciências e Tecnologia, UNESP Univ Estadual Paulista, 19060-900 Presidente Prudente, SP (Brazil); Saja, J.A. de [Universidad de Valladolid, Department of Condensed Matter Physics, Faculty of Sciences (Spain); Rodriguez-Mendez, M.L., E-mail: mluz@eii.uva.es [Universidad de Valladolid, Department of Inorganic Chemistry, Engineers School (Spain)

    2014-12-03

    Graphical abstract: Sensors based on gold nanoparticles and lutetium bisphthalocyanine, co-deposited using Langmuir–Blodgett technique, have demonstrated improved sensing properties towards hydroquinone due to synergistic effects. - Highlights: • Gold nanoparticles and lutetium bisphthalocyanine have been co-deposited using the LB technique. • Films used as voltammetric sensors provide enhanced responses towards hydroquinone. • The efficient electrocatalytic properties are due to synergistic effects. - Abstract: A synergistic electrocatalytic effect was observed in sensors where two electrocatalytic materials (functionalized gold nanoparticles and lutetium bisphthalocyanine) were co-deposited using the Langmuir–Blodgett technique. Films were prepared using a novel method where water soluble functionalised gold nanoparticles [(11-mercaptoundecyl)tetra(ethylene glycol)] (SAuNPs) were inserted in floating films of lutetium bisphthalocyanine (LuPc{sub 2}) and dimethyldioctadecylammonium bromide (DODAB) as the amphiphilic matrix. The formation of stable and homogeneous mixed films was confirmed by π-A isotherms, BAM, UV–vis and Raman spectroscopy, as well as by SEM and TEM microscopy. The synergistic effect towards hydroquinone of the electrodes modified with LuPc{sub 2}:DODAB/SAuNP was characterised by an increase in the intensity of the redox peaks and a reduction of the overpotential. This synergistic electrocatalytic effect arose from the interaction between the SAuNPs and the phthalocyanines that occur in the Langmuir–Blodgett films and from the high surface area provided by the nanostructured films. The sensitivity increased with the amount of LuPc{sub 2} and SAuNPs inserted in the films and limits of detection in the range of 10{sup −7} mol L{sup −1} were attained.

  7. The Absence of the Transcription Factor Yrr1p, Identified from Comparative Genome Profiling, Increased Vanillin Tolerance Due to Enhancements of ABC Transporters Expressing, rRNA Processing and Ribosome Biogenesis in Saccharomyces cerevisiae.

    Science.gov (United States)

    Wang, Xinning; Liang, Zhenzhen; Hou, Jin; Shen, Yu; Bao, Xiaoming

    2017-01-01

    Enhancing the tolerance of Saccharomyces cerevisiae to inhibitors derived from lignocellulose is conducive to producing biofuel and chemicals using abundant lignocellulosic materials. Vanillin is a major type of phenolic inhibitor in lignocellulose hydrolysates for S. cerevisiae . In the present work, the factors beneficial to vanillin resistance in yeast were identified from the vanillin-resistant strain EMV-8, which was derived from strain NAN-27 by adaptive evolution. We found 450 SNPs and 44 genes with InDels in the vanillin-tolerant strain EMV-8 by comparing the genome sequences of EMV-8 and NAN-27. To investigate the effects of InDels, InDels were deleted in BY4741, respectively. We demonstrated that the deletion of YRR1 improved vanillin tolerance of strain. In the presence of 6 mM vanillin, deleting YRR1 increase the maximum specific growth rate and the vanillin consumption rate by 142 and 51%, respectively. The subsequent transcriptome analysis revealed that deleting YRR1 resulted in changed expression of over 200 genes in the presence of 5 mM vanillin. The most marked changes were the significant up-regulation of the dehydrogenase ADH7 , several ATP-binding cassette (ABC) transporters, and dozens of genes involved in ribosome biogenesis and rRNA processing. Coincidently, the crude enzyme solution of BY4741( yrr1 Δ) exhibited higher NADPH-dependent vanillin reduction activity than control. In addition, overexpressing the ABC transporter genes PDR5, YOR1 , and SNQ2 , as well as the RNA helicase gene DBP2 , increased the vanillin tolerance of strain. Interestingly, unlike the marked changes we mentioned above, under vanillin-free conditions, there are only limited transcriptional differences between wildtype and yrr1 Δ. This indicated that vanillin might act as an effector in Yrr1p-related regulatory processes. The new findings of the relationship between YRR1 and vanillin tolerance, as well as the contribution of rRNA processing and ribosome biogenesis to

  8. Theoretical analysis of transcription process with polymerase stalling

    Science.gov (United States)

    Li, Jingwei; Zhang, Yunxin

    2015-05-01

    Experimental evidence shows that in gene transcription RNA polymerase has the possibility to be stalled at a certain position of the transcription template. This may be due to the template damage or protein barriers. Once stalled, polymerase may backtrack along the template to the previous nucleotide to wait for the repair of the damaged site, simply bypass the barrier or damaged site and consequently synthesize an incorrect messenger RNA, or degrade and detach from the template. Thus, the effective transcription rate (the rate to synthesize correct product mRNA) and the transcription effectiveness (the ratio of the effective transcription rate to the effective transcription initiation rate) are both influenced by polymerase stalling events. So far, no theoretical model has been given to discuss the gene transcription process including polymerase stalling. In this study, based on the totally asymmetric simple exclusion process, the transcription process including polymerase stalling is analyzed theoretically. The dependence of the effective transcription rate, effective transcription initiation rate, and transcription effectiveness on the transcription initiation rate, termination rate, as well as the backtracking rate, bypass rate, and detachment (degradation) rate when stalling, are discussed in detail. The results showed that backtracking restart after polymerase stalling is an ideal mechanism to increase both the effective transcription rate and the transcription effectiveness. Without backtracking, detachment of stalled polymerase can also help to increase the effective transcription rate and transcription effectiveness. Generally, the increase of the bypass rate of the stalled polymerase will lead to the decrease of the effective transcription rate and transcription effectiveness. However, when both detachment rate and backtracking rate of the stalled polymerase vanish, the effective transcription rate may also be increased by the bypass mechanism.

  9. The Mycobacterial Transcriptional Regulator whiB7 Gene Links Redox Homeostasis and Intrinsic Antibiotic Resistance*

    Science.gov (United States)

    Burian, Ján; Ramón-García, Santiago; Sweet, Gaye; Gómez-Velasco, Anaximandro; Av-Gay, Yossef; Thompson, Charles J.

    2012-01-01

    Intrinsic drug resistance in Mycobacterium tuberculosis limits therapeutic options for treating tuberculosis. The mycobacterial transcriptional regulator whiB7 contributes to intrinsic resistance by activating its own expression and many drug resistance genes in response to antibiotics. To investigate whiB7 activation, we constructed a GFP reporter to monitor its expression, and we used it to investigate the whiB7 promoter and to screen our custom library of almost 600 bioactive compounds, including the majority of clinical antibiotics. Results showed whiB7 was transcribed from a promoter that was conserved across mycobacteria and other actinomycetes, including an AT-rich sequence that was likely targeted by WhiB7. Expression was induced by compounds having diverse structures and targets, independent of the ability of whiB7 to mediate resistance, and was dependent on media composition. Pretreatment with whiB7 activators resulted in clinically relevant increases in intrinsic drug resistance. Antibiotic-induced transcription was synergistically increased by the reductant dithiothreitol, an effect mirrored by a whiB7-dependent shift to a highly reduced cytoplasm reflected by the ratio of reduced/oxidized mycothiol. These data provided evidence that intrinsic resistance resulting from whiB7 activation is linked to fundamental changes in cell metabolism. PMID:22069311

  10. PMA synergistically enhances apicularen A-induced cytotoxicity by disrupting microtubule networks in HeLa cells

    International Nuclear Information System (INIS)

    Seo, Kang-Sik; Hwang, Byung-Doo; Kim, Jong-Seok; Park, Ji-Hoon; Song, Kyoung-Sub; Yun, Eun-Jin; Park, Jong-Il; Kweon, Gi Ryang; Yoon, Wan-Hee; Lim, Kyu

    2014-01-01

    Combination therapy is key to improving cancer treatment efficacy. Phorbol 12-myristate 13-acetate (PMA), a well-known PKC activator, increases the cytotoxicity of several anticancer drugs. Apicularen A induces cytotoxicity in tumor cells through disrupting microtubule networks by tubulin down-regulation. In this study, we examined whether PMA increases apicularen A-induced cytotoxicity in HeLa cells. Cell viability was examined by thiazolyl blue tetrazolium (MTT) assays. To investigate apoptotic potential of apicularen A, DNA fragmentation assays were performed followed by extracting genomic DNA, and caspase-3 activity assays were performed by fluorescence assays using fluorogenic substrate. The cell cycle distribution induced by combination with PMA and apicularen A was examined by flow cytometry after staining with propidium iodide (PI). The expression levels of target proteins were measured by Western blotting analysis using specific antibodies, and α-tubulin mRNA levels were assessed by reverse transcription polymerase chain reaction (RT-PCR). To examine the effect of combination of PMA and apicularen A on the microtubule architecture, α-tubulin protein and nuclei were visualized by immunofluorescence staining using an anti-α-tubulin antibody and PI, respectively. We found that apicularen A induced caspase-dependent apoptosis in HeLa cells. PMA synergistically increased cytotoxicity and apoptotic sub-G 1 population induced by apicularen A. These effects were completely blocked by the PKC inhibitors Ro31-8220 and Go6983, while caspase inhibition by Z-VAD-fmk did not prevent cytotoxicity. RNA interference using siRNA against PKCα, but not PKCβ and PKCγ, inhibited cytotoxicity induced by combination PMA and apicularen A. PMA increased the apicularen A-induced disruption of microtubule networks by further decreasing α- and β-tubulin protein levels in a PKC-dependent manner. These results suggest that the synergy between PMA and apicularen A is involved by

  11. SIRT1 regulates HIV transcription via Tat deacetylation.

    Directory of Open Access Journals (Sweden)

    Sara Pagans

    2005-02-01

    Full Text Available The human immunodeficiency virus (HIV Tat protein is acetylated by the transcriptional coactivator p300, a necessary step in Tat-mediated transactivation. We report here that Tat is deacetylated by human sirtuin 1 (SIRT1, a nicotinamide adenine dinucleotide-dependent class III protein deacetylase in vitro and in vivo. Tat and SIRT1 coimmunoprecipitate and synergistically activate the HIV promoter. Conversely, knockdown of SIRT1 via small interfering RNAs or treatment with a novel small molecule inhibitor of the SIRT1 deacetylase activity inhibit Tat-mediated transactivation of the HIV long terminal repeat. Tat transactivation is defective in SIRT1-null mouse embryonic fibroblasts and can be rescued by expression of SIRT1. These results support a model in which cycles of Tat acetylation and deacetylation regulate HIV transcription. SIRT1 recycles Tat to its unacetylated form and acts as a transcriptional coactivator during Tat transactivation.

  12. Synergistic effects of resistance training and protein intake: practical aspects.

    Science.gov (United States)

    Guimarães-Ferreira, Lucas; Cholewa, Jason Michael; Naimo, Marshall Alan; Zhi, X I A; Magagnin, Daiane; de Sá, Rafaele Bis Dal Ponte; Streck, Emilio Luiz; Teixeira, Tamiris da Silva; Zanchi, Nelo Eidy

    2014-10-01

    Resistance training is a potent stimulus to increase skeletal muscle mass. The muscle protein accretion process depends on a robust synergistic action between protein intake and overload. The intake of protein after resistance training increases plasma amino acids, which results in the activation of signaling molecules leading to increased muscle protein synthesis (MPS) and muscle hypertrophy. Although both essential and non-essential amino acids are necessary for hypertrophy, the intake of free L-leucine or high-leucine whole proteins has been specifically shown to increase the initiation of translation that is essential for elevated MPS. The literature supports the use of protein intake following resistance-training sessions to enhance MPS; however, less understood are the effects of different protein sources and timing protocols on MPS. The sum of the adaptions from each individual training session is essential to muscle hypertrophy, and thus highlights the importance of an optimal supplementation protocol. The aim of this review is to present recent findings reported in the literature and to discuss the practical application of these results. In that light, new speculations and questions will arise that may direct future investigations. The information and recommendations generated in this review should be of benefit to clinical dietitians as well as those engaged in sports. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. HIV-1 Reverse Transcription

    OpenAIRE

    Hu, Wei-Shau; Hughes, Stephen H.

    2012-01-01

    Reverse transcription and integration are the defining features of the Retroviridae; the common name “retrovirus” derives from the fact that these viruses use a virally encoded enzyme, reverse transcriptase (RT), to convert their RNA genomes into DNA. Reverse transcription is an essential step in retroviral replication. This article presents an overview of reverse transcription, briefly describes the structure and function of RT, provides an introduction to some of the cellular and viral fact...

  14. Synergistic Catalysis: A Powerful Synthetic Strategy for New Reaction Development

    Science.gov (United States)

    Allen, Anna E.; MacMillan, David W. C.

    2012-01-01

    Synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation. This powerful catalysis strategy leads to several benefits, specifically synergistic catalysis can (i) introduce new, previously unattainable chemical transformations, (ii) improve the efficiency of existing transformations, and (iii) create or improve catalytic enantioselectivity where stereocontrol was previously absent or challenging. This perspective aims to highlight these benefits using many of the successful examples of synergistic catalysis found in the literature. PMID:22518271

  15. Transcriptional Networks in the Liver: Hepatocyte Nuclear Factor 6 Function Is Largely Independent of Foxa2

    OpenAIRE

    Rubins, Nir E.; Friedman, Joshua R.; Le, Phillip P.; Zhang, Liping; Brestelli, John; Kaestner, Klaus H.

    2005-01-01

    A complex network of hepatocyte nuclear transcription factors, including HNF6 and Foxa2, regulates the expression of liver-specific genes. The current model, based on in vitro studies, suggests that HNF6 and Foxa2 interact physically. This interaction is thought to synergistically stimulate Foxa2-dependent transcription through the recruitment of p300/CBP by HNF6 and to inhibit HNF6-mediated transcription due to the interference of Foxa2 with DNA binding by HNF6. To test this model in vivo, w...

  16. Synergistic Smart Fuel For Microstructure Mediated Measurements

    Energy Technology Data Exchange (ETDEWEB)

    James A. Smith; Dale K. Kotter; Steven L. Garrett; Randall A. Ali

    2013-07-01

    Advancing the Nuclear Fuel Cycle and Next Generation Nuclear Power Plants requires enhancing our basic understanding of fuel and materials behavior under irradiation. The two most significant issues limiting the effectiveness and lifespan of the fuel are the loss of thermal conductivity of the fuel and the mechanical strength of both fuel and cladding. The core of a nuclear reactor presents an extremely harsh and challenging environment for both sensors and telemetry due to elevated temperatures and large fluxes of energetic and ionizing particles from radioactive decay processes. The majority of measurements are made in reactors using “radiation hardened” sensors and materials. A different approach has been pursued in this research that exploits high temperatures and materials that are robust with respect to ionizing radiation. This synergistically designed thermoacoustic sensor will be self-powered, wireless, and provide telemetry. The novel sensor will be able to provide reactor process information even if external electrical power and communication are unavailable. In addition, the form-factor for the sensor is identical to the existing fuel rods within reactors and contains no moving parts. Results from initial proof of concept experiments designed to characterize porosity, surface properties and monitor gas composition will be discussed.

  17. Synergistic neurotrophic effects of piracetam and thiotriazoline

    Directory of Open Access Journals (Sweden)

    O. A. Gromova

    2016-01-01

    Full Text Available The paper considers the synergy between the nootropic drug piracetam and the metabolic agent thiotriazoline that maintains energy metabolism and survival of neurons and other types of cells. Piracetam, a nootropic drug, a chemical pyrrolidone derivative, is used in neurological, psychiatric, and narcological practice. There is evidence on the positive effect of piracetam in elderly and senile patients with coronary heart disease. This drug is supposed to stimulate redox processes, to enhance glucose utilization, and to improve regional blood flow in the ischemic brain regions. Due to its action, the drug activates glycolytic processes and elevates ATP concentrations in brain tissue. Thiotriazoline is a compound that has antioxidant, anti-ischemic properties. The co-administration of piracetam and thiothriazoline is an innovation area in the treatment of stroke and other brain damages, especially in insulin resistance and high blood glucose levels. The paper considers the neurobiological properties of thiotriazoline and piracetam, which synergistically exert neuroprotective and neurotrophic effects.

  18. Increasing the availability of threonine, isoleucine, valine, and leucine relative to lysine while maintaining an ideal ratio of lysine:methionine alters mammary cellular metabolites, mammalian target of rapamycin signaling, and gene transcription.

    Science.gov (United States)

    Dong, X; Zhou, Z; Wang, L; Saremi, B; Helmbrecht, A; Wang, Z; Loor, J J

    2018-03-14

    Amino acids not only serve as precursors for protein synthesis but also function as signaling molecules that can regulate the mammalian target of rapamycin (mTOR) pathway. Methionine and Lys are the most-limiting AA for milk production and a ratio of ∼3:1 Lys:Met in the metabolizable protein has been determined to be ideal. Besides Met and Lys, recent studies have evaluated Ile, Leu, Val, and Thr as potentially limiting for milk protein synthesis. The objective of this experiment was to determine if varying the ratio of Lys:Thr, Lys:Ile, Lys:Val, and Lys:Leu while maintaining an ideal ratio of Lys:Met and fixed ratio of other essential AA (IPAA) elicits changes in intracellular metabolites, gene transcription related to protein synthesis, and phosphorylation status of mTOR pathway proteins. Immortalized bovine mammary epithelial cell line (MAC-T) cells were incubated for 12 h (n = 5 replicates/treatment) with IPAA (2.9:1 Lys:Met; 1.8:1 Lys:Thr; 2.38:1 Lys:His; 1.23:1 Lys:Val; 1.45:1 Lys:Ile; 0.85:1 Lys:Leu; 2.08:1 Lys:Arg) or IPAA supplemented with Thr, Ile, Val, and Leu to achieve a Lys:Thr 1.3:1 (LT1.3), Lys:Ile 1.29:1 (LI1.29), Lys:Val 1.12:1 (LV1.12), or Lys:Leu 0.78:1 (LL0.78). Compared with IPAA, metabolomics via gas chromatography-mass spectrometry revealed that increases in availability of Thr, Ile, Val, and Leu led to greater concentrations of essential AA (Leu, Ile, Thr), nonessential AA (Gly, Glu, Gln, Ser, Pro, Asp), and various metabolites including uric acid, phosphoric acid, N-acetylglutamic acid, and intermediates of glycolysis and the tricarboxylic acid cycle. Compared with other treatments, LV1.12 led to greater phosphorylation status of serine/threonine kinase B (Akt), mTORC1, and ribosomal protein S6 and lower phosphorylation of α subunit of eukaryotic translation initiation factor 2. In addition, LV1.12 upregulated abundance of CSN2 and both the abundance and promoter methylation of CSN1S1. Although LI1.29 led to the second highest response

  19. Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells.

    Science.gov (United States)

    Xia, Kun; Zhang, Panpan; Hu, Jian; Hou, Huan; Xiong, Mingdi; Xiong, Junping; Yan, Nianlong

    2018-04-01

    Hepatocellular carcinoma is the sixth most prevalent malignant tumor and the third most common cause of cancer-associated mortality. Statins have been investigated for carcinoma prevention and treatment. In addition, receptor-interacting protein 140 (RIP140) has been observed to inhibit the Wnt/β-catenin signaling pathway and cell growth. The present study aimed to investigate whether simvastatin (SV) is able to induce SMCC-7721 cell apoptosis through the Wnt/β-catenin signaling pathway. Initially, a cell model of RIP140 overexpression was established, and then cells were treated with SV. The cell growth, viability and apoptosis were measured by cell counting kit-8 and flow cytometry. Furthermore, the expression levels of RIP140, β-catenin, c-myc and cyclin D1 were detected by reverse transcription-quantitative polymerase chain, western blot analysis and immunofluorescence. The results demonstrated that SV significantly increased the expression of RIP140 in SMCC-7721 cells; however, β-catenin, c-myc and cyclin D1 levels were significantly decreased. Furthermore, the immunofluorescence assay of β-catenin confirmed that SV decreased the content of this protein in SMCC-7721 cells. Notably, RIP140 exerted a synergistic effect on the apoptosis rate induced by SV (RIP140 + SV group), while the alteration in RIP140, β-catenin, c-myc and cyclin D1 levels was more evident in the combination group as compared with the RIP140 or SV alone groups. In conclusion, these results suggested that SV is able to induce the apoptosis of SMCC-7721 cells through the Wnt/β-catenin signaling pathway, as well as that RIP140 and SV exert a synergistic effect on the inhibition of cell proliferation and survival.

  20. Nanomedicine of synergistic drug combinations for cancer therapy - Strategies and perspectives.

    Science.gov (United States)

    Zhang, Rui Xue; Wong, Ho Lun; Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

    2016-10-28

    Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. The Transcription Factor Encyclopedia

    NARCIS (Netherlands)

    Yusuf, Dimas; Butland, Stefanie L.; Swanson, Magdalena I.; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A.; Zhang, Xiao Yu Cindy; Dickman, Christopher T. D.; Fulton, Debra L.; Lim, Jonathan S.; Schnabl, Jake M.; Ramos, Oscar H. P.; Vasseur-Cognet, Mireille; de Leeuw, Charles N.; Simpson, Elizabeth M.; Ryffel, Gerhart U.; Lam, Eric W.-F.; Kist, Ralf; Wilson, Miranda S. C.; Marco-Ferreres, Raquel; Brosens, Jan J.; Beccari, Leonardo L.; Bovolenta, Paola; Benayoun, Bérénice A.; Monteiro, Lara J.; Schwenen, Helma D. C.; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A.; Chakravarthy, Harini; Hoodless, Pamela A.; Mancarelli, M. Michela; Torbett, Bruce E.; Banham, Alison H.; Reddy, Sekhar P.; Cullum, Rebecca L.; Liedtke, Michaela; Tschan, Mario P.; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J.; Eijkelenboom, Astrid; Brown, Philip J.; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L.; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H.; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J.; van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W. Z.; Breslin, Mary B.; Lan, Michael S.; Nanan, Kyster K.; Wegner, Michael; Hou, Juan; Mullen, Rachel D.; Colvin, Stephanie C.; Noy, Peter John; Webb, Carol F.; Witek, Matthew E.; Ferrell, Scott; Daniel, Juliet M.; Park, Jason; Waldman, Scott A.; Peet, Daniel J.; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J.; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M.; Woodcroft, Mark W.; Hough, Margaret R.; Chen, Edwin; Europe-Finner, G. Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; Lebrun, David P.; Biswal, Shyam; Harvey, Christopher J.; Debruyne, Jason P.; Hogenesch, John B.; Hevner, Robert F.; Héligon, Christophe; Luo, Xin M.; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S.; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M.; Bradley, Philip H.; Wasserman, Wyeth W.

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review

  2. The transcriptional landscape

    DEFF Research Database (Denmark)

    Nielsen, Henrik

    2011-01-01

    The application of new and less biased methods to study the transcriptional output from genomes, such as tiling arrays and deep sequencing, has revealed that most of the genome is transcribed and that there is substantial overlap of transcripts derived from the two strands of DNA. In protein codi...

  3. Synergistic anti-proliferative effects of gambogic acid with docetaxel in gastrointestinal cancer cell lines

    Directory of Open Access Journals (Sweden)

    Zou Zhengyun

    2012-04-01

    Full Text Available Summary Background Gambogic acid has a marked anti-tumor effect for gastric and colorectal cancers in vitro and in vivo. However, recent investigations on gambogic acid have focused mainly on mono-drug therapy, and its potential role in cancer therapy has not been comprehensively illustrated. This study aimed to assess the interaction between gambogic acid and docetaxel on human gastrointestinal cancer cells and to investigate the mechanism of gambogic acid plus docetaxel treatment-induced apoptotic cell death. Methods MTT assay was used to determine IC50 values in BGC-823, MKN-28, LOVO and SW-116 cells after gambogic acid and docetaxel administration. Median effect analysis was applied for determination of synergism and antagonism. Synergistic interaction between gambogic acid and docetaxel was evaluated using the combination index (CI method. Furthermore, cellular apoptosis was analyzed by Annexin-V and propidium iodide (PI double staining. Additionally, mRNA expression of drug-associated genes, i.e., β-tublin III and tau, and the apoptosis-related gene survivin, were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR. Results Gambogic acid provided a synergistic effect on the cytotoxicity induced by docetaxel in all four cell lines. The combined application of gambogic acid and docetaxel enhanced apoptosis in gastrointestinal cancer cells. Moreover, gambogic acid markedly decreased the mRNA expression of docetaxel-related genes, including β-tubulin III, tau and survivin, in BGC-823 cells. Conclusions Gambogic acid plus docetaxel produced a synergistic anti-tumor effect in gastrointestinal cancer cells, suggesting that the drug combination may offer a novel treatment option for patients with gastric and colorectal cancers.

  4. Mechanical Properties of Transcription

    Science.gov (United States)

    Sevier, Stuart A.; Levine, Herbert

    2017-06-01

    The mechanical properties of transcription have recently been shown to play a central role in gene expression. However, a full physical characterization of this central biological process is lacking. In this Letter, we introduce a simple description of the basic physical elements of transcription where RNA elongation, RNA polymerase rotation, and DNA supercoiling are coupled. The resulting framework describes the relative amount of RNA polymerase rotation and DNA supercoiling that occurs during RNA elongation. Asymptotic behavior is derived and can be used to experimentally extract unknown mechanical parameters of transcription. Mechanical limits to transcription are incorporated through the addition of a DNA supercoiling-dependent RNA polymerase velocity. This addition can lead to transcriptional stalling and resulting implications for gene expression, chromatin structure and genome organization are discussed.

  5. Bile acid increases expression of the histamine-producing enzyme, histidine decarboxylase, in gastric cells.

    Science.gov (United States)

    Ku, Hye Jin; Kim, Hye Young; Kim, Hyeong Hoe; Park, Hee Ju; Cheong, Jae Hun

    2014-01-07

    To investigate the effect of bile acid on the expression of histidine decarboxylase (HDC), which is a major enzyme involved in histamine production, and gene expression of gastric transcription factors upon cooperative activation. HDC expression was examined by immunohistochemistry, reverse transcriptase polymerase chain reaction, and promoter assay in human gastric precancerous tissues, normal stomach tissue, and gastric cancer cell lines. The relationship between gastric precancerous state and HDC expression induced by bile acid was determined. The association between the expression of HDC and various specific transcription factors in gastric cells was also evaluated. MKN45 and AGS human gastric carcinoma cell lines were transfected with farnesoid X receptor (FXR), small heterodimer partner (SHP), and caudal-type homeodomain transcription factor (CDX)1 expression plasmids. The effects of various transcription factors on HDC expression were monitored by luciferase-reporter promoter assay. Histamine production and secretion in the stomach play critical roles in gastric acid secretion and in the pathogenesis of gastric diseases. Here, we show that bile acid increased the expression of HDC, which is a rate-limiting enzyme of the histamine production pathway. FXR was found to be a primary regulatory transcription factor for bile acid-induced HDC expression. In addition, the transcription factors CDX1 and SHP synergistically enhanced bile acid-induced elevation of HDC gene expression. We confirmed similar expression patterns for HDC, CDX1, and SHP in patient tissues. HDC production in the stomach is associated with bile acid exposure and its related transcriptional regulation network of FXR, SHP, and CDX1.

  6. Digital Inverter Amine Sensing via Synergistic Responses by n and p Organic Semiconductors

    OpenAIRE

    Tremblay, Noah J.; Jung, Byung Jun; Breysse, Patrick; Katz, Howard E.

    2011-01-01

    Chemiresistors and sensitive OFETs have been substantially developed as cheap, scalable, and versatile sensing platforms. While new materials are expanding OFET sensing capabilities, the device architectures have changed little. Here we report higher order logic circuits utilizing OFETs sensitive to amine vapors. The circuits depend on the synergistic responses of paired p- and n-channel organic semiconductors, including an unprecedented analyte-induced current increase by the n-channel semic...

  7. Mechanism of Synergistic Inhibition of Listeria monocytogenes Growth by Lactic Acid, Monolaurin, and Nisin▿

    OpenAIRE

    Tokarskyy, Oleksandr; Marshall, Douglas L.

    2008-01-01

    The combined lactic acid, monolaurin, and nisin effects on time-to-detection (optical density at 600 nm) extension were greater (P < 0.05) than any single or paired combination effect, which demonstrates a synergistic interaction among the antimicrobials. Monolaurin exposure caused C12:0 cell membrane incorporation. Lactic acid caused increased monolaurin C12:0 membrane incorporation, while nisin had no influence. We postulate that lactic acid-enhanced monolaurin C12:0 incorporation into the ...

  8. HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Hongbiao Huang

    Full Text Available Combinations of proteasome inhibitors and histone deacetylases (HDAC inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like activity assay. Here we report that (i the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii the combination also synergistically inhibits tumor growth in vivo; (iii two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

  9. Synergistic interactions of biotic and abiotic environmental stressors on gene expression.

    Science.gov (United States)

    Altshuler, Ianina; McLeod, Anne M; Colbourne, John K; Yan, Norman D; Cristescu, Melania E

    2015-03-01

    Understanding the response of organisms to multiple stressors is critical for predicting if populations can adapt to rapid environmental change. Natural and anthropogenic stressors often interact, complicating general predictions. In this study, we examined the interactive and cumulative effects of two common environmental stressors, lowered calcium concentration, an anthropogenic stressor, and predator presence, a natural stressor, on the water flea Daphnia pulex. We analyzed expression changes of five genes involved in calcium homeostasis - cuticle proteins (Cutie, Icp2), calbindin (Calb), and calcium pump and channel (Serca and Ip3R) - using real-time quantitative PCR (RT-qPCR) in a full factorial experiment. We observed strong synergistic interactions between low calcium concentration and predator presence. While the Ip3R gene was not affected by the stressors, the other four genes were affected in their transcriptional levels by the combination of the stressors. Transcriptional patterns of genes that code for cuticle proteins (Cutie and Icp2) and a sarcoplasmic calcium pump (Serca) only responded to the combination of stressors, changing their relative expression levels in a synergistic response, while a calcium-binding protein (Calb) responded to low calcium stress and the combination of both stressors. The expression pattern of these genes (Cutie, Icp2, and Serca) were nonlinear, yet they were dose dependent across the calcium gradient. Multiple stressors can have complex, often unexpected effects on ecosystems. This study demonstrates that the dominant interaction for the set of tested genes appears to be synergism. We argue that gene expression patterns can be used to understand and predict the type of interaction expected when organisms are exposed simultaneously to natural and anthropogenic stressors.

  10. Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement

    DEFF Research Database (Denmark)

    Czermak, B J; Lentsch, A B; Bless, N M

    1999-01-01

    demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation....... In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions...... increased neutrophil accumulation occurred, as did lung injury. These observations suggest that C5a and MAC function synergistically with a costimulus to enhance chemokine generation and the intensity of the lung inflammatory response....

  11. Transcriptional tools: Small molecules for modulating CBP KIX-dependent transcriptional activators.

    Science.gov (United States)

    Bates, Caleb A; Pomerantz, William C; Mapp, Anna K

    2011-01-01

    Previously it was demonstrated that amphipathic isoxazolidines are able to functionally replace the transcriptional activation domains of endogenous transcriptional activators. In addition, in vitro binding studies suggested that a key binding partner of these molecules is the CREB Binding Protein (CBP), more specifically the KIX domain within this protein. Here we show that CBP plays an essential role in the ability of isoxazolidine transcriptional activation domains to activate transcription in cells. Consistent with this model, isoxazolidines are able to function as competitive inhibitors of the activators MLL and Jun, both of which utilize a binding interaction with KIX to up-regulate transcription. Further, modification of the N2 side chain produced three analogs with enhanced potency against Jun-mediated transcription, although increased cytotoxicity was also observed. Collectively these small KIX-binding molecules will be useful tools for dissecting the role of the KIX domain in a variety of pathological processes. 2010 Wiley Periodicals, Inc.

  12. Phosphorus doped and defects engineered graphene for improved electrochemical sensing: synergistic effect of dopants and defects

    International Nuclear Information System (INIS)

    Chu, Ke; Wang, Fan; Tian, Ye; Wei, Zhen

    2017-01-01

    Heteroatom-doped graphene materials emerged as promising metal-free catalysts have recently attracted a growing interest in electrochemical sensing applications. However, their catalytic activity and sensing performances still need to be further improved. Herein, we reported the development of unique phosphorus (P)-doped and plasma-etched graphene (denoted as PG-E) as an efficient metal-free electrocatalyst for dopamine (DA) sensing. It was demonstrated that introducing both P-dopants and plasma-engineered defects in graphene could synergistically improve the activity toward electrocatalytic oxidation of DA by increasing the accessible active sites and promoting the electron transport capability. The resulting PG-E modified electrode showed exceptional DA sensing performances with low detection limit, high selectivity and good stability. These results suggested that the synergistic effect of dopants and defects might be an important factor for developing the advanced graphene-based metal-free catalysts for electrochemical sensing.

  13. Synergistic extraction of trivalent lanthanoids with 3-phenyl-4-benzoyl-5-isoxazolone and various sulphoxides

    International Nuclear Information System (INIS)

    Sahu, S.K.; Chakravortty, V.; Reddy, M.L.P.; Ramamohan, T.R.

    1999-01-01

    Synergistic extraction of trivalent lanthanoids Nd, Tb and Tm with mixtures of 3-phenyl-4-benzoyl-5-isoxazolone (HPBI) and dioctyl sulphoxide (DOSO), bis-2-ethylhexyl sulphoxide (B2EHSO) or diphenyl sulphoxide (DPhSO) in xylene from perchlorate solution was investigated. Lanthanoids were found to be extracted as Ln(PBI) 3 with HPBI alone. In the presence of sulphoxides, Nd(III) was found to be extracted as Nd(PBI) 3 . S and Nd(PBI) 3 . 2 S (where S = sulphoxide). On the other hand, Tb(III) and Tm(III) were extracted as Tb(PBI) 3 . S and Tm(PBI) 3 . S respectively. The equilibrium constants of the synergistic species were found to increase monotonically with decreasing ionic radii of these metal ions. The addition of a sulphoxide to the metal chelate system not only enhances the extraction efficiency but also improves the selectivities among these trivalent lanthanoids. (orig.)

  14. Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid

    Energy Technology Data Exchange (ETDEWEB)

    Eitsuka, Takahiro, E-mail: eitsuka@nupals.ac.jp [Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603 (Japan); Tatewaki, Naoto; Nishida, Hiroshi; Kurata, Tadao [Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603 (Japan); Nakagawa, Kiyotaka; Miyazawa, Teruo [Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan)

    2014-10-24

    Highlights: • δ-Tocotrienol (δ-T3) and ferulic acid (FA) synergistically inhibit cancer cell growth. • The combination of δ-T3 and FA induces G1 arrest by up-regulating p21. • The synergy is attributed to an increase in the cellular concentration of δ-T3 by FA. - Abstract: Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly δ-tocotrienol (δ-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of δ-T3 and FA markedly reduced cell proliferation relative to δ-T3 alone, and FA had no effect when used alone. Although δ-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of δ-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of δ-T3 by FA. Our results suggest that the combination of δ-T3 and FA may present a new strategy for cancer prevention and therapy.

  15. Porphyromonas gingivalis and Treponema denticola synergistic polymicrobial biofilm development.

    Directory of Open Access Journals (Sweden)

    Ying Zhu

    Full Text Available Chronic periodontitis has a polymicrobial biofilm aetiology and interactions between key bacterial species are strongly implicated as contributing to disease progression. Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia have all been implicated as playing roles in disease progression. P. gingivalis cell-surface-located protease/adhesins, the gingipains, have been suggested to be involved in its interactions with several other bacterial species. The aims of this study were to determine polymicrobial biofilm formation by P. gingivalis, T. denticola and T. forsythia, as well as the role of P. gingivalis gingipains in biofilm formation by using a gingipain null triple mutant. To determine homotypic and polymicrobial biofilm formation a flow cell system was employed and the biofilms imaged and quantified by fluorescent in situ hybridization using DNA species-specific probes and confocal scanning laser microscopy imaging. Of the three species, only P. gingivalis and T. denticola formed mature, homotypic biofilms, and a strong synergy was observed between P. gingivalis and T. denticola in polymicrobial biofilm formation. This synergy was demonstrated by significant increases in biovolume, average biofilm thickness and maximum biofilm thickness of both species. In addition there was a morphological change of T. denticola in polymicrobial biofilms when compared with homotypic biofilms, suggesting reduced motility in homotypic biofilms. P. gingivalis gingipains were shown to play an essential role in synergistic polymicrobial biofilm formation with T. denticola.

  16. Porphyromonas gingivalis and Treponema denticola synergistic polymicrobial biofilm development.

    Science.gov (United States)

    Zhu, Ying; Dashper, Stuart G; Chen, Yu-Yen; Crawford, Simon; Slakeski, Nada; Reynolds, Eric C

    2013-01-01

    Chronic periodontitis has a polymicrobial biofilm aetiology and interactions between key bacterial species are strongly implicated as contributing to disease progression. Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia have all been implicated as playing roles in disease progression. P. gingivalis cell-surface-located protease/adhesins, the gingipains, have been suggested to be involved in its interactions with several other bacterial species. The aims of this study were to determine polymicrobial biofilm formation by P. gingivalis, T. denticola and T. forsythia, as well as the role of P. gingivalis gingipains in biofilm formation by using a gingipain null triple mutant. To determine homotypic and polymicrobial biofilm formation a flow cell system was employed and the biofilms imaged and quantified by fluorescent in situ hybridization using DNA species-specific probes and confocal scanning laser microscopy imaging. Of the three species, only P. gingivalis and T. denticola formed mature, homotypic biofilms, and a strong synergy was observed between P. gingivalis and T. denticola in polymicrobial biofilm formation. This synergy was demonstrated by significant increases in biovolume, average biofilm thickness and maximum biofilm thickness of both species. In addition there was a morphological change of T. denticola in polymicrobial biofilms when compared with homotypic biofilms, suggesting reduced motility in homotypic biofilms. P. gingivalis gingipains were shown to play an essential role in synergistic polymicrobial biofilm formation with T. denticola.

  17. A PAH growth mechanism and synergistic effect on PAH formation in counterflow diffusion flames

    KAUST Repository

    Wang, Yu

    2013-09-01

    A reaction mechanism having molecular growth up to benzene for hydrocarbon fuels with up to four carbon-atoms was extended to include the formation and growth of polycyclic aromatic hydrocarbons (PAHs) up to coronene (C24H12). The new mechanism was tested for ethylene premixed flames at low (20torr) and atmospheric pressures by comparing experimentally observed species concentrations with those of the computed ones for small chemical species and PAHs. As compared to several existing mechanisms in the literature, the newly developed mechanism showed an appreciable improvement in the predicted profiles of PAHs. The new mechanism was also used to simulate PAH formation in counterflow diffusion flames of ethylene to study the effects of mixing propane and benzene in the fuel stream. In the ethylene-propane flames, existing experimental results showed a synergistic effect in PAH concentrations, i.e. PAH concentrations first increased and then decreased with increasing propane mixing. This PAH behavior was successfully captured by the new mechanism. The synergistic effect was predicted to be more pronounced for larger PAH molecules as compared to the smaller ones, which is in agreement with experimental observations. In the experimental study in which the fuel stream of ethylene-propane flames was doped with benzene, a synergistic effect was mitigated for benzene, but was observed for large PAHs. This effect was also predicted in the computed PAH profiles for these flames. To explain these responses of PAHs in the flames of mixture fuels, a pathway analysis has been conducted, which show that several resonantly stabilized species as well as C4H4 and H atom contribute to the enhanced synergistic behaviors of larger PAHs as compared to the small ones in the flames of mixture fuels. © 2013 The Combustion Institute.

  18. Deciphering Transcriptional Regulation

    DEFF Research Database (Denmark)

    Valen, Eivind

    RNA); and ii) translation, in which the mRNA is translated into a protein. This thesis focus on the ¿rst of these steps, transcription, and speci¿cally the initiation of this. Simpli¿ed, initiation is preceded by the binding of several proteins, known as transcription factors (TFs), to DNA. This takes place...... published providing an unbiased overview of the transcription start site (TSS) usage in a tissue. We have paired this method with high-throughput sequencing technology to produce a library of unprecedented depth (DeepCAGE) for the mouse hippocampus. We investigated this in detail and focused particularly...... control spanning the range from completely muted to cranked up to maximum. The volume, in this case, is the production rate of proteins. This production is the result of a two step procedure: i) transcription, in which a small part of DNA from the genome (a gene) is transcribed into an RNA molecule (an m...

  19. Berberine and Evodiamine Act Synergistically Against Human Breast Cancer MCF-7 Cells by Inducing Cell Cycle Arrest and Apoptosis.

    Science.gov (United States)

    Du, Jia; Sun, Yang; Lu, Yi-Yu; Lau, Eric; Zhao, Ming; Zhou, Qian-Mei; Su, Shi-Bing

    2017-11-01

    The synergistic combinations of natural products have long been the basis of Traditional Chinese herbal Medicine formulas. In this study, we investigated the synergistic effects of a combination of berberine and evodiamine against human breast cancer MCF-7 cells in vitro and in vivo, and explored its mechanism. Cell survival was measured using the MTT assay. Apoptosis-related proteins were observed using western blot analysis. Apoptosis was detected with flow cytometric analysis and by Hoechst 33258 staining. Tumor xenografts were used in vivo. Compared to berberine or evodiamine treatments alone, the combination treatment of berberine (25 μM) and evodiamine (15 μM) synergistically inhibited the proliferation of MCF-7 cells in a time-dependent manner and resulted in the G 0 /G 1 phase accumulation of cells that exhibited increased expression levels of the CDK inhibitors p21 and p27 with a concomitant reduction in the expression levels of cell-cycle checkpoint proteins cyclin D1, cyclin E, CDK4, and CDK6. Furthermore, the combination treatment induced apoptosis that was accompanied by increased expression levels of p53 and Bax, reduced expression levels of Bcl-2, activation of caspase-7, and caspase-9, and the cleavage of PARP. The combination of berberine and evodiamine synergistically inhibited tumor growth in vivo in MCF-7 human breast cancer xenografts. Combination of berberine and evodiamine acts synergistically to suppress the proliferation of MCF-7 cells by inducing cell cycle arrest and apoptosis, illustrating the potential synergistic and combinatorial application of bioactive natural products. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  20. Microbial Reverse Electrodialysis Cells for Synergistically Enhanced Power Production

    KAUST Repository

    Kim, Younggy

    2011-07-01

    A new type of bioelectrochemical system for producing electrical power, called a microbial reverse-electrodialysis cell (MRC), was developed to increase voltages and power densities compared to those generated individually by microbial fuel cells (MFCs) or reverse electrodialysis (RED) systems. In RED systems, electrode overpotentials create significant energy losses due to thermodynamically unfavorable electrode reactions, and therefore a large number of stacked cells must be used to have significant energy recovery. This results in high capital costs for the large number of membranes, and increases energy losses from pumping water through a large number of cells. In an MRC, high overpotentials are avoided through oxidation of organic matter by exoelectrogenic bacteria on the anode and oxygen reduction on the cathode. An MRC containing only five pairs of RED cells, fed solutions typical of seawater (600 mM NaCl) and river water (12 mM NaCl) at 0.85 mL/min, produced up to 3.6 W/m2 (cathode surface area) and 1.2-1.3 V with acetate as a substrate. Pumping accounted for <2% of the produced power. A higher flow rate (1.55 mL/min) increased power densities up to 4.3 W/m2. COD removal was 98% with a Coulombic efficiency of 64%. Power production by the individual components was substantially lower with 0.7 W/m2 without salinity driven energy, and <0.015 W/m2 with reduced exoelectrogenic activity due to substrate depletion. These results show that the combination of an MFC and a RED stack synergistically increases performance relative to the individual systems, producing a new type of system that can be used to more efficiently capture salinity driven energy from seawater and river water. © 2011 American Chemical Society.

  1. Locomotor changes in length and EMG activity of feline medial gastrocnemius muscle following paralysis of two synergists

    NARCIS (Netherlands)

    Maas, H.; Gregor, R.J.; Hodson-Tole, E.F.; Farrell, B.J.; English, A.W.; Prilutsky, B.I.

    2010-01-01

    The mechanism of the compensatory increase in electromyographic activity (EMG) of a cat ankle extensor during walking shortly after paralysis of its synergists is not fully understood. It is possible that due to greater ankle Xexion in stance in this situation, muscle spindles are stretched to a

  2. Mathematical description of synergistic interaction between radon and smoking

    International Nuclear Information System (INIS)

    Jin Kyu Kim; Petin, V.G.; Belkina, S.V.

    2007-01-01

    Complete text of publication follows. Background: A certain level of background exposure to ionizing radiation and natural or man-made chemicals is always present in the environment. Radon and its short-lived decay products are considered as important sources of public exposure to the natural radioactivity. It is well known from epidemiological and toxicological studies that synergistic interaction between smoking and radon occurs, which is especially important for high natural background areas. Objective: This study has been done to suggest a mathematical model to describe the synergistic interaction of radon with tobacco smoking, and to demonstrate the ability of the model to describe carcinogenic effects of the combined action. Methods: A simple mathematical model was formulated to describe and predict the synergistic interaction of radon with smoking. The model postulates that the occurrence of synergism is to be expected as a result of additional carcinogenic damage arisen from the interaction of sublesions induced by the two factors under consideration. Results: The predictions of the model were verified by comparison with experimental data published by other researchers. The model appears to be appropriate and the predictions are valid. Conclusions: : The suggested mathematical model predicts the greatest level of synergistic effect and condition under which the maximum synergy is attained. The synergistic effect appeared to decline with any deviation from the optimal value of the ratio of carcinogenic effective damages produced by each agent alone.

  3. In vitro synergistic antioxidant activity and identification of antioxidant components from Astragalus membranaceus and Paeonia lactiflora.

    Directory of Open Access Journals (Sweden)

    Xiaoyan Xu

    Full Text Available Many traditionally used herbs demonstrate significantly better pharmacological effects when used in combination than when used alone. However, the mechanism underlying this synergism is still poorly understood. This study aimed to investigate the synergistic antioxidant activity of Astragalus membranaceus (AME and Paeonia Lactiflora (PL, and identify the potential antioxidant components by 1,1-diphenyl-2-picrylhydrazine (DPPH radical spiking test followed by a high performance liquid chromatography separation combined with diode array detection and tandem mass spectrometry analysis (DPPH-HPLC-DAD-MS/MS. Eight AME-PL combined extracts (E1-E8 were prepared based on bioactivity-guided fractionation. Among them, E1 exhibited the strongest synergistic effect in scavenging DPPH radicals and reducing ferric ions (P<0.05. Moreover, E1 presented strong cytoprotection against H2O2-induced oxidative damage in MRC-5 cells by suppressing the decrease of the superoxide dismutase (SOD, glutathione peroxidase (GSH-Px and catalase (CAT activities. A strong correlation between the increment of total phenolic/flavonoid and synergistic antioxidant activity, especially between the increment of total flavonoid and the increase in ferric reducing power was observed. Finally, seven antioxidant substances were identified in E1 as oxypaeoniflora, catechin, calycosin-7-O-β-D-glucopyranoside, fomononetin-7-O-β-D-glucopyranoside, 9,10-dimethoxy-pterocarpan-3-O-β-D-glucopyranoside, quercetin and 2'-dihydroxy-3',4'-dimethyl-isoflavan-7-O-β-D-glucopyranoside.

  4. Muscle force compensation among synergistic muscles after fatigue of a single muscle.

    Science.gov (United States)

    Stutzig, Norman; Siebert, Tobias

    2015-08-01

    The aim of this study was to examine control strategies among synergistic muscles after fatigue of a single muscle. It was hypothesized that the compensating mechanism is specific for each fatigued muscle. The soleus (SOL), gastrocnemius lateralis (GL) and medialis (GM) were fatigued in separate sessions on different days. In each experiment, subjects (n = 11) performed maximal voluntary contractions prior to and after fatiguing a single muscle (SOL, GL or GM) while the voluntary muscle activity and torque were measured. Additionally, the maximal single twitch torque of the plantarflexors and the maximal spinal reflex activity (H-reflex) of the SOL, GL and GM were determined. Fatigue was evoked using neuromuscular stimulation. Following fatigue the single twitch torque decreased by -20.1%, -19.5%, and -23.0% when the SOL, GL, or GM, have been fatigued. The maximal voluntary torque did not decrease in any session but the synergistic voluntary muscle activity increased significantly. Moreover, we found no alterations in spinal reflex activity. It is concluded that synergistic muscles compensate each other. Furthermore, it seems that self-compensating mechanism of the fatigued muscles occurred additionally. The force compensation does not depend on the function of the fatigued muscle. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Robot- and computer-assisted craniotomy (CRANIO): from active systems to synergistic man-machine interaction.

    Science.gov (United States)

    Cunha-Cruz, V; Follmann, A; Popovic, A; Bast, P; Wu, T; Heger, S; Engelhardt, M; Schmieder, K; Radermacher, K

    2010-01-01

    Computer and robot assistance in craniotomy/craniectomy procedures is intended to increase precision and efficiency of the removal of calvarial tumours, enabling the preoperative design and manufacturing of the corresponding implant. In the framework of the CRANIO project, an active robotic system was developed to automate the milling processes based on a predefined resection planning. This approach allows for a very efficient milling process, but lacks feedback of the intra-operative process to the surgeon. To better integrate the surgeon into the process, a new teleoperated synergistic architecture was designed. This enables the surgeon to realize changes during the procedure and use their human cognitive capabilities. The preoperative planning information is used as guidance for the user interacting with the system through a master-slave architecture. In this article, the CRANIO system is presented together with this new synergistic approach. Experiments have been performed to evaluate the accuracy of the system in active and synergistic modes for the bone milling procedure. The laboratory studies showed the general feasibility of the new concept for the selected medical procedure and determined the accuracy of the system. Although the integration of the surgeon partially reduces the efficiency of the milling process compared with a purely active (automatic) milling, it provides more feedback and flexibility to the user during the intra-operative procedure.

  6. Synergistic action of fatty acids, sulphides and stilbene against acaricide-resistant Rhipicephalus microplus ticks.

    Science.gov (United States)

    Arceo-Medina, G N; Rosado-Aguilar, J A; Rodríguez-Vivas, R I; Borges-Argaez, R

    2016-09-15

    Six compounds in a methanolic extract of Petiveria alliacea stem (cis-stilbene; benzyl disulphide; benzyl trisulphide; and methyl esters of hexadecanoic acid, octadecadienoic acid and octadecenoic acid) are known to exercise acaricide activity against cattle tick Rhipicephalus microplus larvae and adults. The synergistic effect of 57 combinations of these six compounds on acaricide activity against R. microplus was evaluated. Larvae immersion tests produced the lethal concentrations needed to kill 50% (LC 50 ) and 99% (LC 99 ) of the population. Adult immersion tests produced rates (%) for mortality, oviposition inhibition and eclosion inhibition. Individually, none of the compounds (1% concentration) exhibited acaricide activity (mortality ≤2.3%). When combined, however, nine mixtures exhibited a synergistic increase in activity, with high mortality rates (≥92%) in larvae. Values for LC 50 ranged from 0.07 to 0.51% and those for LC 99 from 0.66 to 5.16%. Thirty six compound mixtures had no significant activity (mortality ≤30%) against larvae. Two mixtures exhibited synergism against adults, with high rates (≥92%) of oviposition inhibition. The mixtures based on the benzyl disulphide+benzyl trisulphide pairing produced a synergistic effect against acaricide-resistant R. microplus larva and adults, and are therefore the most promising combination for controlling this ubiquitous ectoparasite. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Synergistic antifungal activity of berberine derivative B-7b and fluconazole.

    Directory of Open Access Journals (Sweden)

    Li Ping Li

    Full Text Available Our previous study demonstrated berberine (BBR and fluconazole (FLC used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. We also suggested BBR played a major antifungal role in the synergism of FLC and BBR, while FLC increased intracellular BBR concentrations. Our following systematic structural modification and reconstruction of BBR core identified the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-ylethyl-2-(substituted phenylacet-amide derivatives 7a-i, including B-7b and B-7d exhibiting remarkable synergistic antifungal activity and low cytotoxicity. Here, the study mainly investigated the synergistic activity of FLC and B-7b and the underlying mechanism. In vitro interaction of FLC and B-7b was investigated against 30 FLC-resistant clinical isolates of C. albicans and non-C. albicans species, including Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida krusei and Cryptococcus neoformans. The potent synergistic activity of B-7b in combination with FLC against FLC-resistant C. albicans was found through the checkerboard microdilution assay. The findings of agar diffusion tests and time-kill curves confirmed its better synergism with FLC. And as expected, B-7b exhibited much lower cytotoxicity than BBR to human umbilical vein endothelial cells. In contrast to BBR, we found that endogenous ROS augmentation was not involved in the synergism of FLC and B-7b. According to the results from our present comparative proteomic study, it seemed that the disruption of protein folding and processing and the weakening of cells' self-defensive ability contributed to the synergism of FLC and B-7b. Together, these results suggested novel scaffold BBR derivative B-7b could be a promising synergist in combination with FLC for the treatment of invasive fungal infections.

  8. Geminivirus mixed infection on pepper plants: Synergistic interaction between PHYVV and PepGMV

    Directory of Open Access Journals (Sweden)

    Rivera-Bustamante Rafael F

    2011-03-01

    Full Text Available Abstract Background PHYVV and PepGMV are plant viruses reported in Mexico and Southern US as causal agents of an important pepper disease known as "rizado amarillo". Mixed infections with PHYVV and PepGMV have been reported in several hosts over a wide geographic area. Previous work suggested that these viruses might interact at the replication and/or movement level in a complex manner. The aim of present report was to study some aspects of a synergistic interaction between PHYVV and PepGMV in pepper plants. These include analyses of symptom severity, viral DNA concentration and tissue localization of both viruses in single and mixed infections. Results Mixed infections with PepGMV and PHYVV induced symptoms more severe than those observed in single viral infections. Whereas plants infected with either virus (single infection presented a remission stage with a corresponding decrease in viral DNA levels, double-infected plants did not present symptom remission and both viral DNA concentrations dramatically increased. In situ hybridization experiments revealed that both viruses are restricted to the vascular tissue. Interestingly, the amount of viral DNA detected was higher in plants inoculated with PepGMV than that observed in PHYVV-infected plants. During mixed infections, the location of both viruses remained similar to the one observed in single infections, although the number of infected cells increases. Infections with the tripartite mixture PHYVV (A+B + PepGMV A produced a similar synergistic infection to the one observed after inoculation with both full viruses. On the contrary, tripartite mixture PepGMV (A+B + PHYVV A did not produce a synergistic interaction. In an attempt to study the contribution of individual genes to the synergism, several mutants of PHYVV or PepGMV were inoculated in combination with the corresponding wild type, second virus (wt PepGMV or wt PHYVV. All combinations tested resulted in synergistic infections, with

  9. Azole Fungicides as Synergists in the Aquatic Environment

    DEFF Research Database (Denmark)

    Bjergager, Maj-Britt Andersen

    hazard.This PhD thesis evaluates the role of the so called azole fungicides as synergists in the aquaticenvironment through an assessment of the effect of sorption, time and azole concentration on theoccurrence and magnitude of synergistic interactions with pyrethroid insecticides towards...... the aquaticcrustacean Daphnia magna in both laboratory experiments and natural-like environments. In the PhDthesis, synergy is defined as happening in mixtures where either EC50 values decrease more than two-foldbelow the prediction by the model of Concentration Addition (horizontal assessment of synergy) or wherethe...... in stormwater runoff ordrain water and in the aquatic environment, the pesticides mainly occur in sorbed form. Sorption istraditionally considered to limit bioaccessibility and toxicity of hydrophobic compounds, hence,synergistic interactions may be limited in natural environments compared to laboratory studies...

  10. Colon cancer associated transcripts in human cancers.

    Science.gov (United States)

    Chen, Yincong; Xie, Haibiao; Gao, Qunjun; Zhan, Hengji; Xiao, Huizhong; Zou, Yifan; Zhang, Fuyou; Liu, Yuchen; Li, Jianfa

    2017-10-01

    Long non-coding RNAs serve as important regulators in complicated cellular activities, including cell differentiation, proliferation and death. Dysregulation of long non-coding RNAs occurs in the formation and progression of cancers. The family of colon cancer associated transcripts, long non-coding RNAs colon cancer associated transcript-1 and colon cancer associated transcript-2 are known as oncogenes involved in various cancers. Colon cancer associated transcript-1 is a novel lncRNA located in 8q24.2, and colon cancer associated transcript-2 maps to the 8q24.21 region encompassing rs6983267. Colon cancer associated transcripts have close associations with clinical characteristics, such as lymph node metastasis, high TNM stage and short overall survival. Knockdown of them can reverse the malignant phenotypes of cancer cells, including proliferation, migration, invasion and apoptosis. Moreover, they can increase the expression level of c-MYC and oncogenic microRNAs via activating a series of complex mechanisms. In brief, the family of colon cancer associated transcripts may serve as potential biomarkers or therapeutic targets for human cancers. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. YuaB functions synergistically with the exopolysaccharide and TasA amyloid fibers to allow biofilm formation by Bacillus subtilis.

    Science.gov (United States)

    Ostrowski, Adam; Mehert, Angela; Prescott, Alan; Kiley, Taryn B; Stanley-Wall, Nicola R

    2011-09-01

    During biofilm formation by Bacillus subtilis, two extracellular matrix components are synthesized, namely, the TasA amyloid fibers and an exopolysaccharide. In addition, a small protein called YuaB has been shown to allow the biofilm to form. The regulatory protein DegU is known to initiate biofilm formation. In this report we show that the main role of DegU during biofilm formation is to indirectly drive the activation of transcription from the yuaB promoter. The N terminus of YuaB constitutes a signal peptide for the Sec transport system. Here we show that the presence of the signal peptide is required for YuaB function. In addition we demonstrate that upon export of YuaB from the cytoplasm, it localizes to the cell wall. We continue with evidence that increased production of TasA and the exopolysaccharide is not sufficient to overcome the effects of a mutation in yuaB, demonstrating the unique involvement of YuaB in forming a biofilm. In line with this, YuaB is not involved in correct synthesis, export, or polymerization of either the TasA amyloid fibers or the exopolysaccharide. Taken together, these findings identify YuaB as a protein that plays a novel role during biofilm formation. We hypothesize that YuaB functions synergistically with the known components of the biofilm matrix to facilitate the assembly of the biofilm matrix. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

  12. After-ripening induced transcriptional changes of hormonal genes in wheat seeds: the cases of brassinosteroids, ethylene, cytokinin and salicylic acid.

    Directory of Open Access Journals (Sweden)

    Vijaya R Chitnis

    Full Text Available Maintenance and release of seed dormancy is regulated by plant hormones; their levels and seed sensitivity being the critical factors. This study reports transcriptional regulation of brassinosteroids (BR, ethylene (ET, cytokinin (CK and salicylic acid (SA related wheat genes by after-ripening, a period of dry storage that decays dormancy. Changes in the expression of hormonal genes due to seed after-ripening did not occur in the anhydrobiotic state but rather in the hydrated state. After-ripening induced dormancy decay appears to be associated with imbibition mediated increase in the synthesis and signalling of BR, via transcriptional activation of de-etiolated2, dwarf4 and brassinosteroid signaling kinase, and repression of brassinosteroid insensitive 2. Our analysis is also suggestive of the significance of increased ET production, as reflected by enhanced transcription of 1-aminocyclopropane-1-carboxylic acid oxidase in after-ripened seeds, and tight regulation of seed response to ET in regulating dormancy decay. Differential transcriptions of lonely guy, zeatin O-glucosyltransferases and cytokinin oxidases, and pseudo-response regulator between dormant and after-ripened seeds implicate CK in the regulation of seed dormancy in wheat. Our analysis also reflects the association of dormancy decay in wheat with seed SA level and NPR independent SA signaling that appear to be regulated transcriptionally by phenylalanine ammonia lyase, and whirly and suppressor of npr1 inducible1 genes, respectively. Co-expression clustering of the hormonal genes implies the significance of synergistic and antagonistic interaction between the different plant hormones in regulating wheat seed dormancy. These results contribute to further our understanding of the molecular features controlling seed dormancy in wheat.

  13. Ultrastrong Bioinspired Graphene-Based Fibers via Synergistic Toughening.

    Science.gov (United States)

    Zhang, Yuanyuan; Li, Yuchen; Ming, Peng; Zhang, Qi; Liu, Tianxi; Jiang, Lei; Cheng, Qunfeng

    2016-04-13

    Ultrastrong bioinspired graphene-based fibers are designed and prepared via synergistic toughening of ionic and covalent bonding. The tensile strength reaches up to 842.6 MPa and is superior to all other reported graphene-based fibers. In addition, its electrical conductivity is as high as 292.4 S cm(-1). This bioinspired synergistic toughening strategy supplies new insight toward the construction of integrated high-performance graphene-based fibers in the near future. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Auxins increase expression of the brassinosteroid receptor and brassinosteroid-responsive genes in Arabidopsis.

    Science.gov (United States)

    Sakamoto, Tomoaki; Fujioka, Shozo

    2013-04-01

    Auxins and brassinosteroids are essential phytohormones that synergistically regulate physiological and developmental processes in plants. Previously, we demonstrated that auxins stimulate brassinosteroid perception by regulating the level of brassinosteroid receptor in rice. Here we showed that auxin treatment increased expression of the Arabidopsis brassinosteroid receptor gene BRI1. The promoter of BRI1 has an auxin-response element that is targeted by auxin-response factor transcription factors. Auxin pretreatment increased the sensitivity to brassinosteroids of brassinosteroid-responsive genes. Although multilevel interactions between auxins and brassinosteroids have previously been reported, our findings suggest a possibility that auxins control the degree of brassinosteroid perception by regulating the expression of gene for brassinosteroid receptor, and this phenomenon is conserved between monocots (rice) and dicots (Arabidopsis).

  15. Synergistic effect of temperature, protein and salt concentration on structures and interactions among lysozyme proteins

    Science.gov (United States)

    Kundu, Sarathi; Aswal, V. K.; Kohlbrecher, Joachim

    2016-07-01

    Synergistic effect of temperature, protein and salt concentration on structures and interactions among lysozyme proteins in solution has been studied using small angle neutron scattering technique. Scattering study shows that for a particular protein concentration, with increasing temperature, short-range attraction decreases but long-range repulsion becomes system specific. In absence of salt, lower value of attractive interaction is obtained, however, in presence of salt it becomes higher and decreases with increasing temperature. For specific condition, weak long range attraction and intermediate range repulsion exists. At higher temperature (90 °C), fractal structure develops and the corresponding fractal dimension depends upon the experimental conditions.

  16. The Transcription Factor Encyclopedia

    DEFF Research Database (Denmark)

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I

    2012-01-01

    mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written......ABSTRACT: Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130...... and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe....

  17. The transcription factor encyclopedia.

    Science.gov (United States)

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A; Zhang, Xiao Yu Cindy; Dickman, Christopher T D; Fulton, Debra L; Lim, Jonathan S; Schnabl, Jake M; Ramos, Oscar H P; Vasseur-Cognet, Mireille; de Leeuw, Charles N; Simpson, Elizabeth M; Ryffel, Gerhart U; Lam, Eric W-F; Kist, Ralf; Wilson, Miranda S C; Marco-Ferreres, Raquel; Brosens, Jan J; Beccari, Leonardo L; Bovolenta, Paola; Benayoun, Bérénice A; Monteiro, Lara J; Schwenen, Helma D C; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A; Chakravarthy, Harini; Hoodless, Pamela A; Mancarelli, M Michela; Torbett, Bruce E; Banham, Alison H; Reddy, Sekhar P; Cullum, Rebecca L; Liedtke, Michaela; Tschan, Mario P; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J; Eijkelenboom, Astrid; Brown, Philip J; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J; Van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W Z; Breslin, Mary B; Lan, Michael S; Nanan, Kyster K; Wegner, Michael; Hou, Juan; Mullen, Rachel D; Colvin, Stephanie C; Noy, Peter John; Webb, Carol F; Witek, Matthew E; Ferrell, Scott; Daniel, Juliet M; Park, Jason; Waldman, Scott A; Peet, Daniel J; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M; Woodcroft, Mark W; Hough, Margaret R; Chen, Edwin; Europe-Finner, G Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; LeBrun, David P; Biswal, Shyam; Harvey, Christopher J; DeBruyne, Jason P; Hogenesch, John B; Hevner, Robert F; Héligon, Christophe; Luo, Xin M; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M; Bradley, Philip H; Wasserman, Wyeth W

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

  18. Overexpression of OrbHLH001, a putative helix-loop-helix transcription factor, causes increased expression of AKT1 and maintains ionic balance under salt stress in rice.

    Science.gov (United States)

    Chen, Yuan; Li, Fei; Ma, Yan; Chong, Kang; Xu, Yunyuan

    2013-01-01

    The basic helix-loop-helix family of proteins, which function as transcription factors, have been intensively studied in plants and animals. However, the molecular mechanism of these factors contributing to stress tolerance is unknown. Here, we report on the overexpression of OrbHLH001 from Dongxiang wild rice (Oryza rufipogon) conferring salt tolerance in transgenic rice plants. The expression of OrbHLH001 was tissue specific, mainly in phloem tissues throughout the plant. Ion assay with the scanning ion-selective electrode technique showed that NaCl stress has a greater influence on Na(+) efflux and K(+) influx in OrbHLH001-overexpressed plants than the wild type. OrbHLH001 protein can induce the expression of OsAKT1 to regulate the Na(+)/K(+) ratio in OrbHLH001-overexpressed plants by specifically binding to an E-box motif in the promoter region of OsAKT1. The mechanism may have potential use in rice molecular breeding. Copyright © 2012 Elsevier GmbH. All rights reserved.

  19. Synergistic effect of polyaspartic acid and iodide ion on corrosion inhibition of mild steel in H2SO4

    International Nuclear Information System (INIS)

    Qian, Bei; Wang, Jing; Zheng, Meng; Hou, Baorong

    2013-01-01

    Highlights: •Polyaspartic acid acts as a modest cathodic inhibitor for mild steel in H 2 SO 4 . •Results revealed synergistic effect between polyaspartic acid and iodide ion. •Inhibition efficiency depends on the temperature of H 2 SO 4 medium. •XPS analysis revealed co-adsorption of polyaspartic acid and iodide ion. -- Abstract: The inhibition effect of polyaspartic acid (PASP) and its synergistic effect with KI on mild steel corrosion in 0.5 M H 2 SO 4 solution are studied by weight loss and electrochemical methods. The inhibition efficiency increases with the concentration of PASP and increases further with the presence of 1 mM KI. Result of the zero charge potential measurement shows that iodide ion promotes the film formation of PASP greatly. The mild steel surfaces after immersion test were analyzed using scanning electron microscopy and X-ray photoelectron spectroscopy. An adsorption model is proposed to elucidate the synergistic mechanism of synergistic effect

  20. Continuous energy recovery and nutrients removal from molasses wastewater by synergistic system of dark fermentation and algal culture under various fermentation types.

    Science.gov (United States)

    Ren, Hong-Yu; Kong, Fanying; Ma, Jun; Zhao, Lei; Xie, Guo-Jun; Xing, Defeng; Guo, Wan-Qian; Liu, Bing-Feng; Ren, Nan-Qi

    2018-03-01

    Synergistic system of dark fermentation and algal culture was initially operated at batch mode to investigate the energy production and nutrients removal from molasses wastewater in butyrate-type, ethanol-type and propionate-type fermentations. Butyrate-type fermentation was the most appropriate fermentation type for the synergistic system and exhibited the accumulative hydrogen volume of 658.3 mL L -1 and hydrogen yield of 131.7 mL g -1 COD. By-products from dark fermentation (mainly acetate and butyrate) were further used to cultivate oleaginous microalgae. The maximum algal biomass and lipid content reached 1.01 g L -1 and 38.5%, respectively. In continuous operation, the synergistic system was stable and efficient, and energy production increased from 8.77 kJ L -1  d -1 (dark fermentation) to 17.3 kJ L -1  d -1 (synergistic system). Total COD, TN and TP removal efficiencies in the synergistic system reached 91.1%, 89.1% and 85.7%, respectively. This study shows the potential of the synergistic system in energy recovery and wastewater treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. The effects of the painkiller diclofenac and hypoxia on gene transcription and antioxidant system in the gills of three-spined stickleback.

    Science.gov (United States)

    Lubiana, Pedro; Prokkola, Jenni M; Nikinmaa, Mikko; Burmester, Thorsten; Kanerva, Mirella; Götting, Miriam

    2016-01-01

    Aquatic organisms face multiple stressors in natural ecosystems. More and more often painkillers are detected in surface waters since their prescription has increased worldwide within the last years. Here we examined the effects of the non-steroidal anti-inflammatory drug (NSAID) diclofenac and hypoxia on three-spined sticklebacks (Gasterosteus aculeatus). We exposed sticklebacks to an environmentally relevant concentration of diclofenac (1μg/L) for 14days, to 24h of hypoxia (2.0mg O2/L), and a combination of both. Hypoxia and diclofenac both can be associated with oxidative stress in fish, but it is unclear whether they would act synergistically. Expression analysis of genes related to antioxidant response, hypoxia response, and chemical metabolism in gills showed that diclofenac alone had little effect, while the combination of hypoxia and diclofenac affected transcript levels most, indicating synergistic effects of these stressors. Of the antioxidant enzymes, only superoxide dismutase activity remained unchanged by treatments, while glutathione peroxidase (GPx) was the most affected antioxidant response on both the transcript and activity levels. Our results suggest that diclofenac may lead to suppressed catalase (CAT) activity but increased GPx activity, probably as compensatory mechanism to remove increasing H2O2 in the gills, and that this response is not affected by hypoxia. The activities of lactate dehydrogenase, CAT, and GPx also showed temporal variability during treatments, which can be attributable to tissue-specific circadian rhythms. Our study shows how responses to NSAIDs and hypoxia can interact in fish, suggesting that getting more insight into temporal variation and about the different levels of regulation of environmental responses is necessary in future studies. Copyright © 2016. Published by Elsevier Inc.

  2. Synergistic estrogenic effects of Fusarium and Alternaria mycotoxins in vitro.

    Science.gov (United States)

    Vejdovszky, Katharina; Hahn, Kathrin; Braun, Dominik; Warth, Benedikt; Marko, Doris

    2017-03-01

    Mycotoxins are toxic secondary metabolites formed by various fungal species that are found as natural contaminants in food. This very heterogeneous group of compounds triggers multiple toxic mechanisms, including endocrine disruptive potential. Current risk assessment of mycotoxins, as for most chemical substances, is based on the effects of single compounds. However, concern on a potential enhancement of risks by interactions of single substances in naturally occurring mixtures has greatly increased recently. In this study, the combinatory effects of three mycoestrogens were investigated in detail. This includes the endocrine disruptors zearalenone (ZEN) and α-zearalenol (α-ZEL) produced by Fusarium fungi and alternariol (AOH), a cytotoxic and estrogenic mycotoxin formed by Alternaria species. For evaluation of effects, estrogen-dependent activation of alkaline phosphatase (AlP) and cell proliferation were tested in the adenocarcinoma cell line Ishikawa. The estrogenic potential varied among the single substances. Half maximum effect concentrations (EC50) for AlP activation were evaluated for α-ZEL, ZEN and AOH as 37 pM, 562 pM and 995 nM, respectively. All three mycotoxins were found to act as partial agonists. The majority of binary combinations, even at very low concentrations in the case of α-ZEL, showed strong synergism in the AlP assay. These potentiating phenomena of mycotoxin mixtures highlight the urgent need to incorporate combinatory effects into future risk assessment, especially when endocrine disruptors are involved. To the best of our knowledge, this study presents the first investigation on synergistic effects of mycoestrogens.

  3. Optimization for the Production of Surfactin with a New Synergistic Antifungal Activity

    Science.gov (United States)

    Liu, Mei; Dai, Huanqin; Song, Fuhang; Yu, Zhenyan; Wang, Shujin; Hu, Jiangchun; Kokare, Chandrakant R.; Zhang, Lixin

    2012-01-01

    Background Two of our long term efforts are to discover compounds with synergistic antifungal activity from metabolites of marine derived microbes and to optimize the production of the interesting compounds produced by microorganisms. In this respect, new applications or mechanisms of already known compounds with a high production yield could be continually identified. Surfactin is a well-known lipopeptide biosurfactant with a broad spectrum of antimicrobial and antiviral activity; however, there is less knowledge on surfactin’s antifungal activity. In this study, we investigated the synergistic antifungal activity of C15-surfactin and the optimization of its production by the response surface method. Methodology/Principal Findings Using a synergistic antifungal screening model, we found that the combination of C15-surfactin and ketoconazole (KTC) showed synergistic antifungal effect on Candida albicans SC5314 when the concentrations of C15-surfactin and KTC were 6.25 µg/mL and 0.004 µg/mL, respectively. These concentrations were lower than their own efficient antifungal concentrations, which are >100 µg/mL and 0.016 µg/mL, respectively. The production of C15-surfactin from Bacillus amyloliquefaciens was optimized by the response surface methodology in shaker flask cultivation. The Plackett-Burman design found sucrose, ammonium nitrate and NaH2PO4.2H2O to have significant effects on C15-surfactin production. The optimum values of the tested variables were 21.17 g/L sucrose, 2.50 g/L ammonium nitrate and 11.56 g/L NaH2PO4·2H2O. A production of 134.2 mg/L, which were in agreement with the prediction, was observed in a verification experiment. In comparison to the production of original level (88.6 mg/L), a 1.52-fold increase had been obtained. Conclusion/Significance This work first found that C15-surfactin was an efficient synergistic antifungal agent, and demonstrated that response surface methodology was an effective method to improve the production of C15

  4. Optimization for the production of surfactin with a new synergistic antifungal activity.

    Directory of Open Access Journals (Sweden)

    Xiangyang Liu

    Full Text Available Two of our long term efforts are to discover compounds with synergistic antifungal activity from metabolites of marine derived microbes and to optimize the production of the interesting compounds produced by microorganisms. In this respect, new applications or mechanisms of already known compounds with a high production yield could be continually identified. Surfactin is a well-known lipopeptide biosurfactant with a broad spectrum of antimicrobial and antiviral activity; however, there is less knowledge on surfactin's antifungal activity. In this study, we investigated the synergistic antifungal activity of C(15-surfactin and the optimization of its production by the response surface method.Using a synergistic antifungal screening model, we found that the combination of C(15-surfactin and ketoconazole (KTC showed synergistic antifungal effect on Candida albicans SC5314 when the concentrations of C(15-surfactin and KTC were 6.25 µg/mL and 0.004 µg/mL, respectively. These concentrations were lower than their own efficient antifungal concentrations, which are >100 µg/mL and 0.016 µg/mL, respectively. The production of C(15-surfactin from Bacillus amyloliquefaciens was optimized by the response surface methodology in shaker flask cultivation. The Plackett-Burman design found sucrose, ammonium nitrate and NaH(2PO(4 x 2H(2O to have significant effects on C(15-surfactin production. The optimum values of the tested variables were 21.17 g/L sucrose, 2.50 g/L ammonium nitrate and 11.56 g/L NaH(2PO(4·2H(2O. A production of 134.2 mg/L, which were in agreement with the prediction, was observed in a verification experiment. In comparison to the production of original level (88.6 mg/L, a 1.52-fold increase had been obtained.This work first found that C(15-surfactin was an efficient synergistic antifungal agent, and demonstrated that response surface methodology was an effective method to improve the production of C(15-surfactin.

  5. Synergistic Adsorption and Flotation of New Mixed Cationic/Nonionic Collectors on Muscovite

    Directory of Open Access Journals (Sweden)

    Hao Jiang

    2017-05-01

    Full Text Available The mixed cationic collector cetyltrimethylammonium chloride (CTAC and nonionic collector octanol (OCT was found to exhibit a synergistic effect on the flotation and adsorption of muscovite. To understand the underlying synergistic mechanism, flotation, contact angle, surface tension, and adsorption measurements were carried out. The results obtained from flotation measurements indicated that the mixed CTAC/OCT exhibits a better collecting ability than CTAC or OCT. The recovery of muscovite with CTAC only rapidly decreased from 97.25% at pH 2.64 to 75.26% at pH 5.82, followed by a flat horizontal at a pH is higher than 6. In contrast, a high recovery of greater than 85% muscovite was observed using mixed CTAC/OCT at α CTAC = 0.67 (the mole ratio of CTAC:OCT = 2:1 over the investigated pH range. From the surface activity parameters (CMC, γ CMC, Γmax, Amin estimated from surface measurements and interaction parameters (βm, βσ, in addition to the micellar and interfacial compositions ( x 1 m , x 1 σ obtained from the theory of regular solutions, a synergistic effect is evident in the mixed micelle and at the water/air interface. Moreover, the mixed CTAC/OCT at α CTAC = 0.67 exhibited the maximum synergistic interaction. The results obtained from surface tension measurements indicated that the mixed CTAC/OCT exhibits considerably higher surface activities compared to single CTAC or OCT. The contact angle results confirmed that the mixed CTAC/OCT is a better collector than the individual CTAC or OCT for the flotation of muscovite. According to the results obtained from adsorption experiments, compared with that of individual CTAC or OCT, the amounts of CTAC and OCT adsorbed on the muscovite surface are considerably increase in the mixed systems because of co-adsorption. Based on these results, the mixed CTAC/OCT exhibits a remarkable synergistic effect during the flotation and adsorption of muscovite.

  6. Combined treatment of xenon and hypothermia in newborn rats--additive or synergistic effect?

    Directory of Open Access Journals (Sweden)

    Hemmen Sabir

    Full Text Available Breathing the inert gas Xenon (Xe enhances hypothermic (HT neuroprotection after hypoxia-ischemia (HI in small and large newborn animal models. The underlying mechanism of the enhancement is not yet fully understood, but the combined effect of Xe and HT could either be synergistic (larger than the two effects added or simply additive. A previously published study, using unilateral carotid ligation followed by hypoxia in seven day old (P7 rats, showed that the combination of mild HT (35°C and low Xe concentration (20%, both not being neuroprotective alone, had a synergistic effect and was neuroprotective when both were started with a 4 h delay after a moderate HI insult. To examine whether another laboratory could confirm this finding, we repeated key aspects of the study.After the HI-insult 120 pups were exposed to different post-insult treatments: three temperatures (normothermia (NT NT37°C, HT35°C, HT32°C or Xe concentrations (0%, 20% or 50% starting either immediately or with a 4 h delay. To assess the synergistic potency of Xe-HT, a second set (n = 101 of P7 pups were exposed to either HT35°C+Xe0%, NT+Xe20% or a combination of HT35°C+Xe20% starting with a 4 h delay after the insult. Brain damage was analyzed using relative hemispheric (ligated side/unligated side brain tissue area loss after seven day survival.Immediate HT32°C (p = 0.042, but not HT35°C significantly reduced brain injury compared to NT37°C. As previously shown, adding immediate Xe50% to HT32°C increased protection. Neither 4 h-delayed Xe20%, nor Xe50% at 37°C significantly reduced brain injury (p>0.050. In addition, neither 4 h-delayed HT35°C alone, nor HT35°C+Xe20% reduced brain injury. We found no synergistic effect of the combined treatments in this experimental model.Combining two treatments that individually were ineffective (delayed HT35°C and delayed Xe20% did not exert neuroprotection when combined, and therefore did not show a synergistic

  7. Machine Dictation and Transcription.

    Science.gov (United States)

    Harvey, Evelyn; And Others

    This instructional package contains both an instructor's manual and a student's manual for a course in machine dictation and transcription. The instructor's manual contains an overview with tips on teaching the course, letters for dictation, and a key to the letters. The student's manual contains an overview of the course and of the skills needed…

  8. Automatic Music Transcription

    Science.gov (United States)

    Klapuri, Anssi; Virtanen, Tuomas

    Written musical notation describes music in a symbolic form that is suitable for performing a piece using the available musical instruments. Traditionally, musical notation indicates the pitch, target instrument, timing, and duration of each sound to be played. The aim of music transcription either by humans or by a machine is to infer these musical parameters, given only the acoustic recording of a performance.

  9. Bayesian Music Transcription

    NARCIS (Netherlands)

    Cemgil, A.T.

    2004-01-01

    Music transcription refers to extraction of a human readable and interpretable description from a recording of a music performance. The final goal is to implement a program that can automatically infer a musical notation that lists the pitch levels of notes and corresponding score positions in any

  10. Inhibitive and Synergistic Properties of Ethanolic Extract of ...

    African Journals Online (AJOL)

    It was also noted that only KCl was synergistic to the ethanol extract of Anogeissus leiocarpus, while other halides tested were antagonistic. All the data acquired reveal that the ethanolic extract of Anogeissus leiocarpus act as an inhibitor in the acid environment due to the phytochemicals: saponin, tannins, flavonoid, ...

  11. Synergistic Effect of Trehalose and Saccharose Pretreatment on ...

    African Journals Online (AJOL)

    2). Osmotic fragility is an important factor in the maintenance of RBC integrity and normal functions [23]. Trehalose and saccharose pretreatment synergistically decreased lyophilization-rehydration-induced damage on. RBC osmotic fragility by reducing the osmotic fragility (Fig. 3). PS is only distributed in the internal side of ...

  12. Synergistic therapy of enalapril and Cordyceps sinensis in the ...

    African Journals Online (AJOL)

    Chronic allograft nephropathy (CAN) still remains an important factor that affects the long-term survival of renal recipients. The aim of the study was to investigate synergistic effect of enalapril (an angiotensin converting enzyme inhibitor, ACEI) and Cordyceps sinensis (Bailing capsule, fermented agent of C. sinensis) on ...

  13. Synergistic Effect of Trehalose and Saccharose Pretreatment on ...

    African Journals Online (AJOL)

    Purpose: To investigate the synergistic effect of trehalose and saccharose pretreatment on maintenance of lyophilized human red blood cell (RBC) quality. Methods: RBCs were pre-treated with trehalose and saccharose, and then lyophilized and re-hydrated. Prior to lyophilization and after re hydration, RBC parameters, ...

  14. Synergistic antibacterial effect of stem bark extracts of Faidherbia ...

    African Journals Online (AJOL)

    The study was aimed at screening the stem bark extracts of Faidherbia albida and Psidium guajava for synergistic antibacterial effect against methicillin resistant Staphylococcus aureus (MRSA). The powdered plant materials were extracted with methanol using cold maceration technique and the extracts were screened for ...

  15. Hybrid Nanotechnologies for Detection and Synergistic Therapies for Breast Cancer

    Science.gov (United States)

    2012-10-01

    diagnostic nanosystems for therapeutic and theranostic targeting of breast cancers . 15. SUBJECT TERMS anti-angiogenesis, phage display, tumor homing...Therapies for Breast Cancer PRINCIPAL INVESTIGATOR: Erkki Ruoslahti, M.D., Ph.D...for Detection and Synergistic Therapies for Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-1-0698 5c. PROGRAM ELEMENT NUMBER

  16. Synergistic effects of ethanolic plant extract mixtures against food ...

    African Journals Online (AJOL)

    Synergistic effects were observed when mixtures of ethanolic plant extract against food-borne pathogen bacteria were used, so this may be a better way to design alternative pathogen control methodologies for food-borne pathogen bacteria. Keywords: Larrea tridentate, Flourensia cernua, Opuntia ficus-indica, ethanolic ...

  17. Synergistic effects of squalene and polyunsaturated fatty acid ...

    African Journals Online (AJOL)

    We have studied the synergistic effects of squalene and polyunsaturated fatty acids (PUFA concentrate) on isoprenaline-induced infarction in rats with respect to changes in the levels of plasma diagnostic marker enzymes and myocardial antioxidant defense system. Intraperitoneal injection of isoprenaline caused a ...

  18. Synergistic interaction between two linear inhibitors on a single ...

    African Journals Online (AJOL)

    ). vanadate (Van) and L-phenylalanine (L-phe) were studied using a modification of the common Yonetani-Theorell procedure proposed for studying synergistic inhibition. The modes of inhibition of ALP by Van and L-phe as analysed using the ...

  19. Carbon dioxide and nisin act synergistically on Listeria monocytogenes

    DEFF Research Database (Denmark)

    Nilsson, Lilian; Chen, Y.H.; Chikindas, M.L.

    2000-01-01

    This paper examines the synergistic action of carbon dioxide and nisin on Listeria monocytogenes Scott A wild-type and nisin-resistant (Nis(r)) cells grown in broth at 4 degrees C. Carbon dioxide extended the lag phase and decreased the specific growth rate of both strains, but to a greater degree...

  20. Synergistic extraction of thorium in presence of neutral donors

    International Nuclear Information System (INIS)

    Biswas, S.; Basu, S.

    1999-01-01

    The effects of neutral organophosphorous compounds on the extraction of thorium by β-hydroxy naphthaldoxime in xylene are reported. Enhancement of extraction is explained in terms of formation of a complex adduct in organic phase. Synergistic coefficients and apparent formation constants of complex adducts are calculated. (author)

  1. Synergistic effect of Murraya koenigii and Telfairia occidentalis ...

    African Journals Online (AJOL)

    Larger zones of inhibition were observed for M. Koenigii extract than T. occidentalis extract, and larger zones of inhibition were observed by their synergy than on their separate use. Synergistic antibacterial activity of the extract ranged from 0 mm to 20.0 ± 0.03 mm, zone of inhibition of M. koenigii extract ranged from 0 mm ...

  2. Tungstate as a synergist to phosphonate-based formulation for ...

    Indian Academy of Sciences (India)

    Administrator

    Tungstate as a synergist to phosphonate based formulation for corrosion control of carbon steel. 641. IEp (%) = 100 [1 – (i′corr/icorr)],. (2) where icorr and i′corr are the corrosion current densi- ties in case of the control and inhibitor solutions respectively. Impedance spectra in the form of Nyquist plots were recorded at ...

  3. Synergistic Activity of Methanolic Extract of Adenium obesum ...

    African Journals Online (AJOL)

    Synergistic Activity of Methanolic Extract of Adenium obesum (Apocynaceae) Stem-Bark and Oxytetracycline against Some Clinical Bacterial Isolates. ... Phytochemical examination of the extract revealed the presence of alkaloids, steroids, saponins, glycosides, anthraquinones, tannins and flavonoids. This result indicated ...

  4. The EZH1-SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT.

    Science.gov (United States)

    Su, Shuai-Kun; Li, Chun-Yuan; Lei, Pin-Ji; Wang, Xiang; Zhao, Quan-Yi; Cai, Yang; Wang, Zhen; Li, Lianyun; Wu, Min

    2016-06-15

    Unlike other members of the polycomb group protein family, EZH1 has been shown to positively associate with active transcription on a genome-wide scale. However, the underlying mechanism for this behavior still remains elusive. Here, we report that EZH1 physically interacts with UXT, a small chaperon-like transcription co-activator. UXT specifically interacts with EZH1 and SUZ12, but not EED. Similar to upon knockdown of UXT, knockdown of EZH1 or SUZ12 through RNA interference in the cell impairs the transcriptional activation of nuclear factor (NF)-κB target genes induced by TNFα. EZH1 deficiency also increases TNFα-induced cell death. Interestingly, chromatin immunoprecipitation and the following next-generation sequencing analysis show that H3K27 mono-, di- and tri-methylation on NF-κB target genes are not affected in EZH1- or UXT-deficient cells. EZH1 also does not affect the translocation of the p65 subunit of NF-κB (also known as RELA) from the cytosol to the nucleus. Instead, EZH1 and SUZ12 regulate the recruitment of p65 and RNA Pol II to target genes. Taken together, our study shows that EZH1 and SUZ12 act as positive regulators for NF-κB signaling and demonstrates that EZH1, SUZ12 and UXT work synergistically to regulate pathway activation in the nucleus. © 2016. Published by The Company of Biologists Ltd.

  5. Are a healthy diet and physical activity synergistically associated with cognitive functioning in older adults?

    NARCIS (Netherlands)

    Nijholt, W.; Jager-Wittenaar, H.; Visser, M.; Van der Schans, C. P.; Hobbelen, J. S. M.

    Previous research has demonstrated that being both physically active and adhering a healthy diet is associated with improved cognitive functioning; however, it remains unclear whether these factors act synergistically. We investigated the synergistic association of a healthy diet and being

  6. Spermine attenuates the action of the DNA intercalator, actinomycin D, on DNA binding and the inhibition of transcription and DNA replication.

    Science.gov (United States)

    Wang, Sheng-Yu; Lee, Alan Yueh-Luen; Lee, Yueh-Luen; Lai, Yi-Hua; Chen, Jeremy J W; Wu, Wen-Lin; Yuann, Jeu-Ming P; Su, Wang-Lin; Chuang, Show-Mei; Hou, Ming-Hon

    2012-01-01

    The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication and transcription. Polyamines (spermine in particular) are almost exclusively bound to nucleic acids and are involved in many cellular processes that require nucleic acids. Until now, the effects of polyamines on DNA intercalator activities have remained unclear because intercalation is the most important mechanism employed by DNA-binding drugs. Herein, using actinomycin D (ACTD) as a model, we have attempted to elucidate the effects of spermine on the action of ACTD, including its DNA-binding ability, RNA and DNA polymerase interference, and its role in the transcription and replication inhibition of ACTD within cells. We found that spermine interfered with the binding and stabilization of ACTD to DNA. The presence of increasing concentrations of spermine enhanced the transcriptional and replication activities of RNA and DNA polymerases, respectively, in vitro treated with ActD. Moreover, a decrease in intracellular polyamine concentrations stimulated by methylglyoxal-bis(guanylhydrazone) (MGBG) enhanced the ACTD-induced inhibition of c-myc transcription and DNA replication in several cancer cell lines. The results indicated that spermine attenuates ACTD binding to DNA and its inhibition of transcription and DNA replication both in vitro and within cells. Finally, a synergistic antiproliferative effect of MGBG and ACTD was observed in a cell viability assay. Our findings will be of significant relevance to future developments in combination with cancer therapy by enhancing the anticancer activity of DNA interactors through polyamine depletion.

  7. Spermine attenuates the action of the DNA intercalator, actinomycin D, on DNA binding and the inhibition of transcription and DNA replication.

    Directory of Open Access Journals (Sweden)

    Sheng-Yu Wang

    Full Text Available The anticancer activity of DNA intercalators is related to their ability to intercalate into the DNA duplex with high affinity, thereby interfering with DNA replication and transcription. Polyamines (spermine in particular are almost exclusively bound to nucleic acids and are involved in many cellular processes that require nucleic acids. Until now, the effects of polyamines on DNA intercalator activities have remained unclear because intercalation is the most important mechanism employed by DNA-binding drugs. Herein, using actinomycin D (ACTD as a model, we have attempted to elucidate the effects of spermine on the action of ACTD, including its DNA-binding ability, RNA and DNA polymerase interference, and its role in the transcription and replication inhibition of ACTD within cells. We found that spermine interfered with the binding and stabilization of ACTD to DNA. The presence of increasing concentrations of spermine enhanced the transcriptional and replication activities of RNA and DNA polymerases, respectively, in vitro treated with ActD. Moreover, a decrease in intracellular polyamine concentrations stimulated by methylglyoxal-bis(guanylhydrazone (MGBG enhanced the ACTD-induced inhibition of c-myc transcription and DNA replication in several cancer cell lines. The results indicated that spermine attenuates ACTD binding to DNA and its inhibition of transcription and DNA replication both in vitro and within cells. Finally, a synergistic antiproliferative effect of MGBG and ACTD was observed in a cell viability assay. Our findings will be of significant relevance to future developments in combination with cancer therapy by enhancing the anticancer activity of DNA interactors through polyamine depletion.

  8. Synergistic effects of fire and elephants on arboreal animals in an African savanna.

    Science.gov (United States)

    Pringle, Robert M; Kimuyu, Duncan M; Sensenig, Ryan L; Palmer, Todd M; Riginos, Corinna; Veblen, Kari E; Young, Truman P

    2015-11-01

    Disturbance is a crucial determinant of animal abundance, distribution and community structure in many ecosystems, but the ways in which multiple disturbance types interact remain poorly understood. The effects of multiple-disturbance interactions can be additive, subadditive or super-additive (synergistic). Synergistic effects in particular can accelerate ecological change; thus, characterizing such synergies, the conditions under which they arise, and how long they persist has been identified as a major goal of ecology. We factorially manipulated two principal sources of disturbance in African savannas, fire and elephants, and measured their independent and interactive effects on the numerically dominant vertebrate (the arboreal gekkonid lizard Lygodactylus keniensis) and invertebrate (a guild of symbiotic Acacia ants) animal species in a semi-arid Kenyan savanna. Elephant exclusion alone (minus fire) had negligible effects on gecko density. Fire alone (minus elephants) had negligible effects on gecko density after 4 months, but increased gecko density twofold after 16 months, likely because the decay of fire-damaged woody biomass created refuges and nest sites for geckos. In the presence of elephants, fire increased gecko density nearly threefold within 4 months of the experimental burn; this occurred because fire increased the incidence of elephant damage to trees, which in turn improved microhabitat quality for geckos. However, this synergistic positive effect of fire and elephants attenuated over the ensuing year, such that only the main effect of fire was evident after 16 months. Fire also altered the structure of symbiotic plant-ant assemblages occupying the dominant tree species (Acacia drepanolobium); this influenced gecko habitat selection but did not explain the synergistic effect of fire and elephants. However, fire-driven shifts in plant-ant occupancy may have indirectly mediated this effect by increasing trees' susceptibility to elephant damage. Our

  9. Development of multifunctional metabolic synergists to suppress the evolution of resistance against pyrethroids in insects that blood feed on humans.

    Science.gov (United States)

    Hardstone, Melissa C; Strycharz, Joseph P; Kim, Junheon; Park, Il-Kwon; Yoon, Kyong Sup; Ahn, Young Joon; Harrington, Laura C; Lee, Si Hyeock; Clark, J Marshall

    2015-06-01

    Pyrethroids are the insecticides of choice when exposure to humans is likely, such as occurs in vector and public-health-related control programs. Unfortunately, the pyrethroids share a common resistance mechanism with dichlorodiphenyltrichloroethane (DDT), knockdown resistance (kdr), and prior extensive use of DDT has predisposed the pyrethroids to cross-resistance via kdr. Given the widespread occurrence of kdr, the use of synergists with pyrethroids is considered to be prudent to guard against the selection of multiply resistant insects. 3-Phenoxybenzyl hexanoate (PBH) was synthesized as a multifunctional pyrethroid synergist that, besides being a surrogate substrate for sequestration/hydrolytic carboxylesterases, now also functions as a substrate for oxidative xenobiotic metabolism. The addition of PBH to permethrin-treated females of the ISOP450 strain of Culex pipiens quinquefasciatus resulted in a threefold increase in synergism, as judged by the synergistic ratio. Similarly, PBH synergized the action of deltamethrin sixfold on females of the common bed bug, Cimex lectularius, and was 2.8-fold more synergistic than piperonyl butoxide (PBO). PBH synergized the action of both type I and type II pyrethroids in a mosquito vector (Cx. p. quinquefasciatus) and in a public-health pest, C. lectularius, respectively, indicating a broad spectrum of action on blood-feeding insects. PBH appears to have residual properties similar to permethrin and is itself non-toxic, unlike PBO, and therefore should be compatible with existing pyrethroid formulations used for insecticide-treated nets and home/residential sprays. © 2014 Society of Chemical Industry.

  10. Auxin signal transcription factor regulates expression of the brassinosteroid receptor gene in rice.

    Science.gov (United States)

    Sakamoto, Tomoaki; Morinaka, Yoichi; Inukai, Yoshiaki; Kitano, Hidemi; Fujioka, Shozo

    2013-02-01

    The phytohormones auxins and brassinosteroids are both essential regulators of physiological and developmental processes, and it has been suggested that they act inter-dependently and synergistically. In rice (Oryza sativa), auxin co-application improves the brassinosteroid response in the rice lamina inclination bioassay. Here, we showed that auxins stimulate brassinosteroid perception by regulating the level of brassinosteroid receptor. Auxin treatment increased expression of the rice brassinosteroid receptor gene OsBRI1. The promoter of OsBRI1 contains an auxin-response element (AuxRE) that is targeted by auxin-response factor (ARF) transcription factors. An AuxRE mutation abolished the induction of OsBRI1 expression by auxins, and OsBRI1 expression was down-regulated in an arf mutant. The AuxRE motif in the OsBRI1 promoter, and thus the transient up-regulation of OsBRI1 expression caused by treatment with indole-3-acetic acid, is essential for the indole-3-acetic acid-induced increase in sensitivity to brassinosteroids. These findings demonstrate that some ARFs control the degree of brassinosteroid perception required for normal growth and development in rice. Although multi-level interactions between auxins and brassinosteroids have previously been reported, our findings suggest a mechanism by which auxins control cellular sensitivity to brassinosteroids, and further support the notion that interactions between auxins and brassinosteroids are extensive and complex. © 2012 The Authors The Plant Journal © 2012 Blackwell Publishing Ltd.

  11. Transcription arrest caused by long nascent RNA chains

    DEFF Research Database (Denmark)

    Bentin, Thomas; Cherny, Dmitry; Larsen, H Jakob

    2004-01-01

    The transcription process is highly processive. However, specific sequence elements encoded in the nascent RNA may signal transcription pausing and/or termination. We find that under certain conditions nascent RNA chains can have a strong and apparently sequence-independent inhibitory effect...... on transcription. Using phage T3 RNA polymerase (T3 RNAP) and covalently closed circular (cccDNA) DNA templates that did not contain any strong termination signal, transcription was severely inhibited after a short period of time. Less than approximately 10% residual transcriptional activity remained after 10 min...... of incubation. The addition of RNase A almost fully restored transcription in a dose dependent manner. Throughout RNase A rescue, an elongation rate of approximately 170 nt/s was maintained and this velocity was independent of RNA transcript length, at least up to 6 kb. Instead, RNase A rescue increased...

  12. Synergistic activity of mecillinam in combination with the beta-lactamase inhibitors clavulanic acid and sulbactam.

    OpenAIRE

    Neu, H C

    1982-01-01

    The beta-lactamase inhibitors clavulanic acid and sulbactam were combined with mecillinam. beta-Lactamase-containing Escherichia coli resistant to mecillinam was synergistically inhibited by both clavulanic acid and sulbactam. beta-Lactamase-containing Enterobacter was synergistically inhibited, but strains lacking beta-lactamases were not synergistically inhibited. Synergistic inhibition was noted for beta-lactamase-containing, mecillinam-resistant Klebsiella, Citrobacter, Serratia, and Salm...

  13. Proofreading of misincorporated nucleotides in DNA transcription

    International Nuclear Information System (INIS)

    Voliotis, Margaritis; Liverpool, Tanniemola B; Cohen, Netta; Molina-París, Carmen

    2012-01-01

    The accuracy of DNA transcription is crucial for the proper functioning of the cell. Although RNA polymerases demonstrate selectivity for correct nucleotides, additional active mechanisms of transcriptional error correction are required to achieve observed levels of fidelity. Recent experimental findings have shed light on a particular mechanism of transcriptional error correction involving: (i) diffusive translocation of the RNA polymerase along the DNA (backtracking) and (ii) irreversible RNA cleavage. This mechanism achieves preferential cleavage of misincorporated nucleotides by biasing the local rates of translocation. Here, we study how misincorporated nucleotides affect backtracking dynamics and how this effect determines the level of transcriptional fidelity. We consider backtracking as a diffusive process in a periodic, one-dimensional energy landscape, which at a coarse-grained level gives rise to a hopping process between neighbouring local minima. We propose a model for how misincorporated nucleotides deform this energy landscape and hence affect the hopping rates. In particular, we show that this model can be used to derive both the theoretical limit on the fidelity (i.e. the minimum fraction of misincorporated nucleotides) and the actual fidelity relative to this optimum, achieved for specific combinations of the cleavage and polymerization rates. Finally, we study how external factors influencing backtracking dynamics affect transcriptional fidelity. We show that biologically relevant loads, similar to those exerted by nucleosomes or other transcriptional barriers, increase error correction. (paper)

  14. The effects of cocaine on HIV transcription.

    Science.gov (United States)

    Tyagi, Mudit; Weber, Jaime; Bukrinsky, Michael; Simon, Gary L

    2016-06-01

    Illicit drug users are a high-risk population for infection with the human immunodeficiency virus (HIV). A strong correlation exists between prohibited drug use and an increased rate of HIV transmission. Cocaine stands out as one of the most frequently abused illicit drugs, and its use is correlated with HIV infection and disease progression. The central nervous system (CNS) is a common target for both drugs of abuse and HIV, and cocaine intake further accelerates neuronal injury in HIV patients. Although the high incidence of HIV infection in illicit drug abusers is primarily due to high-risk activities such as needle sharing and unprotected sex, several studies have demonstrated that cocaine enhances the rate of HIV gene expression and replication by activating various signal transduction pathways and downstream transcription factors. In order to generate mature HIV genomic transcript, HIV gene expression has to pass through both the initiation and elongation phases of transcription, which requires discrete transcription factors. In this review, we will provide a detailed analysis of the molecular mechanisms that regulate HIV transcription and discuss how cocaine modulates those mechanisms to upregulate HIV transcription and eventually HIV replication.

  15. Antibacterial and synergistic effects of Nardostachytis rhizoma ...

    African Journals Online (AJOL)

    Methicillin-resistant Staphylococcus aureus (MRSA) is a serious clinical problem worldwide. Few new drugs are available against MRSA, because it has the ability to acquire resistance to most antibiotics which consequently increases the cost of medication. In the present study, the antibacterial activity of Nardostachytis ...

  16. Digital Inverter Amine Sensing via Synergistic Responses by n and p Organic Semiconductors

    Science.gov (United States)

    Tremblay, Noah J.; Jung, Byung Jun; Breysse, Patrick; Katz, Howard E.

    2013-01-01

    Chemiresistors and sensitive OFETs have been substantially developed as cheap, scalable, and versatile sensing platforms. While new materials are expanding OFET sensing capabilities, the device architectures have changed little. Here we report higher order logic circuits utilizing OFETs sensitive to amine vapors. The circuits depend on the synergistic responses of paired p- and n-channel organic semiconductors, including an unprecedented analyte-induced current increase by the n-channel semiconductor. This represents the first step towards ‘intelligent sensors’ that utilize analog signal changes in sensitive OFETs to produce direct digital readouts suitable for further logic operations. PMID:23754969

  17. Graphene and Carbon Nanotubes Synergistically Improved the Thermal Conductivity of Phenolic Resin

    OpenAIRE

    Wang Han

    2017-01-01

    People discover the synergistic effect of graphene and carbon nanotubes on heat conduction in graphene carbon nanotubes / epoxy resin hybrid composites. In this article we added them into the phenolic resin and test the thermal conductivity. We found the thermal conductivity was increased by 6.5% in the phenolic resin by adding 0.45wt% graphene and 0.15wt% single wall carbon nanotubes (maintain the mass ratio 3:1). So if graphene and carbon nanotubes are added in proportion, thermal conductiv...

  18. Writing throughout the biochemistry curriculum: Synergistic inquiry-based writing projects for biochemistry students.

    Science.gov (United States)

    Mertz, Pamela; Streu, Craig

    2015-01-01

    This article describes a synergistic two-semester writing sequence for biochemistry courses. In the first semester, students select a putative protein and are tasked with researching their protein largely through bioinformatics resources. In the second semester, students develop original ideas and present them in the form of a research grant proposal. Both projects involve multiple drafts and peer review. The complementarity of the projects increases student exposure to bioinformatics and literature resources, fosters higher-order thinking skills, and develops teamwork and communication skills. Student feedback and responses on perception surveys demonstrated that the students viewed both projects as favorable learning experiences. © 2015 The International Union of Biochemistry and Molecular Biology.

  19. Deciphering synergistic characteristics of microbial fuel cell-assisted dye decolorization.

    Science.gov (United States)

    Han, Ke; Yueh, Pei-Lin; Qin, Lian-Jie; Hsueh, Chuan-Chung; Chen, Bor-Yann

    2015-11-01

    This study provided a novel evaluation scheme to quantitatively reveal "synergistic" stimulation of microbial fuel cell (MFC)-assisted dye decolorization for industrial practicability. This work also disclosed why dye decolorization was more electrochemically favorable during simultaneous bioelectricity generation and dye decolorization (SBG&DD). Quantitative assessment upon stimulating effects of different decolorized metabolites on BG and DD alone was also implemented for conclusive remarks. Apparently, using MFC as the method of dye decontamination could considerably increase ca. 40-70% of electron transfer capabilities for SBG&DD, thereby significantly improving the performance of dye decontamination. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Digital Inverter Amine Sensing via Synergistic Responses by n and p Organic Semiconductors.

    Science.gov (United States)

    Tremblay, Noah J; Jung, Byung Jun; Breysse, Patrick; Katz, Howard E

    2011-11-22

    Chemiresistors and sensitive OFETs have been substantially developed as cheap, scalable, and versatile sensing platforms. While new materials are expanding OFET sensing capabilities, the device architectures have changed little. Here we report higher order logic circuits utilizing OFETs sensitive to amine vapors. The circuits depend on the synergistic responses of paired p- and n-channel organic semiconductors, including an unprecedented analyte-induced current increase by the n-channel semiconductor. This represents the first step towards 'intelligent sensors' that utilize analog signal changes in sensitive OFETs to produce direct digital readouts suitable for further logic operations.

  1. Synergistic Effects of Nucleating Agents and Plasticizers on the Crystallization Behavior of Poly(lactic acid

    Directory of Open Access Journals (Sweden)

    Xuetao Shi

    2015-01-01

    Full Text Available The synergistic effect of nucleating agents and plasticizers on the thermal and mechanical performance of PLA nanocomposites was investigated with the objective of increasing the crystallinity and balancing the stiffness and toughness of PLA mechanical properties. Calcium carbonate, halloysite nanotubes, talc and LAK (sulfates were compared with each other as heterogeneous nucleating agents. Both the DSC isothermal and non-isothermal studies indicated that talc and LAK were the more effective nucleating agents among the selected fillers. Poly(D-lactic acid (PDLA acted also as a nucleating agent due to the formation of the PLA stereocomplex. The half crystallization time was reduced by the addition of talc to about 2 min from 37.5 min of pure PLA by the isothermal crystallization study. The dynamic mechanical thermal study (DMTA indicated that nanofillers acted as both reinforcement fillers and nucleating agents in relation to the higher storage modulus. The plasticized PLA studied by DMTA indicated a decreasing glass transition temperature with the increasing of the PEG content. The addition of nanofiller increased the Young’s modulus. PEG had the plasticization effect of increasing the break deformation, while sharply decreasing the stiffness and strength of PLA. The synergistic effect of nanofillers and plasticizer achieved the balance between stiffness and toughness with well-controlled crystallization.

  2. DNA Topoisomerases in Transcription

    DEFF Research Database (Denmark)

    Rødgaard, Morten Terpager

    2015-01-01

    This Ph.D. thesis summarizes the main results of my studies on the interplay between DNA topoisomerases and transcription. The work was performed from 2011 to 2015 at Aarhus University in the Laboratory of Genome Research, and was supervised by associate professor Anni H. Andersen. Most of the ex......This Ph.D. thesis summarizes the main results of my studies on the interplay between DNA topoisomerases and transcription. The work was performed from 2011 to 2015 at Aarhus University in the Laboratory of Genome Research, and was supervised by associate professor Anni H. Andersen. Most...... topoisomerase-DNA cleavage complex. The second study is an investigation of how topoisomerases influence gene regulation by keeping the genome in an optimal topological state....

  3. Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine

    DEFF Research Database (Denmark)

    Liu, Minmin; Ohtani, Hitoshi; Zhou, Wanding

    2016-01-01

    Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological...... at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin......) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes...

  4. saeRS and sarA act synergistically to repress protease production and promote biofilm formation in Staphylococcus aureus.

    Directory of Open Access Journals (Sweden)

    Lara N Mrak

    Full Text Available Mutation of the staphylococcal accessory regulator (sarA limits biofilm formation in diverse strains of Staphylococcus aureus, but there are exceptions. One of these is the commonly studied strain Newman. This strain has two defects of potential relevance, the first being mutations that preclude anchoring of the fibronectin-binding proteins FnbA and FnbB to the cell wall, and the second being a point mutation in saeS that results in constitutive activation of the saePQRS regulatory system. We repaired these defects to determine whether either plays a role in biofilm formation and, if so, whether this could account for the reduced impact of sarA in Newman. Restoration of surface-anchored FnbA enhanced biofilm formation, but mutation of sarA in this fnbA-positive strain increased rather than decreased biofilm formation. Mutation of sarA in an saeS-repaired derivative of Newman (P18L or a Newman saeRS mutant (ΔsaeRS resulted in a biofilm-deficient phenotype like that observed in clinical isolates, even in the absence of surface-anchored FnbA. These phenotypes were correlated with increased production of extracellular proteases and decreased accumulation of FnbA and/or Spa in the P18L and ΔsaeRS sarA mutants by comparison to the Newman sarA mutant. The reduced accumulation of Spa was reversed by mutation of the gene encoding aureolysin, while the reduced accumulation of FnbA was reversed by mutation of the sspABC operon. These results demonstrate that saeRS and sarA act synergistically to repress the production of extracellular proteases that would otherwise limit accumulation of critical proteins that contribute to biofilm formation, with constitutive activation of saeRS limiting protease production, even in a sarA mutant, to a degree that can be correlated with increased enhanced capacity to form a biofilm. Although it remains unclear whether these effects are mediated directly or indirectly, studies done with an sspA::lux reporter suggest they

  5. Eukaryotic transcription factors

    DEFF Research Database (Denmark)

    Staby, Lasse; O'Shea, Charlotte; Willemoës, Martin

    2017-01-01

    Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions are determined by their molecular structures, as exemplified by their structured DNA-binding domains...... them to participate in large interactomes, how they use only a few hydrophobic residues, short sequence motifs, prestructured motifs, and coupled folding and binding for their interactions with co-activators, and how their accessibility to post-translational modification affects their interactions...

  6. Spanish dialects: phonetic transcription

    OpenAIRE

    Moreno Bilbao, M. Asunción; Mariño Acebal, José Bernardo

    1998-01-01

    It is well known that canonical Spanish, the dialectal variant `central' of Spain, so called Castilian, can be transcribed by rules. This paper deals with the automatic grapheme to phoneme transcription rules in several Spanish dialects from Latin America. Spanish is a language spoken by more than 300 million people, has an important geographical dispersion compared among other languages and has been historically influenced by many native languages. In this paper authors expand the Castilian ...

  7. Synergistic activity of antifungal drugs and lipopeptide AC7 against Candida albicans biofilm on silicone

    Directory of Open Access Journals (Sweden)

    Chiara Ceresa

    2017-04-01

    Full Text Available The occurrence of Candida albicans device-associated infections is tightly correlated to the ability of this fungus to form biofilms. The presence of this three-dimensional structure protects cells from host defenses, and significantly increases their resistance to antifungal agents. Lipopeptide biosurfactants are microbial products with interesting antibacterial, antifungal and anti-adhesive properties. Aim of the present study was to investigate a possible synergistic effect of lipopeptide AC7BS in combination with amphotericin B or fluconazole against C. albicans planktonic cells, biofilm formation and 24 h-old biofilms on medical-grade silicone elastomer disks, in simulated physiological conditions. In co-incubation experiments, AC7BS alone was not effective. However, the combination of AC7BS with the antifungal compounds resulted in a synergistic increase in the efficacy of the drugs against planktonic cells and biofilm, leading to a reduction of MICs and SMICs50. In pre-coating conditions, amphotericin B alone and AC7BS alone significantly inhibited C. albicans biofilms. When the two molecules were tested in association, a synergistic effect was observed on different phases of biofilm formation and a lower SMIC50 was detected. The observed synergism could be related to the combination of the AC7BS anti-adhesive activity and the AMB antifungal effect, but also to the ability of the biosurfactant to affect membranes, thus facilitating AMB entry in the cells. These results suggest that AC7BS can be considered a potential inhibitor of C. albicans biofilm on medical insertional materials and its use as coating agent may potentiate the effect of antifungal compounds such as AMB, when applied in combination.

  8. Synergistic interactions of bradykinin, thrombin, interleukin 1 and tumor necrosis factor on prostanoid biosynthesis in human periodontal-ligament cells.

    Science.gov (United States)

    Ransjö, M; Marklund, M; Persson, M; Lerner, U H

    1998-04-01

    Prostaglandins are involved in force-induced orthodontic tooth movement. Bradykinin (BK) and thrombin are known to cause a significant time- and concentration-dependent burst of prostanoid biosynthesis in cultured human periodontal-ligament (PDL) cells. The aim now was to investigate interactive effects between interleukin 1 alpha, -beta (IL-1 alpha, -1 beta), tumour necrosis factor-alpha,-beta (TNF-alpha, -beta) and BK or thrombin on prostaglandin biosynthesis in human PDL cells. IL-1 alpha and -1 beta produced time- and concentration-dependent stimulation of prostanoid biosynthesis [prostaglandin (PG)E2 and 6-keto-PGF1alpha]. Synergistic stimulation of prostanoid biosynthesis was demonstrated when BK or thrombin were added together with IL-1 alpha or -1 beta. BK and IL-1 beta both significantly stimulated the release of [3H]arachidonic acid. No synergistic effect on [3H]arachidonic acid release was seen when BK and IL-1 beta were added simultaneously. These data suggest that the synergistic effect of BK and IL-1 beta on prostanoid biosynthesis is not due to interactions at the receptor level nor to enhanced release of arachidonic acid, but may be due to increased activity of cyclo-oxygenase. Also, TNF-alpha and -beta produced a concentration-dependent stimulation of PGE2 formation in cultured human PDL cells. Synergistic effects of BK and thrombin were demonstrated when PGE2 production was stimulated in combination with TNF-beta. In addition, a synergistic effect on the PGE2 response to IL-1 alpha or -1 beta was demonstrated when added in combination with TNF-alpha. These experiments demonstrate synergistic interactions between BK, thrombin, IL-1 and TNF on prostaglandin biosynthesis in cultured human PDL cells. The findings suggest that inflammatory mediators may act in concert in stimulating prostanoid production in response to pro-inflammatory stimuli. As an inflammatory reaction is seen in the periodontal ligament when teeth are orthodontically treated, this

  9. Proteasome inhibitor carfilzomib interacts synergistically with histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells.

    Science.gov (United States)

    Gao, Minjie; Gao, Lu; Tao, Yi; Hou, Jun; Yang, Guang; Wu, Xiaosong; Xu, Hongwei; Tompkins, Van S; Han, Ying; Wu, Huiqun; Zhan, Fenghuang; Shi, Jumei

    2014-06-01

    In the present study, we investigated the interactions between proteasome inhibitor carfilzomib (CFZ) and histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells. Coexposure of cells to minimally lethal concentrations of CFZ with very low concentration of vorinostat resulted in synergistic antiproliferative effects and enhanced apoptosis in Jurkat T-leukemia cells, accompanied with the sharply increased reactive oxygen species (ROS), the striking decrease in the mitochondrial membrane potential (MMP), the increased release of cytochrome c, the enhanced activation of caspase-9 and -3, and the cleavage of PARP. The combined treatment of Jurkat cells pre-treated with ROS scavengers N-acetylcysteine (NAC) significantly blocked the loss of mitochondrial membrane potential, suggesting that ROS generation was a former event of the loss of mitochondrial membrane potential. Furthermore, NAC also resulted in a marked reduction in apoptotic cells, indicating a critical role for increased ROS generation by combined treatment. In addition, combined treatment arrested the cell cycle in G2-M phase. These results imply that CFZ interacted synergistically with vorinostat in Jurkat T-leukemia cells, which raised the possibility that the combination of carfilzomib with vorinostat may represent a novel strategy in treating T-cell Leukemia. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

  10. Synergistic antibiotic combinations for colistin-resistant Klebsiella pneumoniae.

    Science.gov (United States)

    Kádár, Béla; Kocsis, Béla; Tóth, Ákos; Damjanova, Ivelina; Szász, Máté; Kristóf, Katalin; Nagy, Károly; Szabó, Dóra

    2013-06-01

    In this study antibiotic combinations for multidrug-resistant Klebsiella pneumoniae strains were investigated. The study included a colistin-susceptible and a colistin-resistant KPC-2 producing K. pneumoniae ST258 strains isolated in 2008 and 2009 during an outbreak in Hungary. Antibiotic combinations were analyzed by checkerboard technique and fractional inhibitory concentration indices were calculated. The following antibiotics were tested: ceftazidime, cefotaxime, ceftriaxone, ampicillin, imipenem, ertapenem, amikacin, tobramycin, ciprofloxacin, levofloxacin, moxifloxacin, rifampicin, polymyxin B and colistin. Combinations including 0.25 μg/ml colistin plus 1 μg/ml rifampicin, 0.25 μg/ml polymyxin B plus 1 μg/ml rifampicin, 1 μg/ml imipenem plus 2 μg/ml tobramycin, were found synergistic.These in vitro synergistic combinations suggest potential therapeutical options against infections caused by KPC-2 producing, multidrug-resistant K. pneumoniae ST258.

  11. Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis.

    Science.gov (United States)

    Wu, Xian; Song, Mingyue; Qiu, Peiju; Rakariyatham, Kanyasiri; Li, Fang; Gao, Zili; Cai, Xiaokun; Wang, Minqi; Xu, Fei; Zheng, Jinkai; Xiao, Hang

    2017-04-01

    Different cancer chemopreventive agents may act synergistically and their combination may produce enhanced protective effects against carcinogenesis than each individual agent alone. Herein, we investigated the chemopreventive effects of nobiletin (NBT, a citrus polymethoxyflavone) and atorvastatin (ATST, a lipid-lowering drug) in colon cancer cells/macrophages and an azoxymethane (AOM)-induced colon carcinogenesis rat model. The results demonstrated that co-treatments of NBT/ATST produced enhanced growth inhibitory and anti-inflammatory effects on the colon cancer cells and macrophages, respectively. Isobologram analysis confirmed that these interactions between NBT and ATST were synergistic. NBT/ATST co-treatment also synergistically induced extensive cell cycle arrest and apoptosis in colon cancer cells. Oral administration of NBT (0.1%, w/w in diet) or ATST (0.04%, w/w in diet) significantly decreased colonic tumor incidence and multiplicity in AOM-treated rats. Most importantly, co-treatment of NBT/ATST at their half doses (0.05% NBT + 0.02% ATST, w/w in diet) resulted in even stronger inhibitory effects on colonic tumor incidence and multiplicity than did NBT or ATST alone at higher doses. Statistical analysis confirmed that the enhanced chemopreventive activities against colon carcinogenesis in rats by the NBT/ATST combination were highly synergistic. Our results further demonstrated that NBT/ATST co-treatment profoundly modulated key cellular signaling regulators associated with inflammation, cell proliferation, cell cycle progression, apoptosis, angiogenesis and metastasis in the colon of AOM-treated rats. In conclusion, for the first time, our results demonstrated a strong synergy in inhibiting colon carcinogenesis produced by the co-treatment of NBT and ATST, which provided a scientific basis for using NBT in combination with ATST for colon cancer chemoprevention in humans. © The Author 2017. Published by Oxford University Press. All rights reserved

  12. Gene transcription and electromagnetic fields

    Energy Technology Data Exchange (ETDEWEB)

    Henderson, A.S.

    1992-01-01

    Our overall aim is to obtain sufficient information to allow us to ultimately determine whether ELF EM field exposure is an initiating factor in neoplastic transformation and/or if exposure can mimic characteristics of the second-step counterpart in neoplastic disease. This aim is based on our previous findings that levels of some transcripts are increased in cells exposed to EM fields. While the research is basic in nature, the ramifications have bearing on the general safety of exposure to EM fields in industrial and everyday life. A large array of diverse biological effects are reported to occur as the result of exposure to elf EM fields, suggesting that the cell response to EM fields is at a basic level, presumably initiated by molecular and/or biophysical events at the cell membrane. The hypothesized route is a signal transduction pathway involving membrane calcium fluxes. Information flow resulting from signal transduction can mediate the induction of regulatory factors in the cell, and directly affect how transcription is regulated.

  13. Synergistic effect of baicalein, wogonin and oroxylin A mixture: multistep inhibition of the NF-κB signalling pathway contributes to an anti-inflammatory effect of Scutellaria root flavonoids.

    Science.gov (United States)

    Shimizu, Tomofumi; Shibuya, Nobuhiko; Narukawa, Yuji; Oshima, Naohiro; Hada, Noriyasu; Kiuchi, Fumiyuki

    2018-01-01

    Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE 2 production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein (1), wogonin (2) and oroxylin A (3) on the production of PGE 2 in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1-3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-κB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-κB translocation, it strongly inhibited NF-κB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1-3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE 2 and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-κB signalling pathway.

  14. Fatigue Resistant Bioinspired Composite from Synergistic Two-Dimensional Nanocomponents.

    Science.gov (United States)

    Wan, Sijie; Zhang, Qi; Zhou, Xiaohang; Li, Dechang; Ji, Baohua; Jiang, Lei; Cheng, Qunfeng

    2017-07-25

    Portable and wearable electronics require much more flexible graphene-based electrode with high fatigue life, which could repeatedly bend, fold, or stretch without sacrificing its mechanical properties and electrical conductivity. Herein, a kind of ultrahigh fatigue resistant graphene-based nanocomposite via tungsten disulfide (WS 2 ) nanosheets is synthesized by introducing a synergistic effect with covalently cross-linking inspired by the orderly layered structure and abundant interfacial interactions of nacre. The fatigue life of resultant graphene-based nanocomposites is more than one million times at the stress level of 270 MPa, and the electrical conductivity can be kept as high as 197.1 S/cm after 1.0 × 10 5 tensile testing cycles. These outstanding properties are attributed to the synergistic effect from lubrication of WS 2 nanosheets for deflecting crack propagation, and covalent bonding between adjacent GO nanosheets for bridging crack, which is verified by the molecular dynamics (MD) simulations. The WS 2 induced synergistic effect with covalent bonding offers a guidance for constructing graphene-based nanocomposites with high fatigue life, which have great potential for applications in flexible and wearable electronic devices, etc.

  15. Novel, Synergistic Antifungal Combinations that Target Translation Fidelity

    Science.gov (United States)

    Moreno-Martinez, Elena; Vallieres, Cindy; Holland, Sara L.; Avery, Simon V.

    2015-01-01

    There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone. PMID:26573415

  16. Synergistic combination dry powders for inhaled antimicrobial therapy

    Science.gov (United States)

    Heng, Desmond; Lee, Sie Huey; Teo, Jeanette; Ng, Wai Kiong; Chan, Hak-Kim; Tan, Reginald B. H.

    2013-06-01

    Combination products play an important role in medicine as they offer improved clinical effectiveness, enhanced patient adherence, and reduced administrative costs. In combination antimicrobial therapy, the desired outcome is to extend the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may sometimes emerge from such combinations, leading to treatment failure. Therefore, it is crucial to screen the drug candidates for compatibility and possible antagonistic interactions. This work aims to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary and ternary combinations were prepared via spray drying on a BUCHI® Nano Spray Dryer B-90. All powders were within the respirable size range, and were consisted of spherical particles that were slightly corrugated. The powers yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® DPI at 60 L/min. Time-kill studies carried out against common respiratory tract pathogenic bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia and Acinetobacter baumannii at 1x the minimum inhibitory concentration (MIC) over 24 hours revealed no antagonistic behavior for both combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the binary combination when it was tested against Pseudomonas aeruginosa bacteria.

  17. Synergistic Antimicrobial Effect of Tribulus terrestris and Bitter Almond Extracts

    Directory of Open Access Journals (Sweden)

    Hamid Abtahi

    2014-12-01

    Full Text Available Background: The antimicrobial effects of the extracts of different kinds of plants have been demonstrated in several studies. However, no study has been conducted so far on the synergistic effects of two herbal extracts on their germicidal effects. In this study, in addition to antibacterial effects of the aqueous, methanol or ethanol extracts of Tribulus terrestris and bitter almond on some bacteria, the synergistic effects of the extracts of these two plants were also evaluated. Materials and Methods: In this experimental study, water, methanol and ethanol extracts of seeds were screened against some bacterial strains. Seeds were extracted by percolation method. Aliquots of the extracts at variable concentrations were then incubated with different bacterial strains, and the antimicrobial activities of the extracts from seeds were determined by MIC. Three antibiotics were used as reference compounds for antibacterial activities. Seeds extract inhibited significantly the growth of the tested bacterial strains. Results: The greatest synergistic effect of T. terrestris and bitter almond extracts is detected in methanol and aqueous extracts. Among the bacterial strains tested, Staphylococcus aureus was most susceptibility. Conclusion: The results showed the highest antibacterial effect in the combination of methanol extract of T. terrestris and the aqueous extract of the bitter almond.

  18. Dynamic analysis of stochastic transcription cycles.

    Directory of Open Access Journals (Sweden)

    Claire V Harper

    2011-04-01

    increased the cyclicity. Stochastically timed bursts of transcription in an apparently random subset of cells in a tissue may thus produce an overall coordinated but heterogeneous phenotype capable of acute responses to stimuli.

  19. Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of ALK-Positive Anaplastic Large Cell Lymphoma.

    Science.gov (United States)

    Xu, Wendan; Kim, Ji-Won; Jung, Woo June; Koh, Youngil; Yoon, Sung-Soo

    2017-06-19

    Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant NPM-ALK fusion protein. Both mTOR inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated PI3K/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. Crizotinib combined with everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

  20. Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration.

    Science.gov (United States)

    Miyatake, Kazumasa; Muneta, Takeshi; Ojima, Miyoko; Yamada, Jun; Matsukura, Yu; Abula, Kahaer; Sekiya, Ichiro; Tsuji, Kunikazu

    2016-05-31

    Although osteoarthritis (OA) is a multifactorial disease, little has been reported regarding the cooperative interaction among these factors on cartilage metabolism. Here we examined the synergistic effect of ovariectomy (OVX) and excessive mechanical stress (forced running) on articular cartilage homeostasis in a mouse model resembling a human postmenopausal condition. Mice were randomly divided into four groups, I: Sham, II: OVX, III: Sham and forced running (60 km in 6 weeks), and IV: OVX and forced running. Histological and immunohistochemical analyses were performed to evaluate the degeneration of articular cartilage and synovitis in the knee joint. Morphological changes of subchondral bone were analyzed by micro-CT. Micro-CT analyses showed significant loss of metaphyseal trabecular bone volume/tissue volume (BV/TV) after OVX as described previously. Forced running increased the trabecular BV/TV in all mice. In the epiphyseal region, no visible alteration in bone morphology or osteophyte formation was observed in any of the four groups. Histological analysis revealed that OVX or forced running respectively had subtle effects on cartilage degeneration. However, the combination of OVX and forced running synergistically enhanced synovitis and articular cartilage degeneration. Although morphological changes in chondrocytes were observed during OA initiation, no signs of bone marrow edema were observed in any of the four experimental groups. We report the coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration. Since no surgical procedure was performed on the knee joint directly in this model, this model is useful in addressing the molecular pathogenesis of naturally occurring OA.

  1. Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells.

    Directory of Open Access Journals (Sweden)

    Hai-Shan Peng

    Full Text Available OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1 were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression

  2. Synergistic fuel cycles of the future

    International Nuclear Information System (INIS)

    Meneley, D.A.; Dastur, A.R.

    1997-01-01

    Good neutron economy is the basis of the fuel cycle flexibility in the CANDU reactor. This paper describes the fuel cycle options available to the CANDU owner with special emphasis on resource conservation and waste management. CANDU fuel cycles with low initial fissile content operate with relatively high conversion ratio. The natural uranium cycle provides over 55 % of energy from the plutonium that is created during fuel life. Resource utilization is over 7 MWd/kg NU. This can be improved by slight enrichment (between 0.9 and 1.2 wt % U235) of the fuel. Resource utilization increases to 11 MWd/kg NU with the Slightly Enriched Uranium cycle. Thorium based cycles in CANDU operate at near-breeder efficiency. Obey provide attractive options when used with natural uranium or separated (reactor grade and weapons grade) plutonium as driver fuels. In the latter case, the energy from the U233 plus the initial plutonium content amounts to 3.4 GW(th).d/kg Pu-fissile. The same utilization is expected from the use of FBR plutonium in a CANDU thorium cycle. Extension of natural resource is achieved by the use of spent fuels in CANDU. The LWR/CANDU Tandem cycle leads to an additional 77 % of energy through the use of reprocessed LWR fuel (which has a fissile content of 1.6 wt %) in CANDU. Dry reprocessing of LWR fuel with the OREOX process (a more safeguardable alternative to the PUREX process) provides an additional 50 % energy. Uranium recovered (RU) from separation of plutonium contained in spent LWR fuel provides an additional 15 MWd/kg RU. CANDU's low fissile requirement provides the possibility, through the use of non-fertile targets, of extracting energy from the minor actinides contained in spent fuel. In addition to the resource utilization advantage described above, there is a corresponding reduction in waste arisings with such cycles. This is especially significant when separated plutonium is available as a fissile resource. (author)

  3. Canine Distemper Virus Infection Leads to an Inhibitory Phenotype of Monocyte-Derived Dendritic Cells In Vitro with Reduced Expression of Co-Stimulatory Molecules and Increased Interleukin-10 Transcription

    Science.gov (United States)

    Herder, Vanessa; Stein, Veronika M.; Tipold, Andrea; Urhausen, Carola; Günzel-Apel, Anne-Rose; Rohn, Karl; Baumgärtner, Wolfgang; Beineke, Andreas

    2014-01-01

    Canine distemper virus (CDV) exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs), responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper. PMID:24769532

  4. Canine distemper virus infection leads to an inhibitory phenotype of monocyte-derived dendritic cells in vitro with reduced expression of co-stimulatory molecules and increased interleukin-10 transcription.

    Directory of Open Access Journals (Sweden)

    Visar Qeska

    Full Text Available Canine distemper virus (CDV exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs, responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper.

  5. Synergistic effect on co-gasification reactivity of biomass-petroleum coke blended char.

    Science.gov (United States)

    Wei, Juntao; Guo, Qinghua; Gong, Yan; Ding, Lu; Yu, Guangsuo

    2017-06-01

    In this work, effects of gasification temperature (900°C-1100°C) and blended ratio (3:1, 1:1, 1:3) on reactivity of petroleum coke and biomass co-gasification were studied in TGA. Quantification analysis of active AAEM transformation and in situ investigation of morphological structure variations in gasification were conducted respectively using inductively coupled plasma optical emission spectrometer and heating stage microscope to explore synergistic effect on co-gasification reactivity. The results indicated that char gasification reactivity was enhanced with increasing biomass proportion and gasification temperature. Synergistic effect on co-gasification reactivity was presented after complete generation of biomass ash, and gradually weakened with increasing temperature from 1000°C to 1100°C after reaching the most significant value at 1000°C. This phenomenon was well related with the appearance of molten biomass ash rich in glassy state potassium and the weakest inhibition effect on active potassium transformation during co-gasification at the temperature higher than 1000°C. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Synergistic Enhancement of Cellobiohydrolase Performance on Pretreated Corn Stover by Addition of Xylanase and Esterase Activities

    Energy Technology Data Exchange (ETDEWEB)

    Selig, M. J.; Knoshaug E. P.; Adney, W. S.; Himmel, M. E.; Decker, S. R.

    2007-11-01

    Significant increases in the depolymerization of corn stover cellulose by cellobiohydrolase I (Cel7A) from Trichoderma reesei were observed using small quantities of non-cellulolytic cell wall-degrading enzymes. Purified endoxylanase (XynA), ferulic acid esterase (FaeA), and acetyl xylan esterase (Axe1) all enhanced Cel7A performance on corn stover subjected to hot water pretreatment. In all cases, the addition of these activities improved the effectiveness of the enzymatic hydrolysis in terms of the quantity of cellulose converted per milligram of total protein. Improvement in cellobiose release by the addition of the non-cellulolytic enzymes ranged from a 13-84% increase over Cel7A alone. The most effective combinations included the addition of both XynA and Axe1, which synergistically enhance xylan conversions resulting in additional synergistic improvements in glucan conversion. Additionally, we note a direct relationship between enzymatic xylan removal in the presence of XynA and the enhancement of cellulose hydrolysis by Cel7A.

  7. The Goldilocks contract: The synergistic benefits of combining structure and autonomy for persistence, creativity, and cooperation.

    Science.gov (United States)

    Chou, Eileen Y; Halevy, Nir; Galinsky, Adam D; Murnighan, J Keith

    2017-09-01

    Contracts are commonly used to regulate a wide range of interactions and relationships. Yet relying on contracts as a mechanism of control often comes at a cost to motivation. Integrating theoretical perspectives from psychology, economics, and organizational theory, we explore this control-motivation dilemma inherent in contracts and present the Contract-Autonomy-Motivation-Performance-Structure (CAMPS) model, which highlights the synergistic benefits of combining structure and autonomy. The model proposes that subtle reductions in the specificity of a contract's language can boost autonomy, which increases intrinsic motivation and improves a range of desirable behaviors. Nine field and laboratory experiments found that less specific contracts increased task persistence, creativity, and cooperation, both immediately and longitudinally, because they boosted autonomy and intrinsic motivation. These positive effects, however, only occurred when contracts provided sufficient structure. Furthermore, the effects were limited to control-oriented clauses (i.e., legal clauses), and did not extend to coordination-oriented clauses (i.e., technical clauses). That is, there were synergistic benefits when a contract served as a scaffold that combined structure with general clauses. Overall, the current model and experiments identify a low-cost solution to the common problem of regulating social relationships: finding the right amount of contract specificity promotes desirable outcomes, including behaviors that are notoriously difficult to contract. The CAMPS model and the current set of empirical findings explain why, when, and how contracts can be used as an effective motivational tool. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  8. Tribological and antioxidation synergistic effect study of sulfonate-modified nano calcium carbonate.

    Directory of Open Access Journals (Sweden)

    He Zhongyi

    Full Text Available A middle base number sulphonate-modified nano calcium carbonate (SMC with an average size of 35 nm was synthesized, and its tribological and antioxidation synergistic behaviors with ashless antioxidant N-phenyl-α-naphthylamine (T531 in hydrogenated oil (5Cst were evaluated. The results demonstrate that adding this synthesized additive even at a low amount (<2.0 wt.% can evidently improve its load-carrying capacity by 1.5 times and enhance its antiwear performance; in addition, the friction-reducing effect of additive in the high load was better than that in low load. The SMC have a good synergistic antioxidation effect with T531, which verifies the nano calcium carbonate compound was a kind of multifunctional and high-performance additive. The chemical composition of the rubbing surface which formed on the boundary film was analyzed by using scanning electron microscopy (SEM and X-ray photoelectron spectroscopy (XPS. The results indicating that the excellent antiwear and load-carrying performance could be attributed to the forming of boundary lubrication film which composed of calcium carbonate, oxides, ferrites, sulphide and FeSO4, and so on. Its ability to increase oxidation free energy of base oil is the main reason for increasing its antioxidant collaboration property with ashless antioxidant T531.

  9. Some aspects of synergistic extraction of actinides and lanthanides from mixed aqueous-organic media

    International Nuclear Information System (INIS)

    Shukla, J.P.; Subramanian, M.S.

    1981-01-01

    Various aspects of the synergistic extraction and separation of actinides and lanthanides from mixed aqueous-organic solutions (polar media) have been reviewed. Notable recent developments as well as its current status in solvent extraction systems where the aqueous acidic phase contains an organic solvent which is completely miscible with water, are presented briefly. In general, extraction increases in the presence of an organic component. The less polar the additive, the higher is the tendency to form neutral metal complexes which ultimately brings about an increase in the extraction. In a polar media, synergism has mostly been observed, though antagonism is not uncommon. An attempt has been made to classify the factors that play an important role in polar phase extractions. Also, their influence particularly on the extractability of actinides and lanthanides is discussed. The discussion is limited to the factors affecting the extraction equilibria, effect of dielectric constant of the polar medium, solvation of the extracting agent and to the composition and stability of the metal complex in the organic phase. Hydroxyl (OHsup(-)) bearing organic additives, e.g. alcohols, and solvents not containing the hydroxyl group such as acetone, dimethylsulphoxide, tetrahydrofuran, amides and acetonitrile etc. are the two major classes of organic additives considered in these studies. Generally, synergistic effect in extraction of the ion-association (TBP, TOPO, sulphoxides etc.) or anion exchange (amines etc.) type is relatively more pronounced compared to other extractions. A tabular summary concerning extraction of actinides and lanthanides from polar media is appended for ready reference. (author)

  10. AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Angelo Cerbone

    2012-01-01

    Full Text Available PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc. used to treat hyperlipidemia. Since PPARα transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARα ligands. We analysed the effects of AS601245 (a JNK inhibitor and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARα to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARα ligands and anti-inflammatory agents in humans.

  11. Synergistic effects of dietary bioactive compounds and investigation of Nrf2/HO-1 axis in HIV-1 transgenic rat

    OpenAIRE

    Davinelli, Sergio

    2014-01-01

    Considerable evidence suggests that the combinatorial effect dietary bioactive compounds may be useful in preventing or reducing aging features. Therefore, a synergistic multi-target approach in dietary intervention may be effective in slowing down the aging process and increase healthy aging. Functional foods and nutraceuticals can exert specific anti-aging benefits such as improvement in mitochondrial function or induce neuroprotective effects to counteract the deleterious consequences of o...

  12. NFATc4 and myocardin synergistically up-regulate the expression of LTCC α1C in ET-1-induced cardiomyocyte hypertrophy.

    Science.gov (United States)

    Li, Man; He, Hong-Peng; Gong, Hui-Qin; Zhang, Jian; Ma, Wen-Jian; Zhou, Hao; Cao, Dong-Sun; Wang, Nan; Zhang, Tong-Cun

    2016-06-15

    Dysregulation of Ca(2+) is a central cause of cardiac hypertrophy. The α1C subunit of L-type Ca(2+) channel (LTCC) is a pore-forming protein which is responsible for the voltage-dependent channel gating and channel selectivity for Ca(2+). Myocardin and nuclear factor of activated T-cells c4 (NFATc4) are two key transcription factors in cardiac hypertrophy. We aimed to investigate the underlying mechanism of the transcriptional regulation of LTCC α1C by myocardin and NFATc4 in hypertrophic cardiomyocytes. Endothelin-1 (ET-1) was used to induce cardiomyocyte hypertrophy. Cyclosporin A (CSA) was used to block the activation of calcineurin/NFATc4 pathway in ET-1-treated cardiomyocytes and the expression of LTCC α1C were examined. Overexpression or RNAi interfering experiments were performed to investigate the effects of NFATc4 or myocardin on the transcriptional regulation of LTCC α1C. Interactions between NFATc4 and myocardin or the association of NFATc4 with myocardin promoter were assessed via Co-IP or ChIP assays respectively. In the present study, we found that ET-1 stimulated LTCC α1C transcription in neonatal rat cardiomyocytes partially via the activation of calcineurin/NFATc4 pathway. Overexpression of NFATc4 or myocardin promoted LTCC α1C expression in cardiomyocytes. Ca(2+) channel blocker verapamil or knockdown of α1C inhibited myocardin-induced cardiomyocyte hypertrophy. Further studies showed that NFATc4 interacted with myocardin to synergistically activate the expression of LTCC α1C, moreover, NFATc4 activated myocardin expression by binding to its promoter. Our results suggest a novel mechanism of the transcriptional regulation of LTCC α1C by synergistic activities of NFATc4 and myocardin in ET-1-induced cardiomyocyte hypertrophy. Copyright © 2016. Published by Elsevier Inc.

  13. N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells.

    Science.gov (United States)

    Jump, Sarah M; Kung, Jenny; Staub, Richard; Kinseth, Matthew A; Cram, Erin J; Yudina, Larisa N; Preobrazhenskaya, Maria N; Bjeldanes, Leonard F; Firestone, Gary L

    2008-02-01

    Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as cabbage, broccoli, and Brussels sprouts, induces a G1 cell cycle arrest of human breast cancer cells. Structure-activity relationships of I3C that mediate this anti-proliferative response were investigated using synthetic and natural I3C derivatives that contain substitutions at the indole nitrogen. Nitrogen substitutions included N-alkoxy substituents of one to four carbons in length, which inhibit dehydration and the formation of the reactive indolenine. Analysis of growth and cell cycle arrest of indole-treated human breast cancer cells revealed a striking increase in efficacy of the N-alkoxy I3C derivatives that is significantly enhanced by the presence of increasing carbon lengths of the N-alkoxy substituents. Compared to I3C, the half maximal growth arrest responses occurred at 23-fold lower indole concentration for N-methoxy I3C, 50-fold lower concentration for N-ethoxy I3C, 217-fold lower concentration for N-propoxy I3C, and 470-fold lower concentration for N-butoxy I3C. At these lower concentrations, each of the N-alkoxy substituted compounds induced the characteristic I3C response in that CDK6 gene expression, CDK6 promoter activity, and CDK2 specific enzymatic activity for its retinoblastoma protein substrate were strongly down-regulated. 3-Methoxymethylindole and 3-ethoxymethylindole were approximately as bioactive as I3C, whereas both tryptophol and melatonin failed to induce the cell cycle arrest, showing the importance of the C-3 hydroxy methyl substituent on the indole ring. Taken together, our study establishes the first I3C structure-activity relationship for cytostatic activities, and implicates I3C-based N-alkoxy derivatives as a novel class of potentially more potent experimental therapeutics for breast cancer.

  14. Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells.

    Directory of Open Access Journals (Sweden)

    Karen L Oslund

    Full Text Available Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.

  15. Systematic chemical analysis approach reveals superior antioxidant capacity via the synergistic effect of flavonoid compounds in red vegetative tissues

    Science.gov (United States)

    Qin, Xiaoxiao; Lu, Yanfen; Peng, Zhen; Fan, Shuangxi; Yao, Yuncong

    2018-02-01

    The flavonoid system comprises an abundance of compounds with multiple functions; however, their potential synergism in antioxidant function remains unclear. We established an approach using ever-red (RL) and ever-green leaves (GL) of crabapple cultivars during their development to determine interrelationships among flavonoid compounds. RL scored significantly better than GL in terms of the type, composition, and diversity of flavonoids than GL. Principal component analysis predicted flavonoids in RL to have positive interaction effects, and the total antioxidant capacity was significantly higher than the sum of antioxidant capacities of the individual compounds. This synergy was verified by the high antioxidant capacity in rat serum after feeding on red leaves. Our findings suggest that the synergistic effect is a result of the high transcription levels regulated by McMYBs in RL. In summary, individual flavonoids cooperate in a flavonoid system, thus producing a synergistic antioxidant effect, and the approach used herein can provide insights into the roles of flavonoids and other compounds in future studies.

  16. Synergistic inhibitory effects of deferasirox in combination with decitabine on leukemia cell lines SKM-1, THP-1, and K-562.

    Science.gov (United States)

    Li, Nianyi; Chen, Qinfen; Gu, Jingwen; Li, Shuang; Zhao, Guangjie; Wang, Wei; Wang, Zhicheng; Wang, Xiaoqin

    2017-05-30

    A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS. In this study, we aimed to explore this clinical phenomena in vitro, by exploring the synergistic effect of the iron chelator Deferasirox (DFX) and the DNA methyl transferase inhibitor Decitabine (DAC) in the leukemia cell lines SKM-1, THP-1, and K-562. Treatment with both DFX or DAC promoted apoptosis, induced cell cycle arrest, and inhibited proliferation in all three of these cell lines. The combination of DFX and DAC was much greater than the effect of using either drug alone. DFX showed a synergistic effect with DAC on cell apoptosis in all three cell lines and on cell cycle arrest at the G0/G1 phase in K-562 cells. DFX decreased the ROS levels to varying degrees. In contrast, DAC increased ROS levels and an increase in ROS was also noted when the two drugs were used in combination. Treatment of cells with DAC induced re-expression of ABAT, APAF-1, FADD, HJV, and SMPD3, presumably through demethylation. However the combination of DAC and DFX just had strong synergistic effect on the re-expression of HJV.

  17. Detecting novel low-abundant transcripts in Drosophila

    DEFF Research Database (Denmark)

    Lee, Sanggyu; Bao, Jingyue; Zhou, Guolin

    2005-01-01

    Increasing evidence suggests that low-abundant transcripts may play fundamental roles in biological processes. In an attempt to estimate the prevalence of low-abundant transcripts in eukaryotic genomes, we performed a transcriptome analysis in Drosophila using the SAGE technique. We collected 244......,313 SAGE tags from transcripts expressed in Drosophila embryonic, larval, pupae, adult, and testicular tissue. From these SAGE tags, we identified 40,823 unique SAGE tags. Our analysis showed that 55% of the 40,823 unique SAGE tags are novel without matches in currently known Drosophila transcripts...... in the Drosophila genome. Our study reveals the presence of a significant number of novel low-abundant transcripts in Drosophila, and highlights the need to isolate these novel low-abundant transcripts for further biological studies. Udgivelsesdato: 2005-Jun...

  18. Synergistic Release from Glucose Repression by Mig1 and Ssn Mutations in Saccharomyces Cerevisiae

    Science.gov (United States)

    Vallier, L. G.; Carlson, M.

    1994-01-01

    In the yeast Saccharomyces cerevisiae, glucose repression of SUC2 transcription requires the SSN6-TUP1 repressor complex. It has been proposed that the DNA-binding protein MIG1 secures SSN6-TUP1 to the SUC2 promoter. Here we show that a mig1 deletion does not cause nearly as dramatic a loss of repression as ssn6: glucose-grown mig1 mutants display 20-fold lower SUC2 expression than ssn6 mutants. Thus, repression by SSN6-TUP1 is not mediated solely by MIG1, but also involves MIG1-independent mechanisms. We report that mig1 partially restores SUC2 expression in mutants lacking the SNF1 protein kinase and show that mig1 is allelic to ssn1, a mutation selected as a suppressor of snf1. Other SSN genes identified in this selection were therefore candidates for a role in repression of SUC2. We show that mig1 acts synergistically with ssn2 through ssn5, ssn7, and ssn8 to relieve glucose repression of SUC2 and to suppress the requirement for SNF1. These findings indicate that the SSN proteins contribute to repression of SUC2, and the pleiotropic phenotypes of the ssn mutants suggest global roles in repression. Finally, the regulated SUC2 expression observed in snf1 mig1 mutants indicates that signals regarding glucose availability can be transmitted independently of the SNF1 protein kinase. PMID:8056322

  19. Quantitative analysis of tyrosinase transcripts in blood.

    Science.gov (United States)

    Johansson, M; Pisa, E K; Törmänen, V; Arstrand, K; Kågedal, B

    2000-07-01

    Tyrosinase is an enzyme unique to pigment-forming cells. Methods using this transcript for detection of melanoma cells in blood have given divergent results. Quantitative analytical procedures are therefore needed to study the analytical performance of the methods. Mononucleated cells were isolated by Percoll centrifugation. RNA was isolated by each of three methods: Ultraspec(TM)-II RNA isolation system, FastRNA(TM) GREEN Kit, and QIAamp RNA Blood Mini Kit. cDNA was synthesized using random hexamer primers. A tyrosinase-specific product of 207 bp was amplified by PCR. As an internal standard (and competitor) we used a 207-bp cDNA with a base sequence identical to the tyrosinase target except for a 20-bp probe-binding region. The PCR products were identified by 2, 4-dinitrophenol (DNP)-labeled probes specific for tyrosinase (5'DNP-GGGGAGCCTTGGGGTTCTGG-3') and internal standard (5'DNP-CGGAGCCCCGAAACCACATC-3') and quantified by ELISA. The calibration curves were linear and had a broad dynamic measuring range. A detection limit (2 SD above zero) of 48 transcripts/mL of blood was obtained from a low control. The analytical imprecision was 50% and 48% at concentrations of 1775 and 17 929 transcripts/mL (n = 12 and 14, respectively). With the cell line SK-Mel 28 added to blood and RNA extracted with the Ultraspec, Fast RNA, and QIAamp RNA methods, we found (mean +/- SD) 1716+/-1341, 2670+/-3174, and 24 320+/-5332 transcripts/mL of blood. Corresponding values were 527+/-497, 2497+/-1033, 14 930+/-1927 transcripts/mL of blood when the cell line JKM86-4 was added. One high-risk patient was followed by repeated analysis of tyrosinase transcripts in blood. The melanoma marker 5-S-cysteinyldopa in serum and urine was within reference values, but tyrosinase mRNA was slightly increased (120-168 transcripts/mL of blood). The tyrosinase mRNA increased to 1860 transcripts/mL concomitant with the increase in 5-S-cysteinyldopa; later a spleen metastasis was found. The results

  20. Transcriptional control of secondary growth and wood formation.

    Science.gov (United States)

    Juan Du; Andrew Groover

    2010-01-01

    Secondary growth and wood formation are products of the vascular cambium, a lateral meristem. Although the mechanisms have only recently begun to be uncovered, transcriptional regulation appears increasingly central to the regulation of secondary growth. The importance of transcriptional regulation is illustrated by the correlation of expression of specific classes of...

  1. Synergistic mosquito-repellent activity of Curcuma longa, Pogostemon heyneanus and Zanthoxylum limonella essential oils.

    Science.gov (United States)

    Das, N G; Dhiman, Sunil; Talukdar, P K; Rabha, Bipul; Goswami, Diganta; Veer, Vijay

    2015-01-01

    Mosquito repellents play an important role in preventing man-mosquito contact. In the present study, we evaluated the synergistic mosquito-repellent activity of Curcuma longa, Pogostemon heyneanus and Zanthoxylum limonella essential oils. The mosquito repellent efficacies of three essential oils were evaluated separately and in combination under laboratory and field conditions. N,N-Diethylphenylacetamide (DEPA) and dimethylphthalate (DMP) were used for comparison of the protection time of the mixture of essential oils. At an optimum concentration of 20%, the essential oils of C. longa, Z. limonella and P. heyneanus provided complete protection times (CPTs) of 96.2, 91.4 and 123.4 min, respectively, against Aedes albopictus mosquitoes in the laboratory. The 1:1:2 mixture of the essential oils provided 329.4 and 391.0 min of CPT in the laboratory and field trials, respectively. The percent increases in CPTs for the essential oil mixture were 30 for DMP and 55 for N,N-diethylphenylacetamide (DEPA). The synergistic repellent activity of the essential oils used in the present study might be useful for developing safer alternatives to synthetic repellents for personal protection against mosquitoes. Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

  2. Irreversible electroporation ablation area enhanced by synergistic high- and low-voltage pulses.

    Directory of Open Access Journals (Sweden)

    Chenguo Yao

    Full Text Available Irreversible electroporation (IRE produced by a pulsed electric field can ablate tissue. In this study, we achieved an enhancement in ablation area by using a combination of short high-voltage pulses (HVPs to create a large electroporated area and long low-voltage pulses (LVPs to ablate the electroporated area. The experiments were conducted in potato tuber slices. Slices were ablated with an array of four pairs of parallel steel electrodes using one of the following four electric pulse protocols: HVP, LVP, synergistic HVP+LVP (SHLVP or LVP+HVP. Our results showed that the SHLVPs more effectively necrotized tissue than either the HVPs or LVPs, even when the SHLVP dose was the same as or lower than the HVP or LVP doses. The HVP and LVP order mattered and only HVPs+LVPs (SHLVPs treatments increased the size of the ablation zone because the HVPs created a large electroporated area that was more susceptible to the subsequent LVPs. Real-time temperature change monitoring confirmed that the tissue was non-thermally ablated by the electric pulses. Theoretical calculations of the synergistic effects of the SHLVPs on tissue ablation were performed. Our proposed SHLVP protocol provides options for tissue ablation and may be applied to optimize the current clinical IRE protocols.

  3. Gallium and silicon synergistically promote osseointegration of dental implant in patients with osteoporosis.

    Science.gov (United States)

    Liu, Jinsong; Wu, Zuosu; He, Hongli; Cai, Kaiyong; Zhang, Hualin; Xu, Lihua

    2017-06-01

    Over the last few decades, a wide variety of dental implants have been successfully placed in jaw bones to restore tooth function. But major challenges still remain in patients with osteoporosis involving compromised osseointegration, and the therapeutic methods is far from optimism. Gallium can directly inhibit bone osteolysis, prevent bone calcium release and augment bone mass, which makes Ga unique among the potential antiresorptive drugs. Silicon, as an indispensable modulator in bone formation, presents its bone anabolic effects, while reduces, at least doesn't increase, bone resorption. We hypothesize that the combination of bone anabolic effects of Si and antiresorptive effects of Ga will result in synergistic effects on the improvement of osteointegration under osteoporotic condition. In our strategy, in order to maximize the efficacy while minimize the side effects of ions, a novel titania mesoporous layer fabricated by electrochemical anodization on the surface of titanium implant will be employed as a promising local drug delivery system. The synergistic effects of Ga and Si on improving osseointegration will be verified by animal experiments, and be furthered by clinical trials. Our hypothesis could help to create an option to improve success rate of dental implants in osteoporotic patients. Copyright © 2017. Published by Elsevier Ltd.

  4. Synergistic flame retardant effects between sepiolite and magnesium hydroxide in ethylene-vinyl acetate (EVA matrix

    Directory of Open Access Journals (Sweden)

    2010-04-01

    Full Text Available Some customers are reluctant to change, because the halogen-free solutions may have higher cost. This is one of the reasons that the synergistic effect is always the subject for researchers to pursue. The synergy between sepiolite and magnesium hydroxide (MH in halogen-free flame retardant ethylene-vinyl acetate (EVA copolymer was investigated in the paper through some common facilities, such as limiting oxygen index (LOI, UL-94 test, thermogravimetric analysis (TGA, differential thermal analysis (DTA and cone calorimeter test (CCT. In the wake of the positive results from the LOI and UL-94 tests, the CCT data indicated not only the reduction of heat release rate (HRR and mass loss rates (MLR, but also prolonged ignition time (TTI and depressed smoke release (SR were observed during combustion. Simultaneously, the tensile strength and Young’s modulus of the system were also much better improved with the increase of sepiolite added due to the hydrogen bonds between silanol groups attached to the sepiolite molecules and the ester groups of EVA. The synergistic mechanism has been discussed in the paper in terms of the barrier mechanism in the condensed phase.

  5. Synergistic action of laccases from Trametes hirsuta Bm2 improves decolourization of indigo carmine.

    Science.gov (United States)

    Zapata-Castillo, P; Villalonga-Santana, L; Islas-Flores, I; Rivera-Muñoz, G; Ancona-Escalante, W; Solís-Pereira, S

    2015-09-01

    Laccase isoenzymes (LacI,II,III) produced on wheat bran from Trametes hirsuta were partially purified through anion exchange chromatography. The three isoenzymes had the same MW of 65 kDa, and their main physico-chemical properties were studied. As single isoenzymes, laccases were unable to decolourize dye. Among several mediators evaluated, syringaldehyde was the most effective in dye decolourization (100%). A remarkable increase in dye decolourization was observed when LacI, II, III in mixture or crude enzyme were added to the reaction system, indicating that the laccases acted synergistically. Laccases have a great potential of application in bioremediation processes. White rot fungi produces several laccase isoenzymes and many of them have been purified and characterized. However, the additive or synergic action between laccase isoenzymes in dye decolourization has not yet been described. Such studies will help to better understand their action and to improve the process with isoenzymes mixtures. This study showed synergistic action between isoenzymes laccases produced by Trametes hirsuta Bm2 during decolourization of indigo carmine. © 2015 The Society for Applied Microbiology.

  6. A synergistic method for vibration suppression of an elevator mechatronic system

    Science.gov (United States)

    Knezevic, Bojan Z.; Blanusa, Branko; Marcetic, Darko P.

    2017-10-01

    Modern elevators are complex mechatronic systems which have to satisfy high performance in precision, safety and ride comfort. Each elevator mechatronic system (EMS) contains a mechanical subsystem which is characterized by its resonant frequency. In order to achieve high performance of the whole system, the control part of the EMS inevitably excites resonant circuits causing the occurrence of vibration. This paper proposes a synergistic solution based on the jerk control and the upgrade of the speed controller with a band-stop filter to restore lost ride comfort and speed control caused by vibration. The band-stop filter eliminates the resonant component from the speed controller spectra and jerk control provides operating of the speed controller in a linear mode as well as increased ride comfort. The original method for band-stop filter tuning based on Goertzel algorithm and Kiefer search algorithm is proposed in this paper. In order to generate the speed reference trajectory which can be defined by different shapes and amplitudes of jerk, a unique generalized model is proposed. The proposed algorithm is integrated in the power drive control algorithm and implemented on the digital signal processor. Through experimental verifications on a scale down prototype of the EMS it has been verified that only synergistic effect of controlling jerk and filtrating the reference torque can completely eliminate vibrations.

  7. Fusobacterium nucleatum and Tannerella forsythia Induce Synergistic Alveolar Bone Loss in a Mouse Periodontitis Model

    Science.gov (United States)

    Settem, Rajendra P.; El-Hassan, Ahmed Taher; Honma, Kiyonobu; Stafford, Graham P.

    2012-01-01

    Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late-colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-κB activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single-species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model. PMID:22547549

  8. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaofei; Zhu, Yanshuang [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); He, Huabin [Department of Orthopedics, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Lou, Lianqing; Ye, Weiwei; Chen, Yongxin [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Wang, Jinghe, E-mail: Xiaofeili2000@163.com [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China)

    2013-06-28

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.

  9. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    International Nuclear Information System (INIS)

    Li, Xiaofei; Zhu, Yanshuang; He, Huabin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

    2013-01-01

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis

  10. Synergistic effect of heartwood extractives and quaternary ammonium compounds on termite resistance of treated wood.

    Science.gov (United States)

    Hwang, Won-Joung; Kartal, S Nami; Yoshimura, Tsuyoshi; Imamura, Yuji

    2007-01-01

    This study evaluates the synergistic effect of wood extractives and quaternary ammonium compounds (QACs) on the resistance to termites of several treated wood species. Wood specimens from different natural durability classes were extracted with either hot water alone or hot water + ethanol/benzene. The extracted and unextracted wood specimens were treated with either didecyldimethylammonium tetrafluoroborate (DBF) or commercial didecyldimethylammonium chloride (DDAC) solutions and then exposed to subterranean termites, Coptotermes formosanus Shiraki, for 3 weeks under laboratory conditions. The results showed that extractives of the heartwood portions of the wood species contributed to increased resistance against termite attack in the presence of either DBF or DDAC wood preservatives. The synergistic effect of wood extractives and DBF was much clearer with Pseudotsuga menziesii (Mirbel) Franco and Tsuga heterophylla Sarg wood samples. Further studies are needed for a better understanding of the synergism between wood extractives and either DBF or DDAC using both the sapwood and heartwood portions of the same wood species. Copyright (c) 2006 Society of Chemical Industry.

  11. Spray-drying microencapsulation of synergistic antioxidant mushroom extracts and their use as functional food ingredients.

    Science.gov (United States)

    Ribeiro, Andreia; Ruphuy, Gabriela; Lopes, José Carlos; Dias, Madalena Maria; Barros, Lillian; Barreiro, Filomena; Ferreira, Isabel C F R

    2015-12-01

    In this work, hydroalcoholic extracts of two mushrooms species, Suillus luteus (L.: Fries) (Sl) and Coprinopsis atramentaria (Bull.) (Ca), were studied for their synergistic antioxidant effect and their viability as functional food ingredients tested by incorporation into a food matrix (cottage cheese). In a first step, the individual extracts and a combination of both, showing synergistic effects (Sl:Ca, 1:1), were microencapsulated by spray-drying using maltodextrin as the encapsulating material. The incorporation of free extracts resulted in products with a higher initial antioxidant activity (t0) but declining after 7 days (t7), which was associated with their degradation. However, the cottage cheese enriched with the microencapsulated extracts, that have revealed a lower activity at the initial time, showed an increase at t7. This improvement can be explained by an effective protection provided by the microspheres together with a sustained release. Analyses performed on the studied cottage cheese samples showed the maintenance of the nutritional properties and no colour modifications were noticed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Antibacterial and Drug Synergistic Activities of Mentha longifolia Essential Oil Against Shigella flexneri and Shigella sonnei

    Directory of Open Access Journals (Sweden)

    Maryam Makvandi

    2017-08-01

    Full Text Available Background: Microbial infections such as shigellosis are one of the major health challenges in Iran, especially in Khuzestan province in the south west of Iran. Objective: According to the importance of medicinal plants in the treatment of many infectious diseases, and as a valuable alternative for antibiotics, the aim of this research was to assess the antibacterial and drug synergistic activities of the essential oil from Mentha longifolia, a local plant, against Shigella flexneri and Shigella sonnei as the main causes of shigellosis. Materials and Methods: The M. longifolia essential oil was extracted from the leaves. The antibacterial activities of the essential oil against clinical and standard S. flexneri and S. sonnei strains were detected by the disk diffusion and micro-broth dilution methods. Results: The essential oil of M. longifolia had the most significant antibacterial activity against the clinical strain of S. flexneri. Minimum inhibitory concentration (MIC of 1024 with a concentration of 0.8 mg/mL of essential oil was detected in both the standard and clinical S. flexneri and S. sonnei strains. The essential oil of M. longifolia showed the highest synergistic effect on gentamicin and ampicillin in the clinical isolates of S. flexneri. Conclusion: The results of this study showed that the essential oil of M. longifolia alone or in combination with antimicrobial agents may be useful in the treatment of bacterial infections. In addition, M. longifolia may increase the effect of antibiotics and resolve other antibiotic resistance problems.

  13. Regeneration of Aplysia Bag Cell Neurons is Synergistically Enhanced by Substrate-Bound Hemolymph Proteins and Laminin

    Science.gov (United States)

    Hyland, Callen; Dufrense, Eric R.; Forscher, Paul

    2014-04-01

    We have investigated Aplysia hemolymph as a source of endogenous factors to promote regeneration of bag cell neurons. We describe a novel synergistic effect between substrate-bound hemolymph proteins and laminin. This combination increased outgrowth and branching relative to either laminin or hemolymph alone. Notably, the addition of hemolymph to laminin substrates accelerated growth cone migration rate over ten-fold. Our results indicate that the active factor is either a high molecular weight protein or protein complex and is not the respiratory protein hemocyanin. Substrate-bound factor(s) from central nervous system-conditioned media also had a synergistic effect with laminin, suggesting a possible cooperation between humoral proteins and nervous system extracellular matrix. Further molecular characterization of active factors and their cellular targets is warranted on account of the magnitude of the effects reported here and their potential relevance for nervous system repair.

  14. Transcriptional Regulation in Haematopoiesis:

    DEFF Research Database (Denmark)

    Lauridsen, Felicia K B

    Haematopoietic stem cells (HSCs) are responsible for the formation of all of the distinct mature cell types found in the blood. HSCs can – as the only cells of the haematopoietic system – regenerate all of the blood cells when transplanted into a irradiated host, because they are endowed...... of distinct lineage affiliated genes in the otherwise highly purified HSCs. Taken together, these studies demonstrate the use of our model as a tool for isolating superior HSCs, and show that low-level expression of mature lineage markers is inherent in the highly purified stem cell compartment. In the second...... in transplantation studies. Consistent with this, transcriptome profiling revealed very low expression of cell cycle genes in these reporter-dim HSCs. Sequencing of >1200 single HSCs confirmed that the main source of transcriptional heterogeneity was the cell cycle. It also revealed a low-level expression...

  15. Signal transduction and HIV transcriptional activation after exposure to ultraviolet light and other DNA-damaging agents

    International Nuclear Information System (INIS)

    Valerie, K.; Laster, W.S.; Luhua Cheng; Kirkham, J.C.; Reavey, Peter; Kuemmerle, N.B.

    1996-01-01

    Short wavelength (254 nm) ultraviolet light (UVC) radiation was much more potent in activating transcription of human immunodeficiency virus 1 (HIV) reporter genes stably integrated into the genomes of human and monkey cells than ionizing radiation (IR) from a 137 Cs source at similarly cytotoxic doses. A similar differential was also observed when c-jun transcription levels were examined. However, these transcription levels do not correlate with activation of nuclear factor (NF)-kB and AP-1 measured by band-shift assays, i.e. both types of radiation produce similar increases in NF-kB and AP-1 activity, suggesting existence of additional levels of regulation during these responses. Because of the well-established involvement of cytoplasmic signaling pathways in the cellular response to tumor necrosis factor-α (TNF-α), UVC, and IR using other types of assays, the role of TNF-α in the UVC response of HIV and c-jun was investigated in our cell system. We demonstrate that UVC and TNF-α activate HIV gene expression in a synergistic fashion, suggesting that it is unlikely that TNF-α is involved in UVC activation of HIV transcription in stably transfected HeLa cells. Moreover, maximum TNF-α stimulation resulted in one order of magnitude lower levels of HIV expression than that observed after UVC exposure. We also observed an additive effect of UVC and TNF-α on c-jun steady-state mRNA levels, suggestive of a partial overlap in activation mechanism of c-jun by UVC and TNF-α; yet these responses are distinct to some extent. Our results indicate that the HIV, and to some extent also the c-jun, transcriptional responses to UVC are not the result of TNF-α stimulation and subsequent downstream cytoplasmic signaling events in HeLa cells. In addition to the new data, this report also summarizes our current views regarding UVC-induced activations of HIV gene expression in stably transfected cells. (Author)

  16. Euglena Transcript Processing.

    Science.gov (United States)

    McWatters, David C; Russell, Anthony G

    2017-01-01

    RNA transcript processing is an important stage in the gene expression pathway of all organisms and is subject to various mechanisms of control that influence the final levels of gene products. RNA processing involves events such as nuclease-mediated cleavage, removal of intervening sequences referred to as introns and modifications to RNA structure (nucleoside modification and editing). In Euglena, RNA transcript processing was initially examined in chloroplasts because of historical interest in the secondary endosymbiotic origin of this organelle in this organism. More recent efforts to examine mitochondrial genome structure and RNA maturation have been stimulated by the discovery of unusual processing pathways in other Euglenozoans such as kinetoplastids and diplonemids. Eukaryotes containing large genomes are now known to typically contain large collections of introns and regulatory RNAs involved in RNA processing events, and Euglena gracilis in particular has a relatively large genome for a protist. Studies examining the structure of nuclear genes and the mechanisms involved in nuclear RNA processing have revealed that indeed Euglena contains large numbers of introns in the limited set of genes so far examined and also possesses large numbers of specific classes of regulatory and processing RNAs, such as small nucleolar RNAs (snoRNAs). Most interestingly, these studies have also revealed that Euglena possesses novel processing pathways generating highly fragmented cytosolic ribosomal RNAs and subunits and non-conventional intron classes removed by unknown splicing mechanisms. This unexpected diversity in RNA processing pathways emphasizes the importance of identifying the components involved in these processing mechanisms and their evolutionary emergence in Euglena species.

  17. Initiation of HIV Reverse Transcription

    Directory of Open Access Journals (Sweden)

    Roland Marquet

    2010-01-01

    Full Text Available Reverse transcription of retroviral genomes into double stranded DNA is a key event for viral replication. The very first stage of HIV reverse transcription, the initiation step, involves viral and cellular partners that are selectively packaged into the viral particle, leading to an RNA/protein complex with very specific structural and functional features, some of which being, in the case of HIV-1, linked to particular isolates. Recent understanding of the tight spatio-temporal regulation of reverse transcription and its importance for viral infectivity further points toward reverse transcription and potentially its initiation step as an important drug target.

  18. Synergistic effect of parathyroid hormone and growth hormone on trabecular and cortical bone formation in hypophysectomized rats.

    Science.gov (United States)

    Guevarra, Maria Sarah N; Yeh, James K; Castro Magana, Mariano; Aloia, John F

    2010-01-01

    Growth hormone (GH) deficiency in pediatric patients results in short stature and osteopenia. We postulated that the GH and parathyroid hormone (PTH) combination would result in improvement in bone growth and bone formation. Forty hypophysectomized female rats at age 8 weeks were divided into hypophysectomy (HX), HX + PTH (62.5 microg/kg, s.c. daily), HX + GH (3.33 mg/kg, s.c. daily), and HX + PTH + GH for a 4-week study. GH increased body weight, bone growth, bone mineral content (BMC) and bone mineral density (BMD), whereas PTH increased BMC and BMD without a significant effect on bone size. GH increased both periosteal and endocortical bone formation and cortical size, while PTH increased only endocortical bone formation. GH mitigated the trabecular bone loss by increasing bone formation, while PTH increased bone mass by increasing bone formation and suppressing osteoclast number per bone area. The result of combined intervention shows an increase in trabecular, periosteal and endocortical bone formation and suppression of bone resorption resulting in a synergistic effect on increasing trabecular and cortical bone volume and BMD. The combination treatment of PTH and GH increases bone growth, bone formation, decreases bone resorption and has a synergistic effect on increasing bone density and bone mass. Copyright (c) 2010 S. Karger AG, Basel.

  19. What is Life? Among Other Things, It's a Synergistic Effect!

    Directory of Open Access Journals (Sweden)

    Peter Corning

    2008-10-01

    Full Text Available There have been many different ways of characterizing and describing the phenomenon of life over the years. One aspect that has not often been stressed is lifersquo;s emergent propertiesmdash;the synergies that are produced when many elements or parts combine to produce distinctive new ldquo;wholesrdquo;. Indeed, complex living systems represent a multi-leveled, multi-faceted hierarchy of synergistic effects that has evolved over several billion years. Some of the many examples of synergy at various levels of life are briefly described, and it is emphasized that life is still creating itself and still exploring its potentialities.

  20. Synergistic Effect of Lupenone and Caryophyllene Oxide against Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Glendy Polanco-Hernández

    2013-01-01

    Full Text Available The in vitro trypanocidal activity of a 1 : 4 mixture of lupenone and caryophyllene oxide confirmed a synergistic effect of the terpenoids against epimastigotes forms of T. cruzi (IC50=10.4 μg/mL, FIC = 0.46. In addition, testing of the terpenoid mixture for its capacity to reduce the number of amastigote nests in cardiac tissue and skeletal muscle of infected mice showed a reduction of more than 80% at a dose level of 20.8 mg·kg−1·day−1.

  1. Transcriptional landscape of the human cell cycle.

    Science.gov (United States)

    Liu, Yin; Chen, Sujun; Wang, Su; Soares, Fraser; Fischer, Martin; Meng, Feilong; Du, Zhou; Lin, Charles; Meyer, Clifford; DeCaprio, James A; Brown, Myles; Liu, X Shirley; He, Housheng Hansen

    2017-03-28

    Steady-state gene expression across the cell cycle has been studied extensively. However, transcriptional gene regulation and the dynamics of histone modification at different cell-cycle stages are largely unknown. By applying a combination of global nuclear run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and histone-modification Chip sequencing (ChIP-seq), we depicted a comprehensive transcriptional landscape at the G0/G1, G1/S, and M phases of breast cancer MCF-7 cells. Importantly, GRO-seq and RNA-seq analysis identified different cell-cycle-regulated genes, suggesting a lag between transcription and steady-state expression during the cell cycle. Interestingly, we identified genes actively transcribed at early M phase that are longer in length and have low expression and are accompanied by a global increase in active histone 3 lysine 4 methylation (H3K4me2) and histone 3 lysine 27 acetylation (H3K27ac) modifications. In addition, we identified 2,440 cell-cycle-regulated enhancer RNAs (eRNAs) that are strongly associated with differential active transcription but not with stable expression levels across the cell cycle. Motif analysis of dynamic eRNAs predicted Kruppel-like factor 4 (KLF4) as a key regulator of G1/S transition, and this identification was validated experimentally. Taken together, our combined analysis characterized the transcriptional and histone-modification profile of the human cell cycle and identified dynamic transcriptional signatures across the cell cycle.

  2. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    . Observations: Three patients with idiopathic solar urticaria underwent phototesting with UV-B and UV-A radiation. The minimal urticarial dose (MUD) was determined 15 minutes after irradiation. The patients were subsequently tested with 5 times the MUD, and the reaction was graded every minute for 15 minutes....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

  3. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    Background: It can be difficult to provide patients with idiopathic solar urticaria adequate protection from sunlight. In a nonrandomized controlled trial, we used a standardized phototest procedure to determine the effects of using sunscreen and antihistamine to control idiopathic solar urticaria....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

  4. Zinc finger protein 521 overexpression increased transcript levels of ...

    Indian Academy of Sciences (India)

    2016-02-12

    Feb 12, 2016 ... Dulbecco's modified Eagle medium/Ham's-Nutrient Mixture F-12; EB, embryoid body; EBF1, early B-cell factor 1; FITC, fluorescein isothiocyanate;. Fndc5, firbonectin type III domain containing 5; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; LIF, leukemia inhibitory factor; mESCs, mouse embryonic ...

  5. Zinc finger protein 521 overexpression increased transcript levels of ...

    Indian Academy of Sciences (India)

    ... Iran; Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, ...

  6. Synergistic effect of CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin on food intake regulation in lean mice

    Czech Academy of Sciences Publication Activity Database

    Maletínská, Lenka; Maixnerová, Jana; Matyšková, Resha; Haugvicová, Renata; Pirnik, Z.; Kiss, A.; Železná, Blanka

    2008-01-01

    Roč. 9, č. 101 (2008), s. 1-10 ISSN 1471-2202 R&D Projects: GA ČR GA303/05/0614 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50200510 Keywords : mice * food intake * CART peptide Subject RIV: CE - Biochemistry Impact factor: 2.850, year: 2008

  7. Exploring synergistic benefits of Water-Food-Energy Nexus through multi-objective reservoir optimization schemes.

    Science.gov (United States)

    Uen, Tinn-Shuan; Chang, Fi-John; Zhou, Yanlai; Tsai, Wen-Ping

    2018-03-22

    This study proposed a holistic three-fold scheme that synergistically optimizes the benefits of the Water-Food-Energy (WFE) Nexus by integrating the short/long-term joint operation of a multi-objective reservoir with irrigation ponds in response to urbanization. The three-fold scheme was implemented step by step: (1) optimizing short-term (daily scale) reservoir operation for maximizing hydropower output and final reservoir storage during typhoon seasons; (2) simulating long-term (ten-day scale) water shortage rates in consideration of the availability of irrigation ponds for both agricultural and public sectors during non-typhoon seasons; and (3) promoting the synergistic benefits of the WFE Nexus in a year-round perspective by integrating the short-term optimization and long-term simulation of reservoir operations. The pivotal Shihmen Reservoir and 745 irrigation ponds located in Taoyuan City of Taiwan together with the surrounding urban areas formed the study case. The results indicated that the optimal short-term reservoir operation obtained from the non-dominated sorting genetic algorithm II (NSGA-II) could largely increase hydropower output but just slightly affected water supply. The simulation results of the reservoir coupled with irrigation ponds indicated that such joint operation could significantly reduce agricultural and public water shortage rates by 22.2% and 23.7% in average, respectively, as compared to those of reservoir operation excluding irrigation ponds. The results of year-round short/long-term joint operation showed that water shortage rates could be reduced by 10% at most, the food production rate could be increased by up to 47%, and the hydropower benefit could increase up to 9.33 million USD per year, respectively, in a wet year. Consequently, the proposed methodology could be a viable approach to promoting the synergistic benefits of the WFE Nexus, and the results provided unique insights for stakeholders and policymakers to pursue

  8. Theory of synergistic effects: Hill-type response surfaces as 'null-interaction' models for mixtures.

    Science.gov (United States)

    Schindler, Michael

    2017-08-02

    The classification of effects caused by mixtures of agents as synergistic, antagonistic or additive depends critically on the reference model of 'null interaction'. Two main approaches are currently in use, the Additive Dose (ADM) or concentration addition (CA) and the Multiplicative Survival (MSM) or independent action (IA) models. We compare several response surface models to a newly developed Hill response surface, obtained by solving a logistic partial differential equation (PDE). Assuming that a mixture of chemicals with individual Hill-type dose-response curves can be described by an n-dimensional logistic function, Hill's differential equation for pure agents is replaced by a PDE for mixtures whose solution provides Hill surfaces as 'null-interaction' models and relies neither on Bliss independence or Loewe additivity nor uses Chou's unified general theory. An n-dimensional logistic PDE decribing the Hill-type response of n-component mixtures is solved. Appropriate boundary conditions ensure the correct asymptotic behaviour. Mathematica 11 (Wolfram, Mathematica Version 11.0, 2016) is used for the mathematics and graphics presented in this article. The Hill response surface ansatz can be applied to mixtures of compounds with arbitrary Hill parameters. Restrictions which are required when deriving analytical expressions for response surfaces from other principles, are unnecessary. Many approaches based on Loewe additivity turn out be special cases of the Hill approach whose increased flexibility permits a better description of 'null-effect' responses. Missing sham-compliance of Bliss IA, known as Colby's model in agrochemistry, leads to incompatibility with the Hill surface ansatz. Examples of binary and ternary mixtures illustrate the differences between the approaches. For Hill-slopes close to one and doses below the half-maximum effect doses MSM (Colby, Bliss, Finney, Abbott) predicts synergistic effects where the Hill model indicates 'null

  9. Synergistic effect of alkaline pretreatment and Fe dosing on batch anaerobic digestion of maize straw

    International Nuclear Information System (INIS)

    Khatri, Shailendra; Wu, Shubiao; Kizito, Simon; Zhang, Wanqin; Li, Jiaxi; Dong, Renjie

    2015-01-01

    Highlights: • Synergistic effect of NaOH treatment and Fe dosage to maize straw was investigated. • Combining NaOH treatment and Fe dosing resulted in 57% and 56% higher biogas and methane yield respectively. • Combined treatment shortened the technical digestion time from 48 days to 7 days. • Methane content did not differ significantly among the straw treatments. - Abstract: The synergistic effect of alkaline pretreatment and Fe dosing on anaerobic digestion of maize straw was investigated using mesophilic batch reactors. Three straw treatments were investigated as follows: NaOH (4% and 6%) pretreatment, Fe dosage (50, 200, 1000 and 2000 mg/L), and combined NaOH pretreatment and Fe dosage. Compared to the control, NaOH pretreatment alone increased methane yield by 3.5% (313.3 mL CH 4 /gVS) and 22.5% (370.9 mL CH 4 /gVS) and shortened the technical digestion time (TDT) from 48 days to 19 days and 10 days in 4% NaOH and 6% NaOH pretreatment respectively. Moreover, Fe dosing (200–1000 mg/L) alone gave a methane yield higher (9.4%) than that obtained from 4% NaOH and 7.5% less than the methane yield from 6% NaOH pretreatment; however, the TDT was 10 days longer. Combining NaOH pretreatment and Fe dosage (200–1000 mg/L) significantly increased the methane yield even further to 21.8% (368.8 mL CH 4 /gVS) and 56.2% (472.9 mL CH 4 /gVS), and shortened TDT from 48 days to 13 days and 7 days in 4% NaOH and 6% NaOH pretreatment respectively. This synergistic effect may be attributed to the fact that the alkaline treatment improved accessibility of the biodegradable fraction of the straw while Fe contributed to increased microbial enzyme activity.

  10. An upstream promoter element of the Acanthamoeba castellanii TBP gene binds a DNA sequence specific transcription activating protein, TPBF.

    Science.gov (United States)

    Liu, F; Bateman, E

    1993-01-01

    We have characterized a positive-acting element in the upstream portion of the Acanthamoeba TBP gene promoter. The 27 bp element (TPE), located within the promoter between -97 and -70, stimulates transcription in an orientation independent fashion and tolerates modest changes in its distance from the TATA box. The TPE does not, however, function synergistically nor when positioned 3000 bp 5' or 260 base pairs 3' of the transcription start site. The TPE binds a DNA sequence-dependent factor, TPBF, which we have partly purified. TPBF was characterized using in vitro transcription, DNase I footprinting, methylation interference and electrophoretic mobility shift assays. TPBF does not have a counterpart in HeLa cells, but nonetheless strongly stimulates transcription of the Acanthamoeba TBP gene in mammalian extracts. Our results also suggest that there are additional positively and negatively acting elements within the TBP gene promoter, for which a model is presented. Images PMID:8414988

  11. Synergistic antioxidant activity of green tea with some herbs

    Directory of Open Access Journals (Sweden)

    Dheeraj P Jain

    2011-01-01

    Full Text Available Cardiovascular diseases, cancer, arthritis, etc. are caused by free radicals that are byproducts of metabolic pathways. Selected plants namely Vitis vinifera, Phyllanthus emblica L., Punica granatum, Cinnamomum cassia, Ginkgo biloba L., and Camellia sinensis Linn. are reported to produce antioxidant property. This study is undertaken to support the hypothesis that formulation of a polyherbal combination of these plants shows a synergistic effect with green tea. The extracts of each drug were characterized by phytochemical studies and tests for phenolics and flavonoids. In vitro antioxidant activity for individual drug and its combination was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH, superoxide, and nitric oxide free radical scavenging methods. Our results suggest that a combination of all these herbs with green tea can synergistically enhance antioxidant activity and thus lower doses of each herb with green tea may be used. Antioxidant potential of polyherbal combination was also comparable to that of standard ascorbic acid. Studies showed that selected individual plants contained abundant quantity of phenolics and flavonoids and their polyherbal combination with green tea was found to produce best antioxidant activity among all individual extracts. This will help in avoiding undesirable side effects due to higher doses of single herb.

  12. Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics.

    Science.gov (United States)

    Li, Hongzhe; Steyger, Peter S

    2009-01-01

    Acoustic exposure to high intensity and/or prolonged noise causes temporary or permanent threshold shifts in auditory perception, reflected by reversible or irreversible damage in the cochlea. Aminoglycoside antibiotics, used for treating or preventing life-threatening bacterial infections, also induce cytotoxicity in the cochlea. Combined noise and aminoglycoside exposure, particularly in neonatal intensive care units, can lead to auditory threshold shifts greater than simple summation of the two insults. The synergistic toxicity of acoustic exposure and aminoglycoside antibiotics is not limited to simultaneous exposures. Prior acoustic insult which does not result in permanent threshold shifts potentiates aminoglycoside ototoxicity. In addition, exposure to subdamaging doses of aminoglycosides aggravates noise-induced cochlear damage. The mechanisms by which aminoglycosides cause auditory dysfunction are still being unraveled, but likely include the following: 1) penetration into the endolymphatic fluid of the scala media, 2) permeation of nonselective cation channels on the apical surface of hair cells, and 3) generation of toxic reactive oxygen species and interference with other cellular pathways. Here we discuss the effect of combined noise and aminoglycoside exposure to identify pivotal synergistic events that can potentiate ototoxicity, in addition to a current understanding of aminoglycoside trafficking within the cochlea. Preventing the ototoxic synergy of noise and aminoglycosides is best achieved by using non-ototoxic bactericidal drugs, and by attenuating perceived noise intensity when life-saving aminoglycoside therapy is required.

  13. Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs, which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.

  14. Synergistic impacts of habitat loss and fragmentation on model ecosystems.

    Science.gov (United States)

    Bartlett, Lewis J; Newbold, Tim; Purves, Drew W; Tittensor, Derek P; Harfoot, Michael B J

    2016-09-28

    Habitat loss and fragmentation are major threats to biodiversity, yet separating their effects is challenging. We use a multi-trophic, trait-based, and spatially explicit general ecosystem model to examine the independent and synergistic effects of these processes on ecosystem structure. We manipulated habitat by removing plant biomass in varying spatial extents, intensities, and configurations. We found that emergent synergistic interactions of loss and fragmentation are major determinants of ecosystem response, including population declines and trophic pyramid shifts. Furthermore, trait-mediated interactions, such as a disproportionate sensitivity of large-sized organisms to fragmentation, produce significant effects in shaping responses. We also show that top-down regulation mitigates the effects of land use on plant biomass loss, suggesting that models lacking these interactions-including most carbon stock models-may not adequately capture land-use change impacts. Our results have important implications for understanding ecosystem responses to environmental change, and assessing the impacts of habitat fragmentation. © 2016 The Authors.

  15. Non-equilibrium synergistic effects in atmospheric pressure plasmas.

    Science.gov (United States)

    Guo, Heng; Zhang, Xiao-Ning; Chen, Jian; Li, He-Ping; Ostrikov, Kostya Ken

    2018-03-19

    Non-equilibrium is one of the important features of an atmospheric gas discharge plasma. It involves complicated physical-chemical processes and plays a key role in various actual plasma processing. In this report, a novel complete non-equilibrium model is developed to reveal the non-equilibrium synergistic effects for the atmospheric-pressure low-temperature plasmas (AP-LTPs). It combines a thermal-chemical non-equilibrium fluid model for the quasi-neutral plasma region and a simplified sheath model for the electrode sheath region. The free-burning argon arc is selected as a model system because both the electrical-thermal-chemical equilibrium and non-equilibrium regions are involved simultaneously in this arc plasma system. The modeling results indicate for the first time that it is the strong and synergistic interactions among the mass, momentum and energy transfer processes that determine the self-consistent non-equilibrium characteristics of the AP-LTPs. An energy transfer process related to the non-uniform spatial distributions of the electron-to-heavy-particle temperature ratio has also been discovered for the first time. It has a significant influence for self-consistently predicting the transition region between the "hot" and "cold" equilibrium regions of an AP-LTP system. The modeling results would provide an instructive guidance for predicting and possibly controlling the non-equilibrium particle-energy transportation process in various AP-LTPs in future.

  16. Reactivation of Latent HIV-1 Expression by Engineered TALE Transcription Factors.

    Science.gov (United States)

    Perdigão, Pedro; Gaj, Thomas; Santa-Marta, Mariana; Barbas, Carlos F; Goncalves, Joao

    2016-01-01

    The presence of replication-competent HIV-1 -which resides mainly in resting CD4+ T cells--is a major hurdle to its eradication. While pharmacological approaches have been useful for inducing the expression of this latent population of virus, they have been unable to purge HIV-1 from all its reservoirs. Additionally, many of these strategies have been associated with adverse effects, underscoring the need for alternative approaches capable of reactivating viral expression. Here we show that engineered transcriptional modulators based on customizable transcription activator-like effector (TALE) proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and that combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency. We further show that complementing TALE transcription factors with Vorinostat, a histone deacetylase inhibitor, enhances HIV-1 expression in latency models. Collectively, these findings demonstrate that TALE transcription factors are a potentially effective alternative to current pharmacological routes for reactivating latent virus and that combining synthetic transcriptional activators with histone deacetylase inhibitors could lead to the development of improved therapies for latent HIV-1 infection.

  17. Reactivation of Latent HIV-1 Expression by Engineered TALE Transcription Factors.

    Directory of Open Access Journals (Sweden)

    Pedro Perdigão

    Full Text Available The presence of replication-competent HIV-1 -which resides mainly in resting CD4+ T cells--is a major hurdle to its eradication. While pharmacological approaches have been useful for inducing the expression of this latent population of virus, they have been unable to purge HIV-1 from all its reservoirs. Additionally, many of these strategies have been associated with adverse effects, underscoring the need for alternative approaches capable of reactivating viral expression. Here we show that engineered transcriptional modulators based on customizable transcription activator-like effector (TALE proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and that combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency. We further show that complementing TALE transcription factors with Vorinostat, a histone deacetylase inhibitor, enhances HIV-1 expression in latency models. Collectively, these findings demonstrate that TALE transcription factors are a potentially effective alternative to current pharmacological routes for reactivating latent virus and that combining synthetic transcriptional activators with histone deacetylase inhibitors could lead to the development of improved therapies for latent HIV-1 infection.

  18. The synergistic effects of 2,4-D dimethyl amine and propanil herbicides on weed population in rice agroecosystem

    International Nuclear Information System (INIS)

    Nashriyah Mat; Ramli Ishak; Sabri Junoh; Ismail Sahid

    2002-01-01

    Four treatments with the herbicides 2,4-D dimethyl amine and propanil were carried out in two consecutive rice planting seasons, to study the synergistic effect of 2,4-D dimethyl amine and propanil on rice weed populations at Pasir Panjang, the Northwest Selangor Project (PBLS), Projek Barat Laut Selangor) rice granary area. The treatments were control, 1x recommended rate (single dose), 2x recommended rate (double dose) of 2,4-D dimethyl amine and farmer practice. In all plots, propanil herbicide was applied at similar rate. Among the ecological indices measured were Simpson Index of diversity and importance (I.V.). A total number of 19 weed species was identified and the most common important weed was Najas graminae Del. The second most commonly found important weed was Scirpus lateriflorus Gmel. Other important weeds frequently found were Echinochloa crus-galli (L.) Beauv. and Fimbristylis miliacea (L.) Vahl. In the rice agroecosystem, species diversity of weeds was affected but total weed biomass was not affected synergistically by the mixture of 2,4-D dimethyl amine and propanil. The negative synergistic effect of 2,4-D dimethyl amine and propanil was to increase the total biomass of Scirpus lateriflorus, at 2x recommended dose rate of 2,4-D dimethyl amine. (Author)

  19. Synergistic function of four novel thermostable glycoside hydrolases from a long-term enriched thermophilic methanogenic digester

    Directory of Open Access Journals (Sweden)

    Meng eWang

    2015-05-01

    Full Text Available In biofuel production from lignocellulose, low thermostability and product inhibition strongly restrict the enzyme activities and production process. Application of multiple thermostable glycoside hydrolases, forming an enzyme cocktail, can result in a synergistic action and therefore improve production efficiency and reduce operational costs. Therefore, increasing enzyme thermostabilities and compatibility are important for the biofuel industry. In this study, we reported the screening, cloning and biochemical characterization of four novel thermostable lignocellulose hydrolases from a metagenomic library of a long-term dry thermophilic methanogenic digester community, which were highly compatible with optimal conditions and specific activities. The optimal temperatures of the four enzymes, β-xylosidase, xylanase, β-glucosidase, and cellulase ranged from 60°C to 75°C, and over 80% residual activities were observed after 2 h incubation at 50°C. Mixtures of these hydrolases retained high residual synergistic activities after incubation with cellulose, xylan, and steam-exploded corncob at 50°C for 72 h. In addition, about 55% dry weight of steam-exploded corncob was hydrolyzed to glucose and xylose by the synergistic action of the four enzymes at 50°C for 48 h. This work suggested that since different enzymes from a same ecosystem could be more compatible, screening enzymes from a long-term enriching community could be a favorable strategy.

  20. Synergistic Effects of NDRG2 Overexpression and Radiotherapy on Cell Death of Human Prostate LNCaP Cells.

    Science.gov (United States)

    Alizadeh Zarei, M; Takhshid, M A; Behzad Behbahani, A; Hosseini, S Y; Okhovat, M A; Rafiee Dehbidi, Gh R; Mosleh Shirazi, M A

    2017-09-01

    Radiation therapy is among the most conventional cancer therapeutic modalities with effective local tumor control. However, due to the development of radio-resistance, tumor recurrence and metastasis often occur following radiation therapy. In recent years, combination of radiotherapy and gene therapy has been suggested to overcome this problem. The aim of the current study was to explore the potential synergistic effects of N-Myc Downstream-Regulated Gene 2 (NDRG2) overexpression, a newly identified candidate tumor suppressor gene, with radiotherapy against proliferation of prostate LNCaP cell line. In this study, LNCaP cells were exposed to X-ray radiation in the presence or absence of NDRG2 overexpression using plasmid PSES- pAdenoVator-PSA-NDRG2-IRES-GFP. The effects of NDRG2 overexpression, X-ray radiation or combination of both on the cell proliferation and apoptosis of LNCaP cells were then analyzed using MTT assay and flow cytometery, respectively. Results of MTT assay showed that NDRG2 overexpression and X-ray radiation had a synergistic effect against proliferation of LNCaP cells. Moreover, NDRG2 overexpression increased apoptotic effect of X-ray radiation in LNCaP cells synergistically. Our findings suggested that NDRG2 overexpression in combination with radiotherapy may be an effective therapeutic option against prostate cancer.

  1. Synergistic bactericidal effects of a sublethal concentration of didecyldimethylammonium chloride (DDAC) and low concentrations of nonionic surfactants against Staphylococcus aureus.

    Science.gov (United States)

    Gomi, Mitsuhiro; Osaki, Yukihiko; Mori, Miho; Sakagami, Yoshikazu

    2012-01-01

    DDAC is an effective disinfectant used in the medical and food industries and the environmental field. However, skin irritation in humans occurs at high DDAC concentrations. In this study, we analyzed the combined effect of a low concentration (0.3 ppm) of DDAC and low concentrations (6, 8, and 10 ppm) of 37 products of nonionic surfactants on the bactericidal activity against S. aureus. No bactericidal activity was found at 0.3 ppm DDAC alone. Results showed that a combination of a low concentration of DDAC (0.3 ppm) and some nonionic surfactants tested (synergistic effect of five products ≥ 2.0) improved the bactericidal activity of DDAC. Synergistic effects of DDAC and some nonionic surfactants are desirable and were suggested to occur as follows. Test surfactants acted against the cell walls of S. aureus, which allowed DDAC to act easily on the lipid double membrane in the cell wall, thereby increasing the bactericidal activity of DDAC. In the present study, synergistic effects of a low concentration of DDAC and some nonionic surfactants were observed, a phenomenon that may be considerable value in future developments.

  2. TRH [thyrotropin-releasing hormone] and BAY K 8644 synergistically stimulate prolactin release but not 45Ca2+ uptake

    International Nuclear Information System (INIS)

    Pachter, J.A.; Law, G.J.; Dannies, P.S.

    1988-01-01

    Thyrotropin-releasing hormone (TRH) and the Ca 2+ -channel agonist BAY K 8644 each induced transient increases in prolactin secretion from primary cultures of rat anterior pituitary cells in perfusion. When BAY K 8644 was added after a TRH-induced secretory peak, the additional effect of BAY K 8644 on prolactin release was approximately twofold greater over a 30-min period than the effect of BAY K 8644 on previously untreated cells. TRH and BAY K 8644 were also synergistic when added in the opposite order or simultaneously. Substitution of other agents for BAY K 8644 revealed that only high K + was at least additive with TRH in stimulating prolactin secretion; treatment with TRH inhibited, rather than facilitated, subsequent stimulation of prolactin secretion by angiotensin II or the ionophore A23187. The cooperative effect was not specific for TRH because BAY K 8644 also acted synergistically with angiotensin II or 40 mM K + . In GH 4 C 1 cells, in which TRH and BAY K 8644 were also synergistic in releasing prolactin, measurements with the fluorescent indicator indo-1 showed that TRH and BAY K 8644 could each elevate cytosolic Ca 2+ above the level stimulated by the other. Unexpectedly, TRH was found to inhibit BAY K 8644-stimulated 45 Ca 2+ uptake in both GH 4 C 1 and primary cultured cells. These results indicate that BAY K 8644 and TRH synergistically stimulate prolactin secretion by a mechanism other than a cooperative effect on the activity of dihydropyridine-sensitive Ca 2+ channels

  3. Interrogating transcriptional regulatory sequences in Tol2-mediated Xenopus transgenics.

    Directory of Open Access Journals (Sweden)

    Gabriela G Loots

    Full Text Available Identifying gene regulatory elements and their target genes in vertebrates remains a significant challenge. It is now recognized that transcriptional regulatory sequences are critical in orchestrating dynamic controls of tissue-specific gene expression during vertebrate development and in adult tissues, and that these elements can be positioned at great distances in relation to the promoters of the genes they control. While significant progress has been made in mapping DNA binding regions by combining chromatin immunoprecipitation and next generation sequencing, functional validation remains a limiting step in improving our ability to correlate in silico predictions with biological function. We recently developed a computational method that synergistically combines genome-wide gene-expression profiling, vertebrate genome comparisons, and transcription factor binding-site analysis to predict tissue-specific enhancers in the human genome. We applied this method to 270 genes highly expressed in skeletal muscle and predicted 190 putative cis-regulatory modules. Furthermore, we optimized Tol2 transgenic constructs in Xenopus laevis to interrogate 20 of these elements for their ability to function as skeletal muscle-specific transcriptional enhancers during embryonic development. We found 45% of these elements expressed only in the fast muscle fibers that are oriented in highly organized chevrons in the Xenopus laevis tadpole. Transcription factor binding site analysis identified >2 Mef2/MyoD sites within ~200 bp regions in 6 of the validated enhancers, and systematic mutagenesis of these sites revealed that they are critical for the enhancer function. The data described herein introduces a new reporter system suitable for interrogating tissue-specific cis-regulatory elements which allows monitoring of enhancer activity in real time, throughout early stages of embryonic development, in Xenopus.

  4. Mitotic bookmarking by transcription factors.

    Science.gov (United States)

    Kadauke, Stephan; Blobel, Gerd A

    2013-04-02

    Mitosis is accompanied by dramatic changes in chromatin organization and nuclear architecture. Transcription halts globally and most sequence-specific transcription factors and co-factors are ejected from mitotic chromatin. How then does the cell maintain its transcriptional identity throughout the cell division cycle? It has become clear that not all traces of active transcription and gene repression are erased within mitotic chromatin. Many histone modifications are stable or only partially diminished throughout mitosis. In addition, some sequence-specific DNA binding factors have emerged that remain bound to select sites within mitotic chromatin, raising the possibility that they function to transmit regulatory information through the transcriptionally silent mitotic phase, a concept that has been termed "mitotic bookmarking." Here we review recent approaches to studying potential bookmarking factors with regards to their mitotic partitioning, and summarize emerging ideas concerning the in vivo functions of mitotically bound nuclear factors.

  5. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax.

    Science.gov (United States)

    Mann, Melanie C; Strobel, Sarah; Fleckenstein, Bernhard; Kress, Andrea K

    2014-09-01

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human beta-defensin 2 in middle ear epithelial cells

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    Park Raekil

    2006-01-01

    Full Text Available Abstract Background We recently showed that beta-defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi and that interleukin 1 alpha (IL-1 alpha up-regulates the transcription of beta-defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on beta-defensin 2 up-regulation by the bacterial components. Methods The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media (OM. Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure. Real time quantitative PCR was done to compare the induction of IL-1 alpha or beta-defensin 2 mRNAs and to identify the signaling pathways involved. Direct activation of the beta-defensin 2 promoter was monitored using a beta-defensin 2 promoter-Luciferase construct. An IL-1 alpha blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB4 induction. Results Middle ear epithelial cells released IL-1 alpha when stimulated by NTHi components and this cytokine acted in an autocrine/paracrine synergistic manner with NTHi to up-regulate beta-defensin 2. This synergistic effect of IL-1 alpha on NTHi-induced beta-defensin 2 up-regulation appeared to be mediated by the p38 MAP kinase pathway. Conclusion We demonstrate that IL-1 alpha is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate beta-defensin 2 via the p38 MAP kinase pathway.

  7. Global effects of the CSR-1 RNA interference pathway on the transcriptional landscape.

    Science.gov (United States)

    Cecere, Germano; Hoersch, Sebastian; O'Keeffe, Sean; Sachidanandam, Ravi; Grishok, Alla

    2014-04-01

    Argonaute proteins and their small RNA cofactors short interfering RNAs are known to inhibit gene expression at the transcriptional and post-transcriptional levels. In Caenorhabditis elegans, the Argonaute CSR-1 binds thousands of endogenous siRNAs (endo-siRNAs) that are antisense to germline transcripts. However, its role in gene expression regulation remains controversial. Here we used genome-wide profiling of nascent RNA transcripts and found that the CSR-1 RNA interference pathway promoted sense-oriented RNA polymerase II transcription. Moreover, a loss of CSR-1 function resulted in global increase in antisense transcription and ectopic transcription of silent chromatin domains, which led to reduced chromatin incorporation of centromere-specific histone H3. On the basis of these findings, we propose that the CSR-1 pathway helps maintain the directionality of active transcription, thereby propagating the distinction between transcriptionally active and silent genomic regions.

  8. Identifying salt stress-responsive transcripts from Roselle ( Hibiscus ...

    African Journals Online (AJOL)

    Hibiscus sabdariffa L.). Identifying the potentially novel transcripts responsible for salt stress tolerance in roselle will increase knowledge of the molecular mechanism underlying salt stress responses. In this study, differential display reverse ...

  9. Synergistic effects of some essential oils against fungal spoilage on pear fruit.

    Science.gov (United States)

    Nikkhah, Mehdi; Hashemi, Maryam; Habibi Najafi, Mohammad B; Farhoosh, Reza

    2017-09-18

    The development of natural protective agents as alternatives to chemical fungicides is currently in the spotlight. In the present investigation, chemical composition and antifungal activities of thyme, cinnamon, rosemary and marjoram essential oils (EO), as well as synergism of their possible double and triple combinations were investigated. The compositions of the oils were determined by GC/MS. For determination of antifungal activity against Penicillium expansum and Botrytis cinerea, a broth microdilution method was used. The possible interactions of some essential oil combinations were performed by the two and three-dimensional checkerboard assay and isobologram construction. An in vivo antifungal assay was performed by artificial wounding of pear fruits. The maximum antifungal activity was demonstrated by thyme and cinnamon oils which displayed lower MIC values whereas rosemary and marjoram oils with MIC range between 2500 and 10,000μg/mL exhibited weak antifungal activities against tested fungi. In synergy testing, some double combinations (thyme/cinnamon, thyme/rosemary, cinnamon/rosemary) were found to be synergistic (FICi≤0.5). The triple combination of thyme, cinnamon and rosemary was synergistic for B. cinerea and P. expansum (FICi values of 0.5 and 0.375, respectively); while combination of cinnamon, marjoram and thyme exhibited additive and synergistic effect against P. expansum (FIC=0.625) and B. cinerea (FIC=0.375) respectively. The usage of a mathematical Gompertz model in relation to fungal kinetics, showed that the model could be used to predict growth curves (R 2 =0.993±0.05). For B. cinerea, Gompertz parameters for double and triple combination treatments showed significant increase in lag phase (1.92 and 2.92days, respectively) compared to single treatments. Increase lag time up to 2.82days (P<0.05) also observed in P. expansum treated by triple combination of EOs. Base on the results, the lowest maximum growth rate (0.37mm/day) was observed

  10. Synergistic toxicity of copper and gold compounds inCupriavidus metallidurans.

    Science.gov (United States)

    Wiesemann, Nicole; Bütof, Lucy; Herzberg, Martin; Hause, Gerd; Berthold, Lutz; Etschmann, Barbara; Brugger, Joël; Martinez-Criado, Gema; Dobritzsch, Dirk; Baginsky, Sacha; Reith, Frank; Nies, Dietrich H

    2017-09-22

    The bacterium Cupriavidus metallidurans is capable of reducing toxic gold(I/III)-complexes and biomineralizing them into metallic gold (Au) nanoparticles, thereby mediating the (trans)formation of Au nuggets. In Au-rich soils, most transition metals do not interfere with the resistance of this bacterium to toxic mobile Au-complexes and can be removed from the cell by plasmid-encoded metal efflux systems. Copper is a noticeable exception: the presence of Au-complexes and Cu-ions results in synergistic toxicity, which is accompanied by an increased cytoplasmic Cu content and formation of Au nanoparticles in the periplasm. The periplasmic Cu-oxidase CopA was not essential for formation of the periplasmic Au nanoparticles. As shown with the purified and reconstituted Cu efflux system CupA, Au-complexes block Cu-dependent release of phosphate from ATP by CupA, indicating inhibition of Cu transport. Moreover, Cu resistance of Au-inhibited cells was similar to that of mutants carrying deletions in the genes for the Cu-exporting P IB1 -type ATPases. Consequently, Au-complexes inhibit export of cytoplasmic Cu-ions, leading to an increased cellular Cu-content and decreased Cu/Au resistance. Uncovering the biochemical mechanisms of synergistic Au/Cu-toxicity in C. metallidurans explains the issues this bacterium has to face in auriferous environments, where it is as an important contributor to the environmental Au cycle. Importance C. metallidurans lives in metal-rich environments, including auriferous soils that contain a mixture of toxic transition metal cations. We demonstrate here that copper ions and gold complexes exert synergistic toxicity because gold ions inhibit the copper-exporting P-type ATPase CupA, which is central to copper resistance in this bacterium. Such a situation should occur in soils overlying Au deposits, in which Cu:Au ratios usually are > 1. Appreciating how C. metallidurans solves the problem of living in environments that contain both Au and Cu is

  11. Synergistic induction of CX3CL1 by TNF alpha and IFN gamma in osteoblasts from rheumatoid arthritis: involvement of NF-kappa B and STAT-1 signaling pathways

    Directory of Open Access Journals (Sweden)

    Kuninobu Wakabayashi

    2008-10-01

    Full Text Available Takeo Isozaki, Tsuyoshi Kasama, Ryo Takahashi, Tsuyoshi Odai, Kuninobu Wakabayashi, Hirohito Kanemitsu, Kyoko Nohtomi, Hiroko T Takeuchi, Satoshi Matsukura, Masakazu TezukaDivision of Rheumatology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan, and the Department of Orthopedics, Denencyofu Central Hospital, Tokyo, JapanAbstract: To explore the regulation of CX3CL1 in inflammatory bone diseases, CX3CL1 expression by osteoblasts (OB was examined. Human OB isolated from rheumatoid arthritis (RA patients, osteoarthritis patients, and normal individuals were incubated in the presence of cytokines. Soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay. Expression of CX3CL1 mRNA was examined using quantitative real-time polymerase chain reaction. Although tumor necrosis factor (TNF-α or interferon (IFN-γ alone RA OB induced negligible CX3CL1 secretion, the combination of TNF-α and IFN-γ induced dramatic increases in both soluble CX3CL1 protein and mRNA transcripts. This synergistic effect was more pronounced in OB from RA than in OB from either osteoarthritis or normal individuals. The expression of CX3CL1 was markedly reduced by specific inhibitors of the nuclear factor-κB (NF-κB or STAT-1 transcription factor. These findings suggest that osteoblasts are an important cellular source of CX3CL1 and may play roles in inflammatory bone/joint diseases.Keywords: osteoblast, CX3CL1, chemokine, NF-κB, STAT-1

  12. 21 CFR 12.98 - Official transcript.

    Science.gov (United States)

    2010-04-01

    ..., participants, and counsel have 30 days from the time the transcript becomes available to propose corrections in the transcript of oral testimony. Corrections are permitted only for transcription errors. The... a verbatim stenographic transcript of oral testimony and for necessary copies of the transcript. (b...

  13. Dissection of TALE-dependent gene activation reveals that they induce transcription cooperatively and in both orientations

    Science.gov (United States)

    Streubel, Jana; Baum, Heidi; Grau, Jan; Stuttman, Johannes; Boch, Jens

    2017-01-01

    Plant-pathogenic Xanthomonas bacteria inject transcription activator-like effector proteins (TALEs) into host cells to specifically induce transcription of plant genes and enhance susceptibility. Although the DNA-binding mode is well-understood it is still ambiguous how TALEs initiate transcription and whether additional promoter elements are needed to support this. To systematically dissect prerequisites for transcriptional initiation the activity of one TALE was compared on different synthetic Bs4 promoter fragments. In addition, a large collection of artificial TALEs spanning the OsSWEET14 promoter was compared. We show that the presence of a TALE alone is not sufficient to initiate transcription suggesting the requirement of additional supporting promoter elements. At the OsSWEET14 promoter TALEs can initiate transcription from various positions, in a synergistic manner of multiple TALEs binding in parallel to the promoter, and even by binding in reverse orientation. TALEs are known to shift the transcriptional start site, but our data show that this shift depends on the individual position of a TALE within a promoter context. Our results implicate that TALEs function like classical enhancer-binding proteins and initiate transcription in both orientations which has consequences for in planta target gene prediction and design of artificial activators. PMID:28301511

  14. Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma

    International Nuclear Information System (INIS)

    Miyata, Kohei; Yotsumoto, Fusanori; Nam, Sung Ouk; Odawara, Takashi; Manabe, Sadao; Ishikawa, Toyokazu; Itamochi, Hiroaki; Kigawa, Junzo; Takada, Shuji; Asahara, Hiroshi; Kuroki, Masahide; Miyamoto, Shingo

    2014-01-01

    Ovarian clear cell carcinoma (OCCC) is a worst histological subtype than other ovarian malignant tumor. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. The aims of this study were to validate the efficacy of HB-EGF–targeted therapy for OCCC and to identify the transcription factor that contributed to the induction of HB-EGF by SN38 treatment in OCCC cells. HB-EGF was highly expressed in OCCC cells, and an increase of HB-EGF was induced by SN38 which had only antitumor effect among conventional anticancer agents on OCCC. A specific inhibitor of HB-EGF, a cross-reacting material 197 (CRM197), led to a synergistic increase in the number of apoptotic OCCC cells with the treatment of SN38. The luciferase assay with 5′-deletion promoter constructs identified a GC-rich element between −125 and −178 (the distal transcription start site was denoted +1) as a cis-regulatory region, and the treatment of SN38 induced luciferase activity in this region. An in silico and chromatin immunoprecipitation analysis estimated that SP1 bound to the cis-regulatory region of HB-EGF in OCCC cells. Real-time PCR and cell viability assays showed that the transfection of a small interfering RNA targeting SP1 suppressed the expression of HB-EGF induced by SN38, resulting in the enhanced sensitivity of SN38. Taken together, these results indicate that induction of HB-EGF expression contributed to defense mechanism against treatment of SN38 through the transcriptional activity of SP1 in OCCC cells

  15. Polycomb Responds to Low Levels of Transcription

    Directory of Open Access Journals (Sweden)

    Georgina Berrozpe

    2017-07-01

    Full Text Available How is Polycomb (Pc, a eukaryotic negative regulator of transcription, targeted to specific mammalian genes? Our genome-wide analysis of the Pc mark H3K27me3 in murine cells revealed that Pc is preferentially associated with CpG island promoters of genes that are transcribed at a low level and less so with promoters of genes that are either silent or more highly expressed. Studies of the CpG island promoter of the Kit gene demonstrate that Pc is largely absent when the gene is silent in myeloid cells, as well as when the gene is highly expressed in mast cells. Manipulations that increase transcription in the former case, and reduce it in the latter, increase Pc occupancy. The average negative effect of Pc, we infer, is about 2-fold. We suggest possible biological roles for such negative effects and propose a mechanism by which Pc might be recruited to weakly transcribed genes.

  16. Synergistic effects of atmospheric pressure plasma-emitted components on DNA oligomers: a Raman spectroscopic study.

    Science.gov (United States)

    Edengeiser, Eugen; Lackmann, Jan-Wilm; Bründermann, Erik; Schneider, Simon; Benedikt, Jan; Bandow, Julia E; Havenith, Martina

    2015-11-01

    Cold atmospheric-pressure plasmas have become of increasing importance in sterilization processes especially with the growing prevalence of multi-resistant bacteria. Albeit the potential for technological application is obvious, much less is known about the molecular mechanisms underlying bacterial inactivation. X-jet technology separates plasma-generated reactive particles and photons, thus allowing the investigation of their individual and joint effects on DNA. Raman spectroscopy shows that particles and photons cause different modifications in DNA single and double strands. The treatment with the combination of particles and photons does not only result in cumulative, but in synergistic effects. Profilometry confirms that etching is a minor contributor to the observed DNA damage in vitro. Schematics of DNA oligomer treatment with cold atmospheric-pressure plasma. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Intramolecular synergistic effect of glutamic acid, cysteine and glycine against copper corrosion in hydrochloric acid solution

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Daquan, E-mail: zhdq@sh163.net [Department of Environmental Engineering, Shanghai University of Electric Power, Shanghai 200090 (China); Xie Bin; Gao Lixin; Cai Qirui [Department of Environmental Engineering, Shanghai University of Electric Power, Shanghai 200090 (China); Joo, Hyung Goun; Lee, Kang Yong [Stress Analysis and Failure Design Laboratory, School of Mechanical Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2011-10-31

    The corrosion protection of copper by glutamic acid, cysteine, glycine and their derivative (glutathione) in 0.5 M hydrochloric acid solution has been studied by the electrochemical impedance spectroscopy and cyclic voltammetry. The inhibition efficiency of the organic inhibitors on copper corrosion increases in the order: glutathione > cysteine > cysteine + glutamic acid + glycine > glutamic acid > glycine. Maximum inhibition efficiency for cysteine reaches about 92.9% at 15 mM concentration level. The glutathione can give 96.4% inhibition efficiency at a concentration of 10 mM. The molecular structure parameters were obtained by PM3 (Parametric Method 3) semi-empirical calculation. The intramolecular synergistic effect of glutamic acid, cysteine and glycine moieties in glutathione is attributed to the lower energy of the lowest unoccupied molecular orbital (E{sub LUMO}) level and to the excess hetero-atom adsorption centers and the bigger coverage on the copper surface.

  18. Intramolecular synergistic effect of glutamic acid, cysteine and glycine against copper corrosion in hydrochloric acid solution

    International Nuclear Information System (INIS)

    Zhang Daquan; Xie Bin; Gao Lixin; Cai Qirui; Joo, Hyung Goun; Lee, Kang Yong

    2011-01-01

    The corrosion protection of copper by glutamic acid, cysteine, glycine and their derivative (glutathione) in 0.5 M hydrochloric acid solution has been studied by the electrochemical impedance spectroscopy and cyclic voltammetry. The inhibition efficiency of the organic inhibitors on copper corrosion increases in the order: glutathione > cysteine > cysteine + glutamic acid + glycine > glutamic acid > glycine. Maximum inhibition efficiency for cysteine reaches about 92.9% at 15 mM concentration level. The glutathione can give 96.4% inhibition efficiency at a concentration of 10 mM. The molecular structure parameters were obtained by PM3 (Parametric Method 3) semi-empirical calculation. The intramolecular synergistic effect of glutamic acid, cysteine and glycine moieties in glutathione is attributed to the lower energy of the lowest unoccupied molecular orbital (E LUMO ) level and to the excess hetero-atom adsorption centers and the bigger coverage on the copper surface.

  19. [Synergistic mechanism of steam explosion combined with laccase treatment for straw delignification].

    Science.gov (United States)

    Li, Guanhua; Chen, Hongzhang

    2014-06-01

    Components separation is the key technology in biorefinery. Combination of steam explosion and laccase was used, and synergistic effect of the combined pretreatment was evaluated in terms of physical structure, chemical components and extraction of lignin. The results showed that steam explosion can destroy the rigid structure and increase the specific surface area of straw, which facilitated the laccase pretreatment. The laccase pretreatment can modify the lignin structure based on the Fourier transform infrared test, as a result the delignification of straw was enhanced. Nuclei Growth model with a time dependent rate constant can describe the delignification, and the kinetics parameters indicated that the combined pretreatment improved the reaction sites and made the delignification reaction more sensitive to temperature. The combined pretreatment enhanced delignification, and can be a promising technology as an alternative to the existing pretreatment.

  20. High residue contents indebted by platinum and silica synergistic action during the pyrolysis of silicone formulations.

    Science.gov (United States)

    Delebecq, Etienne; Hamdani-Devarennes, Siska; Raeke, Julia; Lopez Cuesta, José-Marie; Ganachaud, François

    2011-03-01

    The synergistic role of platinum and silica as a way to increase the final residue of pyrolized silicone was investigated and explained, giving new interpretations. Conditions were first set to study the thermal degradation of silicones in the presence of platinum based on the simplest silicone/silica/platinum formulation. Numerous parameters, e.g., platinum and silica content or silica surface modifications, were varied to track their influences on the final residues. A thorough DSC study, together with SEM/EDX and Pyrolysis/GC-MS analyses, led us to propose a three-stage process. The key parameter governing thermal stability and final content of the residue is the conjugated actions of immobilizing/cross-linking PDMS chains. Silica particles tether silicone chains through physical interactions, i.e., hydrogen bonding, facilitating a platinum radically catalyzed cross-linking reaction. Practical implications and possible improvements on LSR formulations are finally given.

  1. Synergistic antibacterial effects of β-lactam antibiotic combined with silver nanoparticles

    Science.gov (United States)

    Li, Ping; Li, Juan; Wu, Changzhu; Wu, Qingsheng; Li, Jian

    2005-09-01

    The bactericidal action of silver (0) nanoparticles and amoxicillin on Escherichia coli is studied, respectively. Increasing concentration of both amoxicillin (0-0.525 mg ml-1) and silver nanoparticles (0-40 µg ml-1) showed a higher antibacterial effect in Luria-Bertani (LB) medium. Escherichia coli cells have different bactericidal sensitivity to them. When amoxicillin and silver nanoparticles are combined, it results in greater bactericidal efficiency on Escherichia coli cells than when they were applied separately. Dynamic tests on bacterial growth indicated that exponential and stationary phases are greatly decreased and delayed in the synergistic effect of amoxicillin and silver nanoparticles. In addition, the effect induced by a preincubation with silver nanoparticles is examined. The results show that solutions with more silver nanoparticles have better antimicrobial effects. One hypothesized mechanism is proposed to explain this phenomenon.

  2. Synergistic antimicrobial therapy using nanoparticles and antibiotics for the treatment of multidrug-resistant bacterial infection

    Science.gov (United States)

    Gupta, Akash; Saleh, Neveen M.; Das, Riddha; Landis, Ryan F.; Bigdeli, Arafeh; Motamedchaboki, Khatereh; Rosa Campos, Alexandre; Pomeroy, Kenneth; Mahmoudi, Morteza; Rotello, Vincent M.

    2017-06-01

    Infections caused by multidrug-resistant (MDR) bacteria pose a serious global burden of mortality, causing thousands of deaths each year. Antibiotic treatment of resistant infections further contributes to the rapidly increasing number of antibiotic-resistant species and strains. Synthetic macromolecules such as nanoparticles (NPs) exhibit broad-spectrum activity against MDR species, however lack of specificity towards bacteria relative to their mammalian hosts limits their widespread therapeutic application. Here, we demonstrate synergistic antimicrobial therapy using hydrophobically functionalized NPs and fluoroquinolone antibiotics for treatment of MDR bacterial strains. An 8-16-fold decrease in antibiotic dosage is achieved in presence of engineered NPs to combat MDR strains. This strategy demonstrates the potential of using NPs to ‘revive’ antibiotics that have been rendered ineffective due to the development of resistance by pathogenic bacteria.

  3. Transcriptional regulation of secondary growth and wood formation.

    Science.gov (United States)

    Du, Juan; Groover, Andrew

    2010-01-01

    Secondary growth and wood formation are products of the vascular cambium, a lateral meristem. Although the mechanisms have only recently begun to be uncovered, transcriptional regulation appears increasingly central to the regulation of secondary growth. The importance of transcriptional regulation is illustrated by the correlation of expression of specific classes of genes with related biological processes occurring at specific stages of secondary growth, including cell division, cell expansion, and cell differentiation. At the same time, transcription factors have been characterized that affect specific aspects of secondary growth, including regulation of the cambium and differentiation of cambial daughter cells. In the present review, we summarize evidence pointing to transcription as a major mechanism for regulation of secondary growth, and outline future approaches for comprehensively describing transcriptional networks underlying secondary growth.

  4. HOXB5 cooperates with NKX2-1 in the transcription of human RET.

    Directory of Open Access Journals (Sweden)

    Jiang Zhu

    Full Text Available The enteric nervous system (ENS regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i HOXB5 transcription factor mediates RET expression, and (ii mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5' upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297, which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype.

  5. Synergistic effects of local temperature enhancements on cellular responses in the context of high-intensity, ultrashort electric pulses.

    Science.gov (United States)

    Song, J; Joshi, R P; Schoenbach, K H

    2011-06-01

    Results of self-consistent analyses of cells show the possibility of temperature increases at membranes in response to a single nanosecond, high-voltage pulse, at least over small sections of the membrane. Molecular Dynamics simulations indicate that such a temperature increase could facilitate poration, which is one example of a bio-process at the plasma membrane. Our study thus suggests that the use of repetitive high-intensity voltage pulses could open up possibilities for a host of synergistic bio-responses involving both thermal and electrically driven phenomena.

  6. Synergistic impacts by an invasive amphipod and an invasive fish explain native gammarid extinction.

    Science.gov (United States)

    Beggel, S; Brandner, J; Cerwenka, A F; Geist, J

    2016-07-14

    Worldwide freshwater ecosystems are increasingly affected by invasive alien species. In particular, Ponto-Caspian gobiid fishes and amphipods are suspected to have pronounced effects on aquatic food webs. However, there is a lack of systematic studies mechanistically testing the potential synergistic effects of invasive species on native fauna. In this study we investigated the interrelations between the invasive amphipod Dikerogammarus villosus and the invasive fish species Neogobius melanostomus in their effects on the native amphipod Gammarus pulex. We hypothesized selective predation by the fish as a driver for displacement of native species resulting in potential extinction of G. pulex. The survival of G. pulex in the presence of N. melanostomus in relation to the presence of D. villosus and availability of shelter was analyzed in the context of behavioural differences between the amphipod species. Gammarus pulex had a significantly higher susceptibility to predation by N. melanostomus compared to D. villosus in all experiments, suggesting preferential predation by this fish on native gammarids. Furthermore, the presence of D. villosus significantly increased the vulnerability of G. pulex to fish predation. Habitat structure was an important factor for swimming activity of amphipods and their mortality, resulting in a threefold decrease in amphipods consumed with shelter habitat structures provided. Behavioral differences in swimming activity were additionally responsible for higher predation rates on G. pulex. Intraguild predation could be neglected within short experimental durations. The results of this study provide evidence for synergistic effects of the two invasive Ponto-Caspian species on the native amphipod as an underlying process of species displacements during invasion processes. Prey behaviour and monotonous habitat structures additionally contribute to the decline of the native gammarid fauna in the upper Danube River and elsewhere.

  7. Synergistic effects of dimethyloxalylglycine and butyrate incorporated into α-calcium sulfate on bone regeneration.

    Science.gov (United States)

    Woo, Kyung Mi; Jung, Hong-Moon; Oh, Joung-Hwan; Rahman, Saeed Ur; Kim, Soung Min; Baek, Jeong-Hwa; Ryoo, Hyun-Mo

    2015-01-01

    Osteogenesis is closely related to angiogenesis, and the combined delivery of angiogenic and osteogenic factors has been suggested to enhance bone regeneration. Small molecules have been explored as alternatives to growth factors for tissue regeneration applications. In this study, we examined the effects of the combined application of angiogenic and osteogenic small molecules on bone regeneration using a prolyl hydroxylase, dimethyloxalylglycine (DMOG), and a histone deacetylase inhibitor, butyrate. In a critical size bone defect model in rats, DMOG and butyrate, which were incorporated into α calcium sulfate (αCS), resulted in synergistic enhancements in bone and blood vessel formation, eventually leading to bone healing, as confirmed by micro-CT and histological analyses. In MC4 pre-osteoblast cultures, DMOG and butyrate enhanced the pro-angiogenic responses and osteoblast differentiation, respectively, which were evaluated based on the levels of hypoxia inducible factor (HIF)-1α protein and the expression of pro-angiogenic molecules (VEGF, home oxidase-1, glucose transporter-1) and by alkaline phosphatase (ALP) activity and the expression of osteoblast phenotype marker molecules (ALP, α1(I)col, osteocalcin, and bone sialoprotein). DMOG combined with butyrate synergistically improved osteoblast differentiation and pro-angiogenic responses, the levels of which were drastically increased in the cultures on αCS disks. Furthermore, it was demonstrated that αCS increased the level of HIF-1α and as a consequence VEGF expression, and supported osteoblast differentiation through the release of calcium ions from the αCS. Altogether, the results of this study provide evidence that a combination treatment with the small molecules DMOG and butyrate can expedite the process of bone regeneration and that αCS can be an efficient delivery vehicle for the small molecules for bone regeneration. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. In vivo synergistic cytogenetic effects of aminophylline on lymphocyte cultures from patients with lung cancer undergoing chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mylonaki, Effie; Manika, Katerina [Pulmonary Department, “G.Papanikolaou” General Hospital, Aristotle University of Thessaloniki (Greece); Zarogoulidis, Paul, E-mail: pzarog@hotmail.com [Pulmonary Department, “G.Papanikolaou” General Hospital, Aristotle University of Thessaloniki (Greece); Domvri, Kalliopi; Voutsas, Vasilis; Zarogoulidis, Kostas [Pulmonary Department, “G.Papanikolaou” General Hospital, Aristotle University of Thessaloniki (Greece); Mourelatos, Dionysios [Biology and Genetics, Medical School, Aristotle University of Thessaloniki (Greece)

    2012-12-15

    Highlights: ► SCEs in vivo, a possible predictor of tumor chemoresponse. ► In vivo exposure to combined treatment, applying the SCE assay. ► Aminophylline enhances DNA instability induced by chemotherapy in vivo. ► In vivo synergistic effect of Aminophylline with the chemotherapeutic agents. - Abstract: Background: The anti-cancer and cytogenetic effects of aminophylline (AM) have been demonstrated in several clinical trials. The aim of the present study was to investigate the in vivo cytogenetic effects of AM in newly diagnosed patients with small cell (SCLC) and non-small cell lung cancer (NSCLC), receiving chemotherapy for the first time. Methods: Sister chromatid exchanges (SCEs) and proliferation rate index (PRI) were evaluated in peripheral blood lymphocyte cultures from six patients with SCLC and six patients with NSCLC after the in vitro addition of AM and after the in vivo administration of AM in patients receiving chemotherapy. Results: The in vitro addition of AM significantly increased SCEs only in SCLC patients (p < 0.001). The in vivo administration of AM after chemotherapy increased SCEs in both cancer types (SCLC: p < 0.001, NSCLC: p = 0.003) and this increase was synergistic, the rates of SCEs in the presence of AM were higher than the expected SCE values if the increases above background for chemotherapy and AM were independent and additive (SCLC: p < 0.001, NSCLC: p = 0.008). Although in both groups of patients cell division delays were observed after the combined chemotherapy plus in vivo AM treatment, the correlation between the magnitude of the SCE response and the PRI depression was not statistically significant (p > 0.05). Conclusions: These observations suggest that AM enhances the results of concurrently administered chemotherapy by synergistically increasing its cytogenetic effects in patients with lung cancer.

  9. Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Adam Shlien

    2016-08-01

    Full Text Available Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation.

  10. Nascent transcription affected by RNA polymerase IV in Zea mays.

    Science.gov (United States)

    Erhard, Karl F; Talbot, Joy-El R B; Deans, Natalie C; McClish, Allison E; Hollick, Jay B

    2015-04-01

    All eukaryotes use three DNA-dependent RNA polymerases (RNAPs) to create cellular RNAs from DNA templates. Plants have additional RNAPs related to Pol II, but their evolutionary role(s) remain largely unknown. Zea mays (maize) RNA polymerase D1 (RPD1), the largest subunit of RNA polymerase IV (Pol IV), is required for normal plant development, paramutation, transcriptional repression of certain transposable elements (TEs), and transcriptional regulation of specific alleles. Here, we define the nascent transcriptomes of rpd1 mutant and wild-type (WT) seedlings using global run-on sequencing (GRO-seq) to identify the broader targets of RPD1-based regulation. Comparisons of WT and rpd1 mutant GRO-seq profiles indicate that Pol IV globally affects transcription at both transcriptional start sites and immediately downstream of polyadenylation addition sites. We found no evidence of divergent transcription from gene promoters as seen in mammalian GRO-seq profiles. Statistical comparisons identify genes and TEs whose transcription is affected by RPD1. Most examples of significant increases in genic antisense transcription appear to be initiated by 3'-proximal long terminal repeat retrotransposons. These results indicate that maize Pol IV specifies Pol II-based transcriptional regulation for specific regions of the maize genome including genes having developmental significance. Copyright © 2015 by the Genetics Society of America.

  11. Transcriptional delay stabilizes bistable gene networks.

    Science.gov (United States)

    Gupta, Chinmaya; López, José Manuel; Ott, William; Josić, Krešimir; Bennett, Matthew R

    2013-08-02

    Transcriptional delay can significantly impact the dynamics of gene networks. Here we examine how such delay affects bistable systems. We investigate several stochastic models of bistable gene networks and find that increasing delay dramatically increases the mean residence times near stable states. To explain this, we introduce a non-Markovian, analytically tractable reduced model. The model shows that stabilization is the consequence of an increased number of failed transitions between stable states. Each of the bistable systems that we simulate behaves in this manner.

  12. Synergistic sporicidal effect of ethanol on a combination of orthophthalaldehyde and didecyldimethylammonium chloride.

    Science.gov (United States)

    Yuan, G; Wei, Q; Tie, J; Wang, C; Rao, L; Zhang, W

    2014-09-01

    The objective of this study was to evaluate the potential synergistic effect of ethanol on a combination of orthophthalaldehyde (OPA) and didecyldimethylammonium chloride (DDAC) against the spores of Bacillus subtilis var. Niger. The quantitative carrier test for sporicidal testing of high-level disinfectants according to the guideline of China (Technical Standard for Disinfection 2002) was used as method. Considerable synergistic effect was observed after a 30-min treatment at 20°C. There was an augment in mean log reduction as the concentration of DDAC was increased ranging from 0·2 to 3 g l(-1) in combination with 6 g l(-1) OPA. Ten and 20% ethanol in combination with 6 g l(-1) OPA and 2 g l(-1) DDAC caused more than a 3-log reduction while either 6 g l(-1) OPA, 2 g l(-1) DDAC and 20% ethanol alone or a combination of two of the three agents produced less than a 1-log reduction. Further, 40-min exposure time of combination of OPA, DDAC and 20% ethanol led to greater than a 5-log reduction in spores, and no spore growth was observed following 60- and 90-min exposures. Orthophthalaldehyde (OPA) is very effective at concentrations far lower than its recommended in-use concentration of 0·5% (w/v) and is equally effective against both the gram-negative and gram-positive bacteria. However, it shows lower activity against spores. The synergistic sporicidal effect exhibited by ethanol on a combination of OPA and DDAC can be considered to enhance sporicidal activity for using in situations of sterilization, to reduce in-use concentration of OPA used alone, which may minimize its side effect. OPA may be a more satisfactory and the first-choice agent to replace glutaraldehyde (GTA) as a high-level disinfectant for medical devices. © 2014 The Society for Applied Microbiology.

  13. Herd Clustering: A synergistic data clustering approach using collective intelligence

    KAUST Repository

    Wong, Kachun

    2014-10-01

    Traditional data mining methods emphasize on analytical abilities to decipher data, assuming that data are static during a mining process. We challenge this assumption, arguing that we can improve the analysis by vitalizing data. In this paper, this principle is used to develop a new clustering algorithm. Inspired by herd behavior, the clustering method is a synergistic approach using collective intelligence called Herd Clustering (HC). The novel part is laid in its first stage where data instances are represented by moving particles. Particles attract each other locally and form clusters by themselves as shown in the case studies reported. To demonstrate its effectiveness, the performance of HC is compared to other state-of-the art clustering methods on more than thirty datasets using four performance metrics. An application for DNA motif discovery is also conducted. The results support the effectiveness of HC and thus the underlying philosophy. © 2014 Elsevier B.V.

  14. Synergistic extraction behaviour of americium from simulated acidic waste solutions

    International Nuclear Information System (INIS)

    Pathak, P.N.; Veeraraghavan, R.; Mohapatra, P.K.; Manchanda, V.K.

    1998-01-01

    The extraction behaviour of americium has been investigated with mixtures of 3-phenyl-4-benzoyl-5-isoxazolone (PBI) and oxodonors viz. tri-n-butyl phosphate (TBP), tri-n-octyl phosphine oxide (TOPO) and di-n-butyl octanamide (DBOA) using dodecane as the diluent from 1-6 M HNO 3 media. It is observed that D Am remains unaltered with PBI concentration (in the range 0.06-0.1 M) at 1.47 M TBP in the entire range of HNO 3 concentration. PBI and TBP in combination appears more promising compared to other synergistic systems. The possibility of using this mixture for americium removal from high level liquid waste solution has been explored. Extraction studies indicated that prior removal of uranium by 20% TBP in dodecane is helpful in the quantitative recovery of americium in three contacts. Effect of lanthanides on D Am is found to be marginal. (orig.)

  15. Synergistic Antipseudomonal Effects of Synthetic Peptide AMP38 and Carbapenems.

    Science.gov (United States)

    Rudilla, Héctor; Fusté, Ester; Cajal, Yolanda; Rabanal, Francesc; Vinuesa, Teresa; Viñas, Miguel

    2016-09-12

    The aim was to explore the antimicrobial activity of a synthetic peptide (AMP38) and its synergy with imipenem against imipenem-resistant Pseudomonas aeruginosa. The main mechanism of imipenem resistance is the loss or alteration of protein OprD. Time-kill and minimal biofilm eradication concentration (MBEC) determinations were carried out by using clinical imipenem-resistant strains. AMP38 was markedly synergistic with imipenem when determined in imipenem-resistant P. aeruginosa. MBEC obtained for the combination of AMP38 and imipenem was of 62.5 μg/mL, whereas the MBEC of each antimicrobial separately was 500 μg/mL. AMP38 should be regarded as a promising antimicrobial to fight MDR P. aeruginosa infections. Moreover, killing effect and antibiofilm activity of AMP38 plus imipenem was much higher than that of colistin plus imipenem.

  16. Synergistic induction of profibrotic PAI-1 by TGF-β and radiation depends on p53

    International Nuclear Information System (INIS)

    Niemantsverdriet, Maarten; Jong, Edwin de; Langendijk, Johannes A.; Kampinga, Harm H.; Coppes, Robert P.

    2010-01-01

    Radiation-induced fibrosis is a severe side effect of radiotherapy. TGF-β and radiation synergistically induce expression of the profibrotic PAI-1 gene and this cooperation potentially involves p53. Here, we demonstrate that p53 is both indispensable and sufficient for the radiation effect inducing synergistic activation of PAI-1 by radiation and TGF-β.

  17. Synergistic extraction of actinides : Part I. Hexa-and pentavalent actinides

    International Nuclear Information System (INIS)

    Patil, S.K.; Ramakrishna, V.V.

    1980-01-01

    A detailed discussion on the reported literature on the synergistic extraction of hexa- and pentavalent actinide ions, by different combinations of extractants and from different aqueous media, is presented. Structural aspects of the various complexes involved in synergism also are reviewed. A short account of the applications based on synergistic extraction is also given. (author)

  18. Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain.

    Directory of Open Access Journals (Sweden)

    Kevin D Broad

    Full Text Available In a range of animal species, exposure of the brain to general anaesthesia without surgery during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex but include an increase in brain cell death. In humans, attempts to link adverse cognitive development to infantile anaesthesia exposure have yielded ambiguous results. One caveat that may influence the interpretation of human studies is that infants are not exposed to general anaesthesia without surgery, raising the possibility that surgery itself, may contribute to adverse cognitive development. Using piglets, we investigated whether a minor surgical procedure increases cell death and disrupts neuro-developmental and cognitively salient gene transcription in the neonatal brain. We randomly assigned neonatal male piglets to a group who received 6h of 2% isoflurane anaesthesia or a group who received an identical anaesthesia plus 15 mins of surgery designed to replicate an inguinal hernia repair. Compared to anesthesia alone, surgery-induced significant increases in cell death in eight areas of the brain. Using RNAseq data derived from all 12 piglets per group we also identified significant changes in the expression of 181 gene transcripts induced by surgery in the cingulate cortex, pathway analysis of these changes suggests that surgery influences the thrombin, aldosterone, axonal guidance, B cell, ERK-5, eNOS and GABAA signalling pathways. This suggests a number of novel mechanisms by which surgery may influence neural and cognitive development independently or synergistically with the effects of anaesthesia.

  19. Chromosomal contact permits transcription between coregulated genes

    CSIR Research Space (South Africa)

    Fanucchi, Stephanie

    2013-10-01

    Full Text Available Transcription of coregulated genes occurs in the context of long-range chromosomal contacts that form multigene complexes. Such contacts and transcription are lost in knockout studies of transcription factors and structural chromatin proteins...

  20. Reconstitution of glucotoxic HIT-T15 cells with somatostatin transcription factor-1 partially restores insulin promoter activity.

    Science.gov (United States)

    Harmon, J S; Tanaka, Y; Olson, L K; Robertson, R P

    1998-06-01

    We have reported that chronic culture of HIT-T15 cells in medium containing supraphysiologic glucose concentrations (11.1 mmol/l) causes a decrease in insulin mRNA levels, insulin content, and insulin release. Furthermore, decreases in insulin gene transcription and binding activity of two essential beta-cell transcription factors, somatostatin transcription factor-1 (STF-1; also known as GSTF, IDX-1, IPF-1, PDX-1, and GSF) and RIPE-3b1 activator, are associated with this glucotoxic effect. In this study, we observed that the loss of RIPE-3b1 occurs much earlier (79% decrease at passage [p]81) than the loss of STF-1 (65% decrease at p104), with abolishment of both factors by p122. Since the STF-1, but not the RIPE-3b1 activator, gene has been cloned, we examined its restorative effects on insulin gene promoter activity after reconstitution with STF-1 cDNA. Basal insulin promoter activities normalized to early (p71-74) passage cells (1.000 +/- 0.069) were 0.4066 +/- 0.093 and 0.142 +/- 0.034 for intermediate (p102-106) and late (p118-122) passage cells, respectively. Early, intermediate, and late passage cells, all chronically cultured in medium containing 11.1 mmol/l glucose, were transfected with STF-1 alone or cotransfected with E2-5, an E-box factor known to be synergistically associated with STF-1. Compared with basal levels, we observed a trend toward an increase in insulin promoter activity in intermediate passage cells with STF-1 transfection (1.43-fold) that became a significant increase when E2-5 was cotransfected (1.78-fold). In late passage cells, transfection of STF-1 alone significantly stimulated a 2.2-fold increase in the insulin promoter activity. Cotransfection of STF-1 and E2-5 in late passage cells stimulated insulin promoter activity 2.8-fold, which was 40% of the activity observed in early passage cells. Control studies in glucotoxic betaTC-6 cells deficient in RIPE-3b1 activator but not STF-1 did not demonstrate an increase in insulin promoter

  1. Transcriptional control of megakaryocyte development.

    Science.gov (United States)

    Goldfarb, A N

    2007-10-15

    Megakaryocytes are highly specialized cells that arise from a bipotent megakaryocytic-erythroid progenitor (MEP). This developmental leap requires coordinated activation of megakaryocyte-specific genes, radical changes in cell cycle properties, and active prevention of erythroid differentiation. These programs result from upregulation of megakaryocyte-selective transcription factors, downregulation of erythroid-selective transcription factors and ongoing mediation of common erythro-megakaryocytic transcription factors. Unlike most developmental programs, no single lineage-unique family of master regulators exerts executive control over the megakaryocytic plan. Rather, an assemblage of non-unique factors and signals converge to determine lineage and differentiation. In human megakaryopoiesis, hereditary disorders of platelet production have confirmed contributions from three distinct transcription factor families. Murine models have extended this repertoire to include multiple additional factors. At a mechanistic level, the means by which these non-unique factors collaborate in the establishment of a perfectly unique cell type remains a central question.

  2. Transcriptional Silencing of Retroviral Vectors

    DEFF Research Database (Denmark)

    Lund, Anders Henrik; Duch, M.; Pedersen, F.S.

    1996-01-01

    Although retroviral vector systems have been found to efficiently transduce a variety of cell types in vitro, the use of vectors based on murine leukemia virus in preclinical models of somatic gene therapy has led to the identification of transcriptional silencing in vivo as an important problem....... Extinction of long-term vector expression has been observed after implantation of transduced hematopoietic cells as well as fibroblasts, myoblasts and hepatocytes. Here we review the influence of vector structure, integration site and cell type on transcriptional silencing. While down-regulation of proviral...... transcription is known from a number of cellular and animal models, major insight has been gained from studies in the germ line and embryonal cells of the mouse. Key elements for the transfer and expression of retroviral vectors, such as the viral transcriptional enhancer and the binding site for the t...

  3. RNA-guided transcriptional regulation

    Science.gov (United States)

    Church, George M.; Mali, Prashant G.; Esvelt, Kevin M.

    2016-02-23

    Methods of modulating expression of a target nucleic acid in a cell are provided including introducing into the cell a first foreign nucleic acid encoding one or more RNAs complementary to DNA, wherein the DNA includes the target nucleic acid, introducing into the cell a second foreign nucleic acid encoding a nuclease-null Cas9 protein that binds to the DNA and is guided by the one or more RNAs, introducing into the cell a third foreign nucleic acid encoding a transcriptional regulator protein or domain, wherein the one or more RNAs, the nuclease-null Cas9 protein, and the transcriptional regulator protein or domain are expressed, wherein the one or more RNAs, the nuclease-null Cas9 protein and the transcriptional regulator protein or domain co-localize to the DNA and wherein the transcriptional regulator protein or domain regulates expression of the target nucleic acid.

  4. Initiation of HIV Reverse Transcription

    OpenAIRE

    Isel, Catherine; Ehresmann, Chantal; Marquet, Roland

    2010-01-01

    Reverse transcription of retroviral genomes into double stranded DNA is a key event for viral replication. The very first stage of HIV reverse transcription, the initiation step, involves viral and cellular partners that are selectively packaged into the viral particle, leading to an RNA/protein complex with very specific structural and functional features, some of which being, in the case of HIV-1, linked to particular isolates. Recent understanding of the tight spatio-temporal regulation of...

  5. Synergistic Sintering of Lignite Fly Ash and Steelmaking Residues towards Sustainable Compacted Ceramics

    Directory of Open Access Journals (Sweden)

    V. G. Karayannis

    2017-01-01

    Full Text Available The development of value-added ceramic materials deriving only from industrial by-products is particularly interesting from technological, economic, and environmental point of views. In this work, the synergistic sintering of ternary and binary mixtures of fly ash, steelmaking electric arc furnace dust, and ladle furnace slag for the synthesis of compacted ceramics is reported. The sintered specimens’ microstructure and mineralogical composition were characterized by SEM-EDS and XRD, respectively. Moreover, the shrinkage, apparent density, water absorption, and Vickers microhardness (HV were investigated at different sintering temperatures and raw material compositions. The characterization of the sintered compacts revealed the successful consolidation of the ceramic microstructures. According to the experimental findings, the ceramics obtained from fly ash/steel dust mixtures exhibited enhanced properties compared to the other mixtures tested. Moreover, the processing temperature affected the final properties of the produced ceramics. Specifically, a 407% HV increase for EAFD and a 2221% increase for the FA-EAFD mixture were recorded, by increasing the sintering temperature from 1050 to 1150°C. Likewise, a 972% shrinkage increase for EAFD and a 577% shrinkage increase for the FA-EAFD mixture were recorded, by increasing the sintering temperature from 1050 to 1150°C. The research results aim at shedding more light on the development of sustainable sintered ceramics from secondary industrial resources towards circular economy.

  6. National Capital Planning Commission Meeting Transcripts

    Data.gov (United States)

    National Capital Planning Commission — Transcripts of the monthly (with the exception of August) National Capital Planning Commission meeting transcripts are provided for research to confirm actions taken...

  7. Transcriptional regulation of mitochondrial HMG-CoA synthase in the control of ketogenesis.

    Science.gov (United States)

    Hegardt, F G

    1998-10-01

    Mitochondrial and cytosolic HMG-CoA synthases are encoded by two different genes. Control of ketogenesis is exerted by transcriptional regulation of mitochondrial HMG-CoA synthase. Fasting, cAMP, and fatty acids increase its transcriptional rate, while refeeding and insulin repress it. Fatty acids increase transcription through peroxisomal proliferator regulatory element (PPRE), to which peroxisome proliferator activated receptor (PPAR) can bind. Other transcription factors such as chicken ovalbumin upstream promoter transcription factor (COUP-TF) and hepatocyte nuclear factor 4 (HNF-4) compete for the PPRE site, modulating the response of PPAR.

  8. Characterization of silver nanoparticles synthesized using Urtica dioica Linn. leaves and their synergistic effects with antibiotics

    Directory of Open Access Journals (Sweden)

    Kumari Jyoti

    2016-07-01

    Full Text Available In continuation of the efforts for synthesizing silver nanoparticles (AgNPs by green chemistry route, here we report a facile bottom-up ‘green’ route for the synthesis of AgNPs using aqueous leaves extract of Urtica dioica (Linn.. The synthesized AgNPs were characterized by UV-vis spectroscopy, X-ray diffraction (XRD, Fourier transform-infrared spectroscopy (FTIR, Zeta-sizer and Zeta-potential, Scanning electron microscopy (SEM, Energy dispersive X-ray (EDX spectroscopy, Transmission electron microscopy (TEM and Selected area electron diffraction (SAED. The results obtained from various characterizations revealed that AgNPs were in the size range of 20–30 nm and crystallized in face-centered-cubic structure. The antibacterial activity against Gram-positive (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus and Staphylococcus epidermidis and Gram-negative (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Salmonella typhimurium bacterial pathogens was demonstrated by synthesized nanoparticles. Further, synergistic effects of AgNPs with various antibiotics were evaluated against above mentioned bacterial pathogens. The results showed that AgNPs in combination with antibiotics have better antibacterial effect as compared with AgNPs alone and hence can be used in the treatment of infectious diseases caused by bacteria. The maximum effect, with a 17.8 fold increase in inhibition zone, was observed for amoxicillin with AgNPs against S. marcescens proving the synergistic role of AgNPs. Therefore, it may be used to augment the activities of antibiotics.

  9. Antimicrobial activity of nisin against the swine pathogen Streptococcus suis and its synergistic interaction with antibiotics.

    Science.gov (United States)

    Lebel, Geneviève; Piché, Fanny; Frenette, Michel; Gottschalk, Marcelo; Grenier, Daniel

    2013-12-01

    Streptococcus suis serotype 2 is known to cause severe infections in pigs, including meningitis, endocarditis and pneumonia. Furthermore, this bacterium is considered an emerging zoonotic agent. Recently, increased antibiotic resistance in S. suis has been reported worldwide. The objective of this study was to evaluate the potential of nisin, a bacteriocin of the lantibiotic class, as an antibacterial agent against the pathogen S. suis serotype 2. In addition, the synergistic activity of nisin in combination with conventional antibiotics was assessed. Using a plate assay, the nisin-producing strain Lactococcus lactis ATCC 11454 proved to be capable of inhibiting the growth of S. suis (n=18) belonging to either sequence type (ST)1, ST25, or ST28. In a microdilution broth assay, the minimum inhibitory concentration (MIC) of purified nisin ranged between 1.25 and 5 μg/mL while the minimum bactericidal concentration (MBC) was between 5 and 10 μg/mL toward S. suis. The use of a capsule-deficient mutant of S. suis indicated that the presence of this polysaccharidic structure has no marked impact on susceptibility to nisin. Following treatment of S. suis with nisin, transmission electron microscopy observations revealed lysis of bacteria resulting from breakdown of the cell membrane. A time-killing curve showed a rapid bactericidal activity of nisin. Lastly, synergistic effects of nisin were observed in combination with several antibiotics, including penicillin, amoxicillin, tetracycline, streptomycin and ceftiofur. This study brought clear evidence supporting the potential of nisin for the prevention and treatment of S. suis infections in pigs. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. ING1 and 5-azacytidine act synergistically to block breast cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Satbir Thakur

    Full Text Available Inhibitor of Growth (ING proteins are epigenetic "readers" that recognize trimethylated lysine 4 of histone H3 (H3K4Me3 and target histone acetyl transferase (HAT and histone deacetylase (HDAC complexes to chromatin.Here we asked whether dysregulating two epigenetic pathways with chemical inhibitors showed synergistic effects on breast cancer cell line killing. We also tested whether ING1 could synergize better with chemotherapeutics that target the same epigenetic mechanism such as the HDAC inhibitor LBH589 (Panobinostat or a different epigenetic mechanism such as 5-azacytidine (5azaC, which inhibits DNA methyl transferases. Simultaneous treatment of breast cancer cell lines with LBH589 and 5azaC did not show significant synergy in killing cells. However, combination treatment of ING1 with either LBH589 or 5azaC did show synergy. The combination of ING1b with 5azaC, which targets two distinct epigenetic mechanisms, was more effective at lower doses and enhanced apoptosis as determined by Annexin V staining and cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP. ING1b plus 5azaC also acted synergistically to increase γH2AX staining indicating significant levels of DNA damage were induced. Adenoviral delivery of ING1b with 5azaC also inhibited cancer cell growth in a murine xenograft model and led to tumor regression when viral concentration was optimized in vivo.These data show that targeting distinct epigenetic pathways can be more effective in blocking cancer cell line growth than targeting the same pathway with multiple agents, and that using viral delivery of epigenetic regulators can be more effective in synergizing with a chemical agent than using two chemotherapeutic agents. This study also indicates that the ING1 epigenetic regulator may have additional activities in the cell when expressed at high levels.

  11. Synergistic radical scavenging potency of curcumin-in-β-cyclodextrin-in-nanomagnetoliposomes

    Energy Technology Data Exchange (ETDEWEB)

    Aadinath, W.; Bhushani, Anu; Anandharamakrishnan, C., E-mail: anandhram@cftri.res.in

    2016-07-01

    Curcumin is a highly potent nutraceutical associated with various health benefits. However, its hydrophobic nature affects its bioavailability and bioactivity, and limits nutraceutical applications. Drug-in-cyclodextrin-in-liposome has the ability to mask the hydrophobic nature of drug and achieve better encapsulation. Also, encapsulating iron oxide nanoparticles (IONPs) within liposomes endow additional beneficial functionalities of IONPs. In the present study, curcumin-β-cyclodextrin inclusion complex (IC) and IONPs were co-encapsulated within liposomes (curcumin-in-β-cyclodextrin-in-nanomagnetoliposomes) to achieve the synergistic antioxidant potential of curcumin and IONPs. IC of curcumin-β-cyclodextrin was prepared by a simple rapid method and successful inclusion was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). Mean diameter of IONPs was found to be 180 nm and X-ray diffraction pattern confirmed the formation of hematite nanoparticles. Band gap energy calculated using absorption spectra was 2.25 eV, which falls in close proximity with the theoretically calculated values of hematite. Mean diameter of curcumin-in-β-cyclodextrin-in-nanomagnetoliposomes was 67 nm and encapsulation efficiency of curcumin was found to be 71%. Further, the co-encapsulated particles possessed significantly low IC{sub 50} value (64.7791 μg/ml, p < 0.01) compared to conventional curcumin liposome and IONPs, indicating its synergistically enhanced radical scavenging property. - Highlights: • Curcumin-in-β-cyclodextrin-in-nanomagnetoliposomes (mean diameter, 67 nm) has been prepared. • Encapsulation efficiency of curcumin was found to be 71%. • IONPs in the nano-carrier play dual role of targeted delivery and radical scavenging activities. • Conjunction of IONPs and curcumin into the liposomes increases the radical scavenging activity.

  12. Radioactive EGFR Antibody Cetuximab in Multimodal Cancer Treatment: Stability and Synergistic Effects With Radiotherapy

    International Nuclear Information System (INIS)

    Rades, Dirk; Wolff, Christian; Nadrowitz, Roger; Breunig, Christian; Schild, Steven E.; Baehre, Manfred; Meller, Birgit

    2009-01-01

    Purpose: Systemic therapies when added to whole brain radiotherapy have failed to improve the survival of patients with multiple brain metastases. The epidermal growth factor receptor antibody cetuximab is an attractive option, if it is able to cross the blood-brain barrier. This might be proven with molecular imaging if the radiolabeled antibody is stable long enough to be effective. This study investigated the stability of radiolabeled cetuximab (Erbitux) ( 131 I-Erbi) and potential synergistic effects with radiotherapy in vitro. Methods and Materials: Two cell lines were investigated, A431 with numerous epidermal growth factor receptors, and JIMT without epidermal growth factor receptors. We labeled 0.4 mg cetuximab with 50 MBq of [ 131 I] iodide. Stability was determined for 72 h. The cell cultures were incubated with 131 I-Erbi or cold cetuximab for 72 h. Uptake and cell proliferation were measured every 24 h after no radiotherapy or irradiation with 2, 4, or 10 Gy. Results: The radiolabeling yield of 131 I-Erbi was always >80%. The radiochemical purity was still 93.6% after 72 h. A431 cells showed a 131 I-Erbi uptake about 100-fold greater than the JIMT controls. After 48 h, the A431 cultures showed significantly decreased proliferation. At 72 h after irradiation, 131 I-Erbi resulted in more pronounced inhibition of cell proliferation than the cold antibody in all radiation dose groups. Conclusion: 131 I-Erbi was stable for ≤72 h. Radiotherapy led to increased tumor cell uptake of 131 I-Erbi. Radiotherapy and 131 I-Erbi synergistically inhibited tumor cell proliferation. These results provide the prerequisite data for a planned in vivo study of whole brain radiotherapy plus cetuximab for brain metastases.

  13. Strong synergistic effects in PLA/PCL blends: Impact of PLA matrix viscosity.

    Science.gov (United States)

    Ostafinska, Aleksandra; Fortelný, Ivan; Hodan, Jiří; Krejčíková, Sabina; Nevoralová, Martina; Kredatusová, Jana; Kruliš, Zdeněk; Kotek, Jiří; Šlouf, Miroslav

    2017-05-01

    Blends of two biodegradable polymers, poly(lactic acid) (PLA) and poly(ϵ-caprolactone) (PCL), with strong synergistic improvement in mechanical performance were prepared by melt-mixing using the optimized composition (80/20) and the optimized preparation procedure (a melt-mixing followed by a compression molding) according to our previous study. Three different PLA polymers were employed, whose viscosity decreased in the following order: PLC ≈ PLA1 > PLA2 > PLA3. The blends with the highest viscosity matrix (PLA1/PCL) exhibited the smallest PCL particles (d∼0.6μm), an elastic-plastic stable fracture (as determined from instrumented impact testing) and the strongest synergistic improvement in toughness (>16× with respect to pure PLA, exceeding even the toughness of pure PCL). According to the available literature, this was the highest toughness improvement in non-compatiblized PLA/PCL blends ever achieved. The decrease in the matrix viscosity resulted in an increase in the average PCL particle size and a dramatic decrease in the overall toughness: the completely stable fracture (for PLA1/PCL) changed to the stable fracture followed by unstable crack propagation (for PLA2/PCL) and finally to the completely brittle fracture (for PLA3/PCL). The stiffness of all blends remained at well acceptable level, slightly above the theoretical predictions based on the equivalent box model. Despite several previous studies, the results confirmed that PLA and PCL could behave as compatible polymers, but the final PLA/PCL toughness is extremely sensitive to the PCL particle size distribution, which is influenced by both processing conditions and PLA viscosity. PLA/PCL blends with high stiffness (due to PLA) and toughness (due to PCL) are very promising materials for medical applications, namely for the bone tissue engineering. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Synergistic capture of Clostridium botulinum Type A neurotoxin by scFv antibodies to novel epitopes

    Energy Technology Data Exchange (ETDEWEB)

    Gray, Sean A.; Barr, John R.; Kalb, Suzanne R.; Marks, James D.; Baird, Cheryl L.; Cangelosi, Gerard A.; Miller, Keith D.; Feldhaus, Michael J.

    2011-10-01

    A non-immune library of human single chain fragment variable (scFv) antibodies displayed on Saccharomyces cerevisiae was screened for binding to the Clostridium botulinum neurotoxin serotype A binding domain [BoNT/A (Hc)] with the goal of identifying scFv to novel epitopes. To do this, an antibody-mediated labeling strategy was used in which antigen-binding yeast clones were selected after labeling with previously characterized monoclonal antibodies (MAbs) specific to the Hc. Twenty unique scFv clones were isolated that bound Hc. Of these, three also bound to full-length BoNT/A toxin complex with affinities ranging from 5 nM to 170 nM. Epitope binning showed that the three unique clones recognized at least two epitopes that were distinct from one another and from the detection MAbs. After production in E. coli, the scFv were coupled to magnetic particles and tested for their ability to capture BoNT/A holotoxin using an Endopep-MS assay. In this assay, toxin captured by scFv coated magnetic particles was detected by incubation of the complex with a peptide containing a BoNT/A-specific cleavage sequence. Mass spectrometry was used to detect the ratio of intact peptide to cleavage products as evidence for toxin capture. When tested individually, each of the scFv showed a weak positive Endopep-MS result. However, when the particles were coated with all three scFv simultaneously, they exhibited significantly higher Endopep-MS activity, consistent with synergistic binding. These results demonstrate novel approaches toward the isolation and characterization of scFv antibodies specific to unlabeled antigen. They also provide evidence that distinct scFv antibodies can work synergistically to increase the efficiency of antigen capture onto a solid support.

  15. Studies on The Synergistic Effect of Some Irradiated Essential Oils in Some Food Products

    International Nuclear Information System (INIS)

    Hanafy, M.A.A.

    2013-01-01

    Cumin, rosemary and thyme essential oils were gamma irradiated. Then, antibacterial and antioxidant activities were studied to measure the synergistic effect of their essential oils mixtures. 4, 6 and 4 kGy were the recommended doses for cumin, rosemary and thyme, respectively according to antimicrobial activity (agar well-diffusion) against S. typhimurium, S. aureus, B. cereus and E. coli. There were no changes in the physiochemical properties due to irradiation but, some changes occurred in the GC/MS analysis where, the amount of oxygenated compounds increased in cumin and thyme essential oils while, the oxygenated compounds decreased in rosemary essential oil. The mixture made from non-irradiated cumin (C 0 ) and rosemary (R 0 ) essential oils were showed the highest antimicrobial activity against E. coil and B. cereus at 50 μl. Mixtures made from non-irradiated cumin and thyme (T 0 ) essential oils showed the highest antimicrobial activity against B. cereus. Mixtures made form irradiated cumin at dose 4 kGy (C 4 ) and rosemary at dose 6 kGy (R 6 ) essential oils introduced promising antimicrobial activity as well as C 0 XR 0 mixture. Fraction inhibitory concentrations (FIC) were studied against selected four bacterial strains for measuring synergistic activity however, (FIC) represented indifference in all essential oils mixtures but, the C 0 X R 0 mixture against B. cereus (0.375) and E. coli (0.375) was synergy (below 0.5). Furthermore, the FIC shows addition in case of R 0 XT 0 , C 2 XR 6 , C 4 XR 6 and R 6 XT 4 against B. cereus. And in case of C 4 XR 6 against S. typhimurium. Preliminary experiment represented that 0.2, 0.4 and 0.1% were the acceptable odor in sunflower oil supplemented with rosemary, cumin and thyme essential oils, respectively.

  16. Synergistic protection against acute flurothyl-induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone.

    Science.gov (United States)

    Simeone, Timothy A; Matthews, Stephanie A; Simeone, Kristina A

    2017-08-01

    We have previously found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) contributes to the mechanism of action of the ketogenic diet (KD), an established treatment for pediatric refractory epilepsy. We have found that the KD increases brain PPARγ and that inhibition or genetic loss of PPARγ prevents the antiseizure effects of the KD on (1) acutely induced seizures in nonepileptic mice and (2) spontaneous recurrent seizures in epileptic mice. Here, we tested the hypothesis that adjuvant treatment of KD-treated mice with a PPARγ agonist, pioglitazone, would result in an additive effect. Acute seizures were induced in three groups of C57Bl/6 mice by inhalation exposure to flurothyl gas. In Group 1, mice were weaned onto either a standard diet or KD comprised of a fat:carbohydrate/protein ratio of either 6:1, 3:1, or 1:1 for 2 weeks. In Group 2, vehicle or pioglitazone (0.1, 1, 10, 80 mg/kg) was administered 4 h prior to flurothyl exposure. In Group 3, vehicle or increasing doses of pioglitazone were administered to KD-treated mice 4 h prior to flurothyl exposure. Latency times to clonic seizures and generalized tonic-clonic (GTC) seizures were recorded, and isobolographic analysis was used to determine combinatorial interactions. Neither KD treatment nor pioglitazone alone or in combination affected clonic seizures. However, the latency to GTC seizures was dose-dependently and significantly increased by both KD (~57%, p < 0.05) and pioglitazone (~28%, p < 0.05). Coadministration of an ineffective 1:1 KD and pioglitazone resulted in ~47-55% (p < 0.05) increase in latency to GTC. Isobolographic analysis indicated a synergistic interaction of the KD and pioglitazone. These results suggest coadministration may enable reduction of the KD ratio without loss of seizure protection. Such adjuvant treatment could improve quality of life and limit adverse effects of a classic KD or high-dose pioglitazone. Wiley Periodicals, Inc

  17. Identifying Natural syNergist from Pongamia pinnata Using High-Speed Counter-Current Chromatography Combined with Isobolographic Analysis

    Directory of Open Access Journals (Sweden)

    Hao Yin

    2017-03-01

    Full Text Available For identifying the synergistic compounds from Pongamia pinnata, an approach based on high-speed counter-current chromatography (HSCCC combined with isobolographic analysis was designed to detect the synergistic effects in the complex mixture [...

  18. Tudor-SN Interacts with Piwi Antagonistically in Regulating Spermatogenesis but Synergistically in Silencing Transposons in Drosophila.

    Science.gov (United States)

    Ku, Hsueh-Yen; Gangaraju, Vamsi K; Qi, Hongying; Liu, Na; Lin, Haifan

    2016-01-01

    Piwi proteins associate with piRNAs and functions in epigenetic programming, post-transcriptional regulation, transposon silencing, and germline development. However, it is not known whether the diverse functions of these proteins are molecularly separable. Here we report that Piwi interacts with Tudor-SN (Tudor staphylococcal nuclease, TSN) antagonistically in regulating spermatogenesis but synergistically in silencing transposons. However, it is not required for piRNA biogenesis. TSN is known to participate in diverse molecular functions such as RNAi, degradation of hyper-edited miRNAs, and spliceosome assembly. We show that TSN colocalizes with Piwi in primordial germ cells (PGCs) and embryonic somatic cells. In adult ovaries and testes, TSN is ubiquitously expressed and enriched in the cytoplasm of both germline and somatic cells. The tsn mutants display a higher mitotic index of spermatogonia, accumulation of spermatocytes, defects in meiotic cytokinesis, a decreased number of spermatids, and eventually reduced male fertility. Germline-specific TSN-expression analysis demonstrates that this function is germline-dependent. Different from other known Piwi interters, TSN represses Piwi expression at both protein and mRNA levels. Furthermore, reducing piwi expression in the germline rescues tsn mutant phenotype in a dosage-dependent manner, demonstrating that Piwi and TSN interact antagonistically in germ cells to regulate spermatogenesis. However, the tsn deficiency has little, if any, impact on piRNA biogenesis but displays a synergistic effect with piwi mutants in transposon de-silencing. Our results reveal the biological function of TSN and its contrasting modes of interaction with Piwi in spermatogenesis, transposon silencing, and piRNA biogenesis.

  19. Tudor-SN Interacts with Piwi Antagonistically in Regulating Spermatogenesis but Synergistically in Silencing Transposons in Drosophila.

    Directory of Open Access Journals (Sweden)

    Hsueh-Yen Ku

    2016-01-01

    Full Text Available Piwi proteins associate with piRNAs and functions in epigenetic programming, post-transcriptional regulation, transposon silencing, and germline development. However, it is not known whether the diverse functions of these proteins are molecularly separable. Here we report that Piwi interacts with Tudor-SN (Tudor staphylococcal nuclease, TSN antagonistically in regulating spermatogenesis but synergistically in silencing transposons. However, it is not required for piRNA biogenesis. TSN is known to participate in diverse molecular functions such as RNAi, degradation of hyper-edited miRNAs, and spliceosome assembly. We show that TSN colocalizes with Piwi in primordial germ cells (PGCs and embryonic somatic cells. In adult ovaries and testes, TSN is ubiquitously expressed and enriched in the cytoplasm of both germline and somatic cells. The tsn mutants display a higher mitotic index of spermatogonia, accumulation of spermatocytes, defects in meiotic cytokinesis, a decreased number of spermatids, and eventually reduced male fertility. Germline-specific TSN-expression analysis demonstrates that this function is germline-dependent. Different from other known Piwi interters, TSN represses Piwi expression at both protein and mRNA levels. Furthermore, reducing piwi expression in the germline rescues tsn mutant phenotype in a dosage-dependent manner, demonstrating that Piwi and TSN interact antagonistically in germ cells to regulate spermatogenesis. However, the tsn deficiency has little, if any, impact on piRNA biogenesis but displays a synergistic effect with piwi mutants in transposon de-silencing. Our results reveal the biological function of TSN and its contrasting modes of interaction with Piwi in spermatogenesis, transposon silencing, and piRNA biogenesis.

  20. Computational Investigations of Post-Transcriptional Regulation

    DEFF Research Database (Denmark)

    Rasmussen, Simon Horskjær

    and miRNA regulation was studied by cross-linking immunoprecipitation (CLIP) and RBP double knockdown experiments. A comprehensive analysis of 107 CLIP datasets of 49 RBPs demonstrated that RBPs modulate miRNA regulation. Results suggest it is mediated by RBP-binding hotspots that likely...... investigated using high-throughput data. Analysis of IMP RIP-seq, iCLIP and RNA-seq datasets identified transcripts associated with cytoplasmic IMP ribonucleoproteins. Many of these transcripts were functionally involved in actin cytoskeletal remodeling. Further analyses of this data permitted estimation...... of a bipartite motif, composed of an AU-rich and a CA-rich domain. In addition, a regulatory motif discovery method was developed and applied to identify motifs using differential expression data and CLIP-data in the above investigations. This thesis increased the understanding of the role of RBPs in mi...

  1. Transcriptional Regulation of Emergency Granulopoiesis in Leukemia

    Directory of Open Access Journals (Sweden)

    Shirin Hasan

    2018-03-01

    Full Text Available Neutropenic conditions are prevalent in leukemia patients and are often associated with increased susceptibility to infections. In fact, emergency granulopoiesis (EG, a process regulating neutrophil homeostasis in inflammatory conditions and infections, may occur improperly in leukemic conditions, leading to reduced neutrophil counts. Unfortunately, the mechanisms central to dysfunctional EG remain understudied in both leukemia patients and leukemic mouse models. However, despite no direct studies on EG response in leukemia are reported, recently certain transcription factors (TFs have been found to function at the crossroads of leukemia and EG. In this review, we present an update on TFs that can potentially govern the fate of EG in leukemia. Transcriptional control of Fanconi DNA repair pathway genes is also highlighted, as well as the newly discovered role of Fanconi proteins in innate immune response and EG. Identifying the TFs regulating EG in leukemia and dissecting their underlying mechanisms may facilitate the discovery of therapeutic drugs for the treatment of neutropenia.

  2. Transcriptional repressor DREAM regulates trigeminal noxious perception.

    Science.gov (United States)

    Benedet, Tomaso; Gonzalez, Paz; Oliveros, Juan C; Dopazo, Jose M; Ghimire, Kedar; Palczewska, Malgorzata; Mellstrom, Britt; Naranjo, Jose R

    2017-05-01

    Expression of the downstream regulatory element antagonist modulator (DREAM) protein in dorsal root ganglia and spinal cord is related to endogenous control mechanisms of acute and chronic pain. In primary sensory trigeminal neurons, high levels of endogenous DREAM protein are preferentially localized in the nucleus, suggesting a major transcriptional role. Here, we show that transgenic mice expressing a dominant active mutant of DREAM in trigeminal neurons show increased responses following orofacial sensory stimulation, which correlates with a decreased expression of prodynorphin and brain-derived neurotrophic factor in trigeminal ganglia. Genome-wide analysis of trigeminal neurons in daDREAM transgenic mice identified cathepsin L and the monoglyceride lipase as two new DREAM transcriptional targets related to pain. Our results suggest a role for DREAM in the regulation of trigeminal nociception. This article is part of the special article series "Pain". © 2016 International Society for Neurochemistry.

  3. Lysine-specific demethylase 1 (LSD1 Is required for the transcriptional repression of the telomerase reverse transcriptase (hTERT gene.

    Directory of Open Access Journals (Sweden)

    Qingjun Zhu

    Full Text Available BACKGROUND: Lysine-specific demethylase 1 (LSD1, catalysing demethylation of mono- and di-methylated histone H3-K4 or K9, exhibits diverse transcriptional activities by mediating chromatin reconfiguration. The telomerase reverse transcriptase (hTERT gene, encoding an essential component for telomerase activity that is involved in cellular immortalization and transformation, is silent in most normal human cells while activated in up to 90% of human cancers. It remains to be defined how exactly the transcriptional activation of the hTERT gene occurs during the oncogenic process. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we determined the effect of LSD1 on hTERT transcription. In normal human fibroblasts with a tight hTERT repression, a pharmacological inhibition of LSD1 led to a weak hTERT expression, and a robust induction of hTERT mRNA was observed when LSD1 and histone deacetylases (HDACs were both inhibited. Small interference RNA-mediated depletion of both LSD1 and CoREST, a co-repressor in HDAC-containing complexes, synergistically activated hTERT transcription. In cancer cells, inhibition of LSD1 activity or knocking-down of its expression led to significant increases in levels of hTERT mRNA and telomerase activity. Chromatin immunoprecipitation assay showed that LSD1 occupied the hTERT proximal promoter, and its depletion resulted in elevated di-methylation of histone H3-K4 accompanied by increased H3 acetylation locally in cancer cells. Moreover, during the differentiation of leukemic HL60 cells, the decreased hTERT expression was accompanied by the LSD1 recruitment to the hTERT promoter. CONCLUSIONS/SIGNIFICANCE: LSD1 represses hTERT transcription via demethylating H3-K4 in normal and cancerous cells, and together with HDACs, participates in the establishment of a stable repression state of the hTERT gene in normal or differentiated malignant cells. The findings contribute to better understandings of h

  4. Diospyros lotus leaf and grapefruit stem extract synergistically ameliorate atopic dermatitis-like skin lesion in mice by suppressing infiltration of mast cells in skin lesions.

    Science.gov (United States)

    Cho, Byoung Ok; Che, Denis Nchang; Yin, Hong Hua; Shin, Jae Young; Jang, Seon Il

    2017-05-01

    Atopic dermatitis, a chronic relapsing and pruritic inflammation of the skin also thought to be involved in, or caused by immune system destruction is an upsetting health problem due to its continuously increasing incidence especially in developed countries. Mast cell infiltration in atopic dermatitis skin lesions and its IgE-mediated activation releases various cytokines and chemokines that have been implicated in the pathogenesis of atopic dermatitis. This study was aimed at investigating synergistic anti-inflammatory, anti-pruritic and anti-atopic dermatitis effects of Diospyros lotus leaf extract (DLE) and Muscat bailey A grapefruit stem extract (GFSE) in atopic dermatitis-like induced skin lesions in mice. Combinations of DLE and GFSE inhibited TNF-α and IL-6 production more than DLE or GFSE in PMA plus calcium ionophore A23187-activated HMC-1 cells. DLE and GFSE synergistically inhibited compound 48/80-induced dermal infiltration of mast cells and reduced scratching behavior than DLE or GFSE. Furthermore, DLE and GFSE synergistically showed a stronger ameliorative effect in skin lesions by reducing clinical scores; dermal infiltration of mast cells; ear and dorsal skin thickness; serum IgE and IL-4 production in atopic dermatitis-like mice. Collectively, these results suggest that DLE and GFSE synergistically exhibit anti-atopic dermatitis effects in atopic dermatitis-like skin lesions in mice. Copyright © 2017. Published by Elsevier Masson SAS.

  5. Targeted HIV-1 Latency Reversal Using CRISPR/Cas9-Derived Transcriptional Activator Systems.

    Directory of Open Access Journals (Sweden)

    Julia K Bialek

    Full Text Available CRISPR/Cas9 technology is currently considered the most advanced tool for targeted genome engineering. Its sequence-dependent specificity has been explored for locus-directed transcriptional modulation. Such modulation, in particular transcriptional activation, has been proposed as key approach to overcome silencing of dormant HIV provirus in latently infected cellular reservoirs. Currently available agents for provirus activation, so-called latency reversing agents (LRAs, act indirectly through cellular pathways to induce viral transcription. However, their clinical performance remains suboptimal, possibly because reservoirs have diverse cellular identities and/or proviral DNA is intractable to the induced pathways. We have explored two CRISPR/Cas9-derived activator systems as targeted approaches to induce dormant HIV-1 proviral DNA. These systems recruit multiple transcriptional activation domains to the HIV 5' long terminal repeat (LTR, for which we have identified an optimal target region within the LTR U3 sequence. Using this target region, we demonstrate transcriptional activation of proviral genomes via the synergistic activation mediator complex in various in culture model systems for HIV latency. Observed levels of induction are comparable or indeed higher than treatment with established LRAs. Importantly, activation is complete, leading to production of infective viral particles. Our data demonstrate that CRISPR/Cas9-derived technologies can be applied to counteract HIV latency and may therefore represent promising novel approaches in the quest for HIV elimination.

  6. Synergistic effects of non-Apis bees and honey bees for pollination services

    Science.gov (United States)

    Brittain, Claire; Williams, Neal; Kremen, Claire; Klein, Alexandra-Maria

    2013-01-01

    In diverse pollinator communities, interspecific interactions may modify the behaviour and increase the pollination effectiveness of individual species. Because agricultural production reliant on pollination is growing, improving pollination effectiveness could increase crop yield without any increase in agricultural intensity or area. In California almond, a crop highly dependent on honey bee pollination, we explored the foraging behaviour and pollination effectiveness of honey bees in orchards with simple (honey bee only) and diverse (non-Apis bees present) bee communities. In orchards with non-Apis bees, the foraging behaviour of honey bees changed and the pollination effectiveness of a single honey bee visit was greater than in orchards where non-Apis bees were absent. This change translated to a greater proportion of fruit set in these orchards. Our field experiments show that increased pollinator diversity can synergistically increase pollination service, through species interactions that alter the behaviour and resulting functional quality of a dominant pollinator species. These results of functional synergy between species were supported by an additional controlled cage experiment with Osmia lignaria and Apis mellifera. Our findings highlight a largely unexplored facilitative component of the benefit of biodiversity to ecosystem services, and represent a way to improve pollinator-dependent crop yields in a sustainable manner. PMID:23303545

  7. How synergistic or antagonistic effects may influence the mutual hazard ranking of chemicals

    Directory of Open Access Journals (Sweden)

    Lars Carlsen

    2015-04-01

    Full Text Available The presence of various agents, including humic materials, nanomaterials, microplastics, or simply specific chemical compounds, may cause changes in the apparent persistence, bioaccumulation, and/or toxicity (PBT of a chemical compound leading to an either increased or decreased PBT characteristics and thus an increased or decreased hazard evaluation. In the present paper, a series chloro-containing obsolete pesticides is studied as an illustrative example. Partial order methodology is used to quantify how changed P, B, or T characteristics of methoxychlor (MEC influences the measure of the hazard of MEC, relative to the other 11 compounds in the series investigated. Not surprisingly, an increase in one of the three indicators (P, B, or T lead to an increased average order and thus an increased relative hazard as a result of a synergistic effect. A decrease in one of the indicator values analogously causes a decreased average order/relative hazard through an antagonistic effect; the effect, however, being less pronounced. It is further seen that the effect of changing the apparent value of the three indicators is different. Thus, persistence apparently is more important that bioaccumulation which again appears more important than toxicity, which is in agreement with previous work. The results are discussed with reference to the European chemicals framework on registration, evaluation and authorization of chemicals (REACH framework.

  8. Synergistic effects of non-Apis bees and honey bees for pollination services.

    Science.gov (United States)

    Brittain, Claire; Williams, Neal; Kremen, Claire; Klein, Alexandra-Maria

    2013-03-07

    In diverse pollinator communities, interspecific interactions may modify the behaviour and increase the pollination effectiveness of individual species. Because agricultural production reliant on pollination is growing, improving pollination effectiveness could increase crop yield without any increase in agricultural intensity or area. In California almond, a crop highly dependent on honey bee pollination, we explored the foraging behaviour and pollination effectiveness of honey bees in orchards with simple (honey bee only) and diverse (non-Apis bees present) bee communities. In orchards with non-Apis bees, the foraging behaviour of honey bees changed and the pollination effectiveness of a single honey bee visit was greater than in orchards where non-Apis bees were absent. This change translated to a greater proportion of fruit set in these orchards. Our field experiments show that increased pollinator diversity can synergistically increase pollination service, through species interactions that alter the behaviour and resulting functional quality of a dominant pollinator species. These results of functional synergy between species were supported by an additional controlled cage experiment with Osmia lignaria and Apis mellifera. Our findings highlight a largely unexplored facilitative component of the benefit of biodiversity to ecosystem services, and represent a way to improve pollinator-dependent crop yields in a sustainable manner.

  9. The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma

    International Nuclear Information System (INIS)

    Tagde, A; Singh, H; Kang, M H; Reynolds, C P

    2014-01-01

    Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM

  10. Maize Iranian mosaic virus shows a descending transcript accumulation order in plant and insect hosts.

    Science.gov (United States)

    Hortamani, Mozhgan; Massah, Amir; Izadpanah, Keramat

    2018-04-01

    Maize Iranian mosaic virus (MIMV) is a distinct member of the genus Nucleorhabdovirus. In this study, expression of all MIMV genes in maize for four weeks after inoculation and in inoculative planthoppers was examined using a quantitative RT-PCR (RT-qPCR) assay. Accumulation of MIMV P, gene 3, M, G and L transcripts relative to N transcripts was measured and normalized to 18S rRNA in maize plants and to the ribosomal protein S13 gene (RPS13) in planthoppers using the comparative C T method. In plants, higher levels of MIMV N transcripts were found relative to other transcripts, while MIMV L transcripts were at the lowest levels. The highest accumulation of MIMV transcripts was found at 14 days postinoculation (dpi). At 21 dpi, we found the lowest transcript levels for all genes, which increased again at 28 dpi, although in lower amounts than at 14 dpi. In Laodelphax striatellus, MIMV M, G and L transcripts accumulated at lower levels than other transcripts. The gene 3 transcript level was high in both plants and planthoppers. Our results showed that transcript accumulation for the MIMV genes was similar in both hosts and followed the pattern of sequential transcriptional attenuation from the 3' to the 5' end of the genome, similar to vertebrate rhabdoviruses. These results indicate that the regulation of virus gene transcription for this plant-infecting rhabdovirus is similar to that of some vertebrate-infecting rhabdoviruses.

  11. Negative elongation factor NELF controls transcription of immediate early genes in a stimulus-specific manner

    International Nuclear Information System (INIS)

    Fujita, Toshitsugu; Piuz, Isabelle; Schlegel, Werner

    2009-01-01

    The transcription rate of immediate early genes (IEGs) is controlled directly by transcription elongation factors at the transcription elongation step. Negative elongation factor (NELF) and 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) sensitivity-inducing factor (DSIF) stall RNA polymerase II (pol II) soon after transcription initiation. Upon induction of IEG transcription, DSIF is converted into an accelerator for pol II elongation. To address whether and how NELF as well as DSIF controls overall IEG transcription, its expression was reduced using stable RNA interference in GH4C1 cells. NELF knock-down reduced thyrotropin-releasing hormone (TRH)-induced transcription of the IEGs c-fos, MKP-1, and junB. In contrast, epidermal growth factor (EGF)-induced transcription of these IEGs was unaltered or even slightly increased by NELF knock-down. Thus, stable knock-down of NELF affects IEG transcription stimulation-specifically. Conversely, DSIF knock-down reduced both TRH- and EGF-induced transcription of the three IEGs. Interestingly, TRH-induced activation of the MAP kinase pathway, a pathway essential for transcription of the three IEGs, was down-regulated by NELF knock-down. Thus, stable knock-down of NELF, by modulating intracellular signaling pathways, caused stimulation-specific loss of IEG transcription. These observations indicate that NELF controls overall IEG transcription via multiple mechanisms both directly and indirectly

  12. Synergistic effects of total ionizing dose on single event upset sensitivity in static random access memory under proton irradiation

    International Nuclear Information System (INIS)

    Xiao Yao; Guo Hong-Xia; Zhang Feng-Qi; Zhao Wen; Wang Yan-Ping; Zhang Ke-Ying; Ding Li-Li; Luo Yin-Hong; Wang Yuan-Ming; Fan Xue

    2014-01-01

    Synergistic effects of the total ionizing dose (TID) on the single event upset (SEU) sensitivity in static random access memories (SRAMs) were studied by using protons. The total dose was cumulated with high flux protons during the TID exposure, and the SEU cross section was tested with low flux protons at several cumulated dose steps. Because of the radiation-induced off-state leaka