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Sample records for topoisomerase ib small

  1. 2-Alkynoic fatty acids inhibit topoisomerase IB from Leishmania donovani.

    Science.gov (United States)

    Carballeira, Néstor M; Cartagena, Michelle; Sanabria, David; Tasdemir, Deniz; Prada, Christopher F; Reguera, Rosa M; Balaña-Fouce, Rafael

    2012-10-01

    2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2-HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC(50)=5.3±0.7μM. The potency of LdTopIB inhibition follows the trend 2-ODA>2-HDA>2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC(50)=11.0μM), but it was less effective against other protozoa, Trypanosoma cruzi (IC(50)=48.1μM) and Trypanosoma brucei rhodesiense (IC(50)=64.5μM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA>2-HDA>2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Topoisomerase IB of Deinococcus radiodurans resolves guanine ...

    Indian Academy of Sciences (India)

    2015-11-28

    Nov 28, 2015 ... All the oligonucleotides men- tioned here were ... further reactions with DraTopoIB were carried out at 37°C ... of G4 DNA moves faster than unfolded and intermolecular .... for its action on intramolecular G4 DNA structure was.

  3. topIb, a phylogenetic hallmark gene of Thaumarchaeota encodes a functional eukaryote-like topoisomerase IB.

    Science.gov (United States)

    Dahmane, Narimane; Gadelle, Danièle; Delmas, Stéphane; Criscuolo, Alexis; Eberhard, Stephan; Desnoues, Nicole; Collin, Sylvie; Zhang, Hongliang; Pommier, Yves; Forterre, Patrick; Sezonov, Guennadi

    2016-04-07

    Type IB DNA topoisomerases can eliminate torsional stresses produced during replication and transcription. These enzymes are found in all eukaryotes and a short version is present in some bacteria and viruses. Among prokaryotes, the long eukaryotic version is only observed in archaea of the phylum Thaumarchaeota. However, the activities and the roles of these topoisomerases have remained an open question. Here, we demonstrate that all available thaumarchaeal genomes contain a topoisomerase IB gene that defines a monophyletic group closely related to the eukaryotic enzymes. We show that the topIB gene is expressed in the model thaumarchaeon Nitrososphaera viennensis and we purified the recombinant enzyme from the uncultivated thaumarchaeon Candidatus Caldiarchaeum subterraneum. This enzyme is active in vitro at high temperature, making it the first thermophilic topoisomerase IB characterized so far. We have compared this archaeal type IB enzyme to its human mitochondrial and nuclear counterparts. The archaeal enzyme relaxes both negatively and positively supercoiled DNA like the eukaryotic enzymes. However, its pattern of DNA cleavage specificity is different and it is resistant to camptothecins (CPTs) and non-CPT Top1 inhibitors, LMP744 and lamellarin D. This newly described thermostable topoisomerases IB should be a promising new model for evolutionary, mechanistic and structural studies. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. A natural anticancer agent thaspine targets human topoisomerase IB.

    Science.gov (United States)

    Castelli, Silvia; Katkar, Prafulla; Vassallo, Oscar; Falconi, Mattia; Linder, Stig; Desideri, Alessandro

    2013-02-01

    The different steps of the topoisomerase I catalytic cycle have been analyzed in the presence of the plant alkaloid thaspine (1- (2-(Dimethylamino)ethyl)-3,8-dimethoxychromeno[5,4,3-cde]chromene-5,10-dione), known to induce apoptosis in colon carcinoma cells. The experiments indicate that thaspine inhibits both the cleavage and the religation steps of the enzyme reaction. The inhibition is reversible and the effect is enhanced upon pre-incubation. Molecular docking simulations of thaspine over topoisomerase I, in the presence or absence of the DNA substrate, show that thaspine, when interacting with the enzyme alone in the closed or in the open state, can bind in proximity of the active residues preventing the cleavage reaction, whilst when docked with the enzyme-DNA cleavable complex intercalates between the DNA bases in a way similar to that found for camptothecin, explaining its religation inhibition. These results unequivocally demonstrate that thaspine targets human topoisomerase I .

  5. Functional Expression of a DNA-Topoisomerase IB from Cryptosporidium parvum

    Directory of Open Access Journals (Sweden)

    César Ordóñez

    2009-01-01

    Full Text Available Cryptosporidium parvum, one of the most important causative organisms of human diarrheas during childhood, contains a monomeric DNA-topoisomerase IB (CpTopIB in chromosome 7. Heterologous expression of CpTopIB gene in a budding yeast strain lacking this activity proves that the cryptosporidial enzyme is functional in vivo. The enzymatic activity is comprised in a single polypeptide, which contains all the structural features defining a fully active TopIB. Relaxation activity of the yeast extracts was detected only when CpTopIB ORF was expressed in a yeast expression system showing time and protein dependence under steady state kinetic conditions. The susceptibility of CpTopIB-transformed yeast to the irreversible inhibitor camptothecin and its water-soluble derivatives (topotecan and SN-38 was assessed.

  6. The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice

    OpenAIRE

    Chowdhury, Sayan; Mukherjee, Tulika; Mukhopadhyay, Rupkatha; Mukherjee, Budhaditya; Sengupta, Souvik; Chattopadhyay, Sharmila; Jaisankar, Parasuraman; Roy, Syamal; Majumder, Hemanta K

    2012-01-01

    Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA–protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topois...

  7. Unraveling the structure of the variola topoisomerase IB-DNA complex: a possible new twist on smallpox therapy.

    Science.gov (United States)

    Osheroff, Neil

    2006-10-01

    Smallpox is a serious and highly contagious disease that is caused by the variola virus. It is one of the most severe infectious human diseases known, with mortality rates as high as 30%. A successful worldwide vaccination program led to the eradication of smallpox in 1980. However, the high transmission rate of variola virus, coupled with the deadly nature of smallpox, makes this virus a potentially devastating weapon for bioterrorism. Currently, there is no specific treatment for smallpox. However, a recent article on the structure of a variola topoisomerase IB-DNA complex provides an intriguing starting point for the rational design of drugs with potential activity against smallpox.

  8. The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice

    Science.gov (United States)

    Chowdhury, Sayan; Mukherjee, Tulika; Mukhopadhyay, Rupkatha; Mukherjee, Budhaditya; Sengupta, Souvik; Chattopadhyay, Sharmila; Jaisankar, Parasuraman; Roy, Syamal; Majumder, Hemanta K

    2012-01-01

    Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA–protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA–protein binary complexes and thus stabilizes the ‘cleavable complex’ formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis. PMID:23027614

  9. Transcription profiling suggests that mitochondrial topoisomerase IB acts as a topological barrier and regulator of mitochondrial DNA transcription.

    Science.gov (United States)

    Dalla Rosa, Ilaria; Zhang, Hongliang; Khiati, Salim; Wu, Xiaolin; Pommier, Yves

    2017-12-08

    Mitochondrial DNA (mtDNA) is essential for cell viability because it encodes subunits of the respiratory chain complexes. Mitochondrial topoisomerase IB (TOP1MT) facilitates mtDNA replication by removing DNA topological tensions produced during mtDNA transcription, but it appears to be dispensable. To test whether cells lacking TOP1MT have aberrant mtDNA transcription, we performed mitochondrial transcriptome profiling. To that end, we designed and implemented a customized tiling array, which enabled genome-wide, strand-specific, and simultaneous detection of all mitochondrial transcripts. Our technique revealed that Top1mt KO mouse cells process the mitochondrial transcripts normally but that protein-coding mitochondrial transcripts are elevated. Moreover, we found discrete long noncoding RNAs produced by H-strand transcription and encompassing the noncoding regulatory region of mtDNA in human and murine cells and tissues. Of note, these noncoding RNAs were strongly up-regulated in the absence of TOP1MT. In contrast, 7S DNA, produced by mtDNA replication, was reduced in the Top1mt KO cells. We propose that the long noncoding RNA species in the D-loop region are generated by the extension of H-strand transcripts beyond their canonical stop site and that TOP1MT acts as a topological barrier and regulator for mtDNA transcription and D-loop formation.

  10. Single-molecule supercoil-relaxation assay as a screening tool to determine the mechanism and efficacy of human topoisomerase IB inhibitors

    Science.gov (United States)

    Seol, Yeonee; Zhang, Hongliang; Agama, Keli; Lorence, Nicholas; Pommier, Yves; Neuman, Keir C.

    2015-01-01

    Human nuclear type IB topoisomerase (Top1) inhibitors are widely used and powerful anti-cancer agents. In this study, we introduce and validate a single-molecule supercoil relaxation assay as a molecular pharmacology tool for characterizing therapeutically relevant Top1 inhibitors. Using this assay, we determined the effects on Top1 supercoil relaxation activity of four Top1 inhibitors; three clinically relevant: camptothecin, LMP-400, LMP-776 (both indenoisoquinoline derivatives), and one natural product in preclinical development, lamellarin-D. Our results demonstrate that Top1 inhibitors have two distinct effects on Top1 activity: a decrease in supercoil relaxation rate and an increase in religation inhibition. The type and magnitude of the inhibition mode depend both on the specific inhibitor and on the topology of the DNA substrate. In general, the efficacy of inhibition is significantly higher with supercoiled than with relaxed DNA substrates. Comparing single-molecule inhibition with cell growth inhibition (IC50) measurements showed a correlation between the binding time of the Top1 inhibitors and their cytotoxic efficacy, independent of the mode of inhibition. This study demonstrates that the single-molecule supercoil relaxation assay is a sensitive method to elucidate the detailed mechanisms of Top1 inhibitors and is relevant for the cellular efficacy of Top1 inhibitors. PMID:26351326

  11. Ru/Fe bimetallic complexes: Synthesis, characterization, cytotoxicity and study of their interactions with DNA/HSA and human topoisomerase IB.

    Science.gov (United States)

    Takarada, Jessica E; Guedes, Adriana P M; Correa, Rodrigo S; Silveira-Lacerda, Elisângela de P; Castelli, Silvia; Iacovelli, Federico; Deflon, Victor Marcelo; Batista, Alzir Azevedo; Desideri, Alessandro

    2017-12-15

    Three ruthenium/iron-based compounds, 1: [Ru(MIm)(bipy)(dppf)]PF 6 (MIm = 2-mercapto-1-methylimidazole anion), 2: [RuCl(Im)(bipy)(dppf)]PF 6 (Im = imidazole), and 3: [Ru(tzdt)(bipy)(dppf)]PF 6 (tzdt = 1,3-thiazolidine-2-thione anion) (dppf = 1,1'-bis(diphenylphosphine)ferrocene and bipy = 2,2'-bipyridine), were synthesized, and characterized by elemental analyses, conductivity, UV/Vis, IR, 1 H, 13 C and 31 P{1H} NMR spectroscopies, and by electrochemical technique. The complex 3 was also characterized by single-crystal X-ray. The three ruthenium(II) complexes show cytotoxicity against DU-145 (prostate carcinoma cells) and A549 (lung carcinoma cells) tumor cells. The free ligands do not exhibit any cytotoxic activity, such as evident by the IC 50 values higher than 200 μM. UV/Vis and viscosity experiments showed that the complexes interact weakly with the DNA molecule, via electrostatic forces. The interaction of the complexes 1-3 with the HSA is moderate, with K b values in range of 10 5 -10 7  M -1 , presenting a static mechanism of interaction stabilized by hydrophobic. Complexes 2 and 3 showed high affinity for the FA7 HSA site as evidenced by fluorescence spectroscopy and molecular docking. Complexes 1-3 were tested as potential human Topoisomerase IB inhibitors by analysing the different steps of the enzyme catalytic cycle. The results indicate that all compounds efficiently inhibit the DNA relaxation and the cleavage reaction, in which the effect increases upon pre-incubation. Complexes 1 and 2 are also able to slow down the religation reaction. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Insights from the structure of a smallpox virus topoisomerase-DNA transition state mimic

    Science.gov (United States)

    Perry, Kay; Hwang, Young; Bushman, Frederic D.; Van Duyne, Gregory D.

    2010-01-01

    Summary Poxviruses encode their own type IB topoisomerases (TopIBs) which release superhelical tension generated by replication and transcription of their genomes. To investigate the reaction catalyzed viral TopIBs, we have determined the structure of a variola virus topoisomerase-DNA complex trapped as a vanadate transition state mimic. The structure reveals how the viral TopIB enzymes are likely to position the DNA duplex for ligation following relaxation of supercoils and identifies the sources of friction observed in single molecule experiments that argue against free rotation. The structure also identifies a conformational change in the leaving group sugar that must occur prior to cleavage and reveals a mechanism for promoting ligation following relaxation of supercoils that involves a novel Asp-minor groove interaction. Overall, the new structural data support a common catalytic mechanism for the TopIB superfamily but indicate distinct methods for controlling duplex rotation in the small vs. large enzyme subfamilies. PMID:20152159

  13. Expressions of topoisomerase IIα and BCRP in metastatic cells are associated with overall survival in small cell lung cancer patients.

    Science.gov (United States)

    Rijavec, Matija; Silar, Mira; Triller, Nadja; Kern, Izidor; Cegovnik, Urška; Košnik, Mitja; Korošec, Peter

    2011-09-01

    The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-naïve metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. Metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIα (TOPIIα)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIα in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIα and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIα in chemo-naïve metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIα and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.

  14. Correlation between topoisomerase I and tyrosyl-DNA phosphodiesterase 1 activities in non-small cell lung cancer tissue

    DEFF Research Database (Denmark)

    Jakobsen, Ann-Katrine; Lauridsen, Kristina Lystlund; Samuel, Evelyn Benuja

    2015-01-01

    Topoisomerase I (TOP1) regulates DNA topology during replication and transcription whereas tyrosyl-DNA phosphodiesterase 1 (TDP1) is involved in the repair of several types of DNA damages, including damages from defective TOP1 catalysis. TOP1 is the target of chemotherapeutic drugs of the camptot......Topoisomerase I (TOP1) regulates DNA topology during replication and transcription whereas tyrosyl-DNA phosphodiesterase 1 (TDP1) is involved in the repair of several types of DNA damages, including damages from defective TOP1 catalysis. TOP1 is the target of chemotherapeutic drugs...... of the camptothecin family (CPT). TDP1 has in cell line based assays been shown to counteract the effect of CPT. We have quantified the enzymatic activities of TOP1 and TDP1 in paired (tumor and adjacent non-tumor) samples from non-small cell lung cancer (NSCLC) patients and show that in NSCLC TOP1 and TDP1...... activities are significantly upregulated in the tumor tissue. Furthermore, we found a positive correlation between the TDP1 activity and the tumor percentage (TOP1 activity did not correlate with the tumor percentage) as well as between the activities of TOP1 and TDP1 both within the tumor and the non...

  15. Post-Infectious IBS (IBS-PI)

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  16. Medications (for IBS)

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  19. Medications (for IBS)

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  1. Medications (for IBS)

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  2. Medications (for IBS)

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  3. Identification of a minimal functional linker in human topoisomerase I by domain swapping with Cre recombinase

    DEFF Research Database (Denmark)

    Hougaard, Rikke Frøhlich; Juul, Sissel; Vinther, Maria

    2008-01-01

    . In this study we replace 86 amino acids including the linker domain of the cellular type IB topoisomerase, human topoisomerase I, with four, six, or eight amino acids from the corresponding short loop region in Cre recombinase. In vitro characterization of the resulting chimeras, denoted Cropos, reveals...

  4. Medications (for IBS)

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  11. IBS Diet

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  13. Introduction to IBS

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  16. Fractionated irradiation of H69 small-cell lung cancer cells causes stable radiation and drug resistance with increased MRP1, MRP2, and topoisomerase IIα expression

    International Nuclear Information System (INIS)

    Henness, Sheridan; Davey, Mary W.; Harvie, Rozelle M.; Davey, Ross A.

    2002-01-01

    Purpose: After standard treatment with chemotherapy and radiotherapy, small-cell lung cancer (SCLC) often develops resistance to both treatments. Our aims were to establish if fractionated radiation treatment alone would induce radiation and drug resistance in the H69 SCLC cell line, and to determine the mechanisms of resistance. Methods and Materials: H69 SCLC cells were treated with fractionated X-rays to an accumulated dose of 37.5 Gy over 8 months to produce the H69/R38 subline. Drug and radiation resistance was determined using the MTT (3,-4,5 dimethylthiazol-2,5 diphenyltetrazolium bromide) cell viability assay. Protein expression was analyzed by Western blot. Results: The H69/R38 subline was resistant to radiation (2.0 ± 0.2-fold, p<0.0001), cisplatin (14 ± 7-fold, p < 0.001), daunorubicin (6 ± 3-fold, p<0.05), and navelbine (1.7 ± 0.15-fold, p<0.02). This was associated with increased expression of the multidrug resistance-associated proteins, MRP1 and MRP2, and topoisomerase IIα and decreased expression of glutathione-S-transferase π (GSTπ) and bcl-2 and decreased cisplatin accumulation. Treatment with 4 Gy of X-rays produced a 66% decrease in MRP2 in the H69 cells with no change in the H69/R38 cells. This treatment also caused a 5-fold increase in topoisomerase IIα in the H69/R38 cells compared with a 1.5-fold increase in the H69 cells. Conclusions: Fractionated radiation alone can lead to the development of stable radiation and drug resistance and an altered response to radiation in SCLC cells

  17. Medications (for IBS)

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  19. 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....

  20. Medications (for IBS)

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  1. [Isolation and partial characterization of DNA topoisomerase I from the nucleoids of white mustard chloroplasts].

    Science.gov (United States)

    Belkina, G G; Pogul'skaia, E V; Iurina, N P

    2004-01-01

    DNA topoisomerase was isolated for the first time from nucleoids of white mustard (Sinapis alba L.) chloroplasts. The enzyme had a molecular weight of 70 kDa; it was ATP-independent, required the presence of mono- (K+) and bivalent (Mg2+) cations, and was capable of relaxing both negatively and positively supercoiled DNA. These results suggest that the enzyme isolated belongs to type IB DNA topoisomerases.

  2. Medications (for IBS)

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  5. Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resistance

    NARCIS (Netherlands)

    de Jong, Steven; Zijlstra, J G; Mulder, Nanno; de Vries, Liesbeth

    1991-01-01

    Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These drugs are cytotoxic due to the formation of a cleavable complex between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo

  6. Medications (for IBS)

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  7. The small intestine and irritable bowel syndrome (IBS): a batch process model.

    Science.gov (United States)

    Dobson, Brian C

    2008-11-01

    Faults in a batch process model of the small intestine create the symptoms of all types of irritable bowel syndrome. The model has three sequential processing sections corresponding to the natural divisions of the intestine. It is governed by a brain controller that is divided into four sub-controllers, each with a unique neurotransmitter. Each section has a sub-controller to manage transport. Sensors in the walls of the intestine provide input and output goes to the muscles lining the walls of the intestine. The output controls the speed of the food soup, moves it in both directions, mixes it, controls absorption, and transfers it to the next section at the correct speed (slow). The fourth sub-controller manages the addition of chemicals. It obtains input from the first section of the process via the signalling hormone Cholecystokinin and sends output to the muscles that empty the gall bladder and pancreas. The correct amounts of bile salts and enzymes are then added to the first section. The sub-controllers produce output only when input is received. When output is missing the enteric nervous system applies a default condition. This default condition normally happens when no food is in the intestine. If food is in the intestine and a transport sub-controller fails to provide output then the default condition moves the food soup to the end of that section. The movement is in one direction only (forward), at a speed dependent on the amount and type of fibre present. Cereal, bean and vegetable fibre causes high speeds. This default high speed transport causes irritable bowel syndrome. A barrier is created when a section moving fast at the default speed, precedes a section controlled by a transport sub-controller. Then the sub-controller constricts the intestine to stop the fast flow. The barrier causes constipation, cramping, and bloating. Diarrhoea results when the section terminating the process moves at the fast default speed. Two problems can occur to prevent

  8. Medications (for IBS)

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  9. Medications (for IBS)

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    Full Text Available ... Gallery Contact Us About IBS Twitter Facebook YouTube Search Search ... About Us What is IBS? What is IBS? ... the Day Art of IBS Gallery Contact Us Search Medications Details Medications Last Updated: 01 July 2017 ...

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    Full Text Available ... and Holidays Personal Stories IBS Awareness Month IBS Awareness Month Tips of the Day ... IBS Medications Probiotics and Antibiotics Pharmacologic, or drug, therapy is best used in irritable bowel syndrome (IBS) ...

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    Full Text Available ... Treatments Medications Psychological Treatments Online Studies News You Can Use Living With IBS Relationships and IBS Pregnancy ... Treatments Medications Psychological Treatments Online Studies News You Can Use Living With IBS Relationships and IBS Pregnancy ...

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  1. Cervical Cancer Stage IB

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    ... hyphen, e.g. -historical Searches are case-insensitive Cervical Cancer Stage IB Add to My Pictures View /Download : ... 1613x1200 View Download Large: 3225x2400 View Download Title: Cervical Cancer Stage IB Description: Stage IB1 and IB2 cervical ...

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    Full Text Available ... IBS Medications Probiotics and Antibiotics Psychological Treatments Understanding Stress Cognitive Behavioral Therapy Relaxation Techniques for IBS Take Part in Online Studies Working With Your Doctor Successful relationships with healthcare providers are an important part of ...

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    Full Text Available ... Diet Complementary or Alternative Treatments Medications Psychological Treatments Online Studies News You Can Use Living With IBS ... Diet Complementary or Alternative Treatments Medications Psychological Treatments Online Studies News You Can Use Living With IBS ...

  5. Medications (for IBS)

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  6. Medications (for IBS)

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    Full Text Available ... have limited benefit for treating IBS. In some persons they relieve abdominal pain or discomfort, usually if ... Anti-anxiety medications – can be helpful for some people with IBS, mainly those with emotional distress. There ...

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    Full Text Available ... the lack of effective treatment for the overall improvement of multiple symptoms in IBS patients. However, new ... IFFGD Our Mission Awareness Activities Advocacy Activities Research Leadership Industry Council Contact us IBS Treatment Working With ...

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    Full Text Available ... the lack of effective treatment for the overall improvement of multiple symptoms in IBS patients. However, new ... effective in treating IBS in multi-center, high quality clinical trials. These are prescription medications intended for ...

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    Full Text Available ... Agents Antidiarrheal Agents Antidepressant Medications Newer IBS Medications Probiotics and Antibiotics Pharmacologic, or drug, therapy is best ... Agents Antidiarrheal Agents Antidepressant Medications Newer IBS Medications ... Psychological Treatments Understanding Stress Cognitive Behavioral ...

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    Full Text Available ... Treatments IBS Diet Low FODMAP Diet Complementary or Alternative Treatments Medications Psychological Treatments Online Studies News You ... Treatments IBS Diet Low FODMAP Diet Complementary or Alternative Treatments Medications Psychological Treatments Online Studies News You ...

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    Full Text Available ... in IBS Sleep and Irritable Bowel Syndrome Gynecological Aspects of Irritable Bowel Syndrome Symptom Diary Testing in ... in IBS Sleep and Irritable Bowel Syndrome Gynecological Aspects of Irritable Bowel Syndrome Symptom Diary Testing in ...

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  14. Medications (for IBS)

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    Full Text Available ... of IBS Gallery Contact Us About IBS Twitter Facebook YouTube Search Search ... About Us What is IBS? ... and more! Sign up for eNewsletter: Site map | Privacy & Security | Terms of Use | Contact Us This information ...

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    Full Text Available ... Agents Antidepressant Medications Newer IBS Medications Probiotics and Antibiotics Psychological Treatments Understanding Stress Cognitive Behavioral Therapy Relaxation Techniques for ...

  16. Medications (for IBS)

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    Full Text Available ... Tips on Finding a Doctor Doctor Visit Worksheet Words to Know Changing Doctors IBS Symptom Treatments IBS ... arises requiring an expert’s care. © Copyright 1998-2018 International Foundation for Functional Gastrointestinal Disorders, Inc. (IFFGD). All ...

  17. IBS Treatment Options

    Science.gov (United States)

    ... 01 July 2017 Print A short bout of abdominal pain and diarrhea or constipation now and then is not unusual. But long-term or recurring symptoms are not normal. They may signal irritable bowel syndrome (IBS) – and are generally treatable. IBS Treatments Depend ...

  18. Medications (for IBS)

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    Full Text Available ... Global Treatments IBS Diet What to Do and What to Avoid Foods That Cause Cramping and Diarrhea Foods that Cause ... 12 Week Elimination Diet for IBS Rice-Based Foods Low-FODMAP Diet What Are FODMAPs? Effects of FODMAPs on the Gut ...

  19. Medications (for IBS)

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    Full Text Available ... Global Treatments IBS Diet What to Do and What to Avoid Foods That Cause Cramping and Diarrhea Foods that Cause Gas and Bloating Dietary Fiber 12 Week Elimination Diet for IBS Rice-Based Foods Low-FODMAP Diet What Are FODMAPs? Effects of FODMAPs on the Gut ...

  20. Human small cell lung cancer NYH cells selected for resistance to the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187 demonstrate a functional R162Q mutation in the Walker A consensus ATP binding domain of the alpha isoform

    DEFF Research Database (Denmark)

    Wessel, I; Jensen, L H; Jensen, P B

    1999-01-01

    in expression of the beta isoform. Sequencing of the entire topoisomerase IIalpha cDNA from NYH/187 cells demonstrated a homozygous G-->A point mutation at nucleotide 485, leading to a R162Q conversion in the Walker A consensus ATP binding site (residues 161-165 in the alpha isoform), this being the first drug......-selected mutation described at this site. Western blotting after incubation with ICRF-187 showed no depletion of the alpha isoform in NYH/187 cells in contrast to wild-type (wt) cells, whereas equal depletion of the beta isoform was observed in the two sublines. Alkaline elution assay demonstrated a lack...... of inhibition of etoposide-induced DNA single-stranded breaks in NYH/187 cells, whereas this inhibition was readily apparent in NYH cells. Site-directed mutagenesis in human topoisomerase IIalpha introduced into a yeast Saccharomyces cerevisiae strain with a temperature-conditional yeast TOP2 mutant...

  1. Medications (for IBS)

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    Full Text Available ... do not respond to physician counseling and dietary manipulations. What's a medication? Anything you take for a ... Psychological Treatments Understanding Stress Cognitive Behavioral Therapy Relaxation Techniques for IBS Take Part in Online Studies Working ...

  2. Medications (for IBS)

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    Full Text Available ... J. Lembo, MD, Instructor of Medicine, Harvard Medical School; Division of Gastroenterology, Beth Israel Deaconess Medical Center, ... About IFFGD Our Mission Awareness Activities Advocacy Activities Research Leadership Industry Council Contact us IBS Treatment Working ...

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    Full Text Available ... your doctor about it. He or she can help you monitor quality, effectiveness, possible interactions with other ... effectively treat multiple symptoms of IBS. Laxatives – can help treat symptoms of constipation. Laxatives should be used ...

  4. Medications (for IBS)

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    Full Text Available ... IFFGD Our Mission Awareness Activities Advocacy Activities Research Leadership Industry Council Contact us IBS Treatment Working With ... doctor. We advise seeing a physician whenever a health problem arises requiring an expert’s care. © Copyright 1998- ...

  5. Medications (for IBS)

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    Full Text Available ... for some people with IBS, mainly those with emotional distress. There are also effective medications available that ... This Article Help You? IFFGD is a nonprofit education and research organization. Our mission is to inform, ...

  6. Medications (for IBS)

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    Full Text Available ... effective medications available that relieve the pain and improve the changes in bowel habit. They may need ... effective in treating IBS in multi-center, high quality clinical trials. These are prescription medications intended for ...

  7. Medications (for IBS)

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    Full Text Available ... severe symptoms which do not respond to physician counseling and dietary manipulations. What's a medication? Anything you ... Therapy Relaxation Techniques for IBS Take Part in Online Studies Working With Your Doctor Successful relationships with ...

  8. Medications (for IBS)

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    Full Text Available ... include bran or psyllium. Anticholinergics/Antispasmodics – have limited benefit for treating IBS. In some persons they relieve ... This Article Help You? IFFGD is a nonprofit education and research organization. Our mission is to inform, ...

  9. Medications (for IBS)

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    Full Text Available ... He or she can help you monitor quality, effectiveness, possible interactions with other medicines you may be ... Read more about newer IBS medications. Summary The effectiveness of various agents differs between individuals. A medication ...

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    Full Text Available ... Help You? IFFGD is a nonprofit education and research organization. Our mission is to inform, assist, and ... About IFFGD Our Mission Awareness Activities Advocacy Activities Research Leadership Industry Council Contact us IBS Treatment Working ...

  12. Medications (for IBS)

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  13. Medications (for IBS)

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    Full Text Available ... be taken on a more long-term basis. These include low dose antidepressant agents or the relatively ... IBS in multi-center, high quality clinical trials. These are prescription medications intended for specific use under ...

  14. Medications (for IBS)

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  15. Medications (for IBS)

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    Full Text Available ... have limited benefit for treating IBS. In some persons they relieve abdominal pain or discomfort, usually if ... Summary The effectiveness of various agents differs between individuals. A medication regimen must be carefully chosen by ...

  16. Medications (for IBS)

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    Full Text Available ... for some people with IBS, mainly those with emotional distress. There are also effective medications available that ... not linked to depression, but rather likely to effects on the brain and the gut. Antidepressant medications ...

  17. Medications (for IBS)

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    Full Text Available ... Read more about antidiarrheal agents. Anti-anxiety medications – can be helpful for some people with IBS, mainly those with emotional distress. There are also effective medications available that relieve ...

  18. Medications (for IBS)

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  19. Medications (for IBS)

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    Full Text Available ... MA. Last modified on February 23, 2015 at 12:18:55 PM Treatment Understanding and Managing Pain ... Foods that Cause Gas and Bloating Dietary Fiber 12 Week Elimination Diet for IBS Rice-Based Foods ...

  20. Medications (for IBS)

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    Full Text Available ... discomfort, usually if the symptoms occur soon after eating. Examples include dicyclomine (Bentyl), and hyoscyamine (Levsin). Read ... treatment of IBS symptoms is not linked to depression, but rather likely to effects on the brain ...

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  4. Medications (for IBS)

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  5. Electrostatics of DNA-DNA juxtapositions: consequences for type II topoisomerase function

    International Nuclear Information System (INIS)

    Randall, Graham L; Pettitt, B Montgomery; Buck, Gregory R; Zechiedrich, E Lynn

    2006-01-01

    Type II topoisomerases resolve problematic DNA topologies such as knots, catenanes, and supercoils that arise as a consequence of DNA replication and recombination. Failure to remove problematic DNA topologies prohibits cell division and can result in cell death or genetic mutation. Such catastrophic consequences make topoisomerases an effective target for antibiotics and anticancer agents. Despite their biological and clinical importance, little is understood about how a topoisomerase differentiates DNA topologies in a molecule that is significantly larger than the topoisomerase itself. It has been proposed that type II topoisomerases recognize angle and curvature between two DNA helices characteristic of knotted and catenated DNA to account for the enzyme's preference to unlink instead of link DNA. Here we consider the electrostatic potential of DNA juxtapositions to determine the possibility of juxtapositions occurring through Brownian diffusion. We found that despite the large negative electrostatic potential formed between two juxtaposed DNA helices, a bulk counterion concentration as small as 50 mM provides sufficient electrostatic screening to prohibit significant interaction beyond an interhelical separation of 3 nm in both hooked and free juxtapositions. This suggests that instead of electrostatics, mechanical forces such as those occurring in anaphase, knots, catenanes, or the writhe of supercoiled DNA may be responsible for the formation of DNA juxtapositions

  6. Medications (for IBS)

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    Full Text Available ... treatment of IBS symptoms is not linked to depression, but rather likely to effects on the brain ... problem arises requiring an expert’s care. © Copyright 1998-2018 International Foundation for Functional Gastrointestinal Disorders, Inc. (IFFGD). ...

  7. Medications (for IBS)

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    Full Text Available ... include bran or psyllium. Anticholinergics/Antispasmodics – have limited benefit for treating IBS. In some persons they relieve abdominal pain or discomfort, usually if the symptoms occur soon after eating. Examples include dicyclomine (Bentyl), and hyoscyamine (Levsin). Read ...

  8. Medications (for IBS)

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    Full Text Available ... treatment of IBS symptoms is not linked to depression, but rather likely to effects on the brain ... whenever a health problem arises requiring an expert’s care. © Copyright 1998-2018 International Foundation for Functional Gastrointestinal ...

  9. Medications (for IBS)

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    Full Text Available ... IFFGD Our Mission Awareness Activities Advocacy Activities Research Leadership Industry Council Contact us IBS Treatment Working With ... We advise seeing a physician whenever a health problem arises requiring an expert’s care. © Copyright 1998-2018 ...

  10. Medications (for IBS)

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    Full Text Available ... of a physician. Read more about laxatives. Bulking agents – provided they relieve and don’t worsen symptoms, can ease stool passage. Examples include bran or psyllium. Anticholinergics/Antispasmodics – have limited benefit for treating IBS. In some persons they relieve ...

  11. TOPOISOMERASE-I AND TOPOISOMERASE-II ACTIVITY IN HUMAN BREAST, CERVIX, LUNG AND COLON-CANCER

    NARCIS (Netherlands)

    MCLEOD, HL; DOUGLAS, F; OATES, M; SYMONDS, RP; PRAKASH, D; VANDERZEE, AGJ; KAYE, SB; BROWN, R; KEITH, WN

    1994-01-01

    The identification of human DNA topoisomerases as cellular targets for active anti-cancer drugs has stimulated further interest in topoisomerase function in tumour biology. Topoisomerase I and II catalytic activity is detectable in many normal and malignant tissues. However, little is known about

  12. PprA contributes to Deinococcus radiodurans resistance to nalidixic acid, genome maintenance after DNA damage and interacts with deinococcal topoisomerases.

    Directory of Open Access Journals (Sweden)

    Swathi Kota

    Full Text Available PprA is known to contribute to Deinococcus radiodurans' remarkable capacity to survive a variety of genotoxic assaults. The molecular bases for PprA's role(s in the maintenance of the damaged D. radiodurans genome are incompletely understood, but PprA is thought to promote D. radiodurans's capacity for DSB repair. PprA is found in a multiprotein DNA processing complex along with an ATP type DNA ligase, and the D. radiodurans toposiomerase IB (DraTopoIB as well as other proteins. Here, we show that PprA is a key contributor to D. radiodurans resistance to nalidixic acid (Nal, an inhibitor of topoisomerase II. Growth of wild type D. radiodurans and a pprA mutant were similar in the absence of exogenous genotoxic insults; however, the pprA mutant exhibited marked growth delay and a higher frequency of anucleate cells following treatment with DNA-damaging agents. We show that PprA interacts with both DraTopoIB and the Gyrase A subunit (DraGyrA in vivo and that purified PprA enhances DraTopoIB catalysed relaxation of supercoiled DNA. Thus, besides promoting DNA repair, our findings suggest that PprA also contributes to preserving the integrity of the D. radiodurans genome following DNA damage by interacting with DNA topoisomerases and by facilitating the actions of DraTopoIB.

  13. Isolation and partial characterisation of a mammalian cell mutant hypersensitive to topoisomerase II inhibitors and X-rays

    International Nuclear Information System (INIS)

    Davies, S.M.; Davies, S.L.; Hickson, I.D.; Hall, A.G.

    1990-01-01

    The authors have isolated, following one-step mutagenesis, a Chinese hamster ovary cell mutant hypersensitive to the intercalating agent, adriamycin. This agent exerts at least part of its cytotoxic action via inhibition of the nuclear enzyme, topoisomerase II. The mutant, designated ADR-3, showed hypersensitivity to all classes of topoisomerase II inhibitors, inlcuding actinomycin D, amsacrine (m-AMSA), etoposide (VP16) and mitoxantrone. ADR-3 cells also showed cross-sensitivity to ionizing radiation, but not no UV light. Topoisomerase II activity was elevated to a small but significant degree in ADR-3 cells, and this was reflected in a 1.5-fold higher level of topoisomerase II protein in ADR-3 than in CHO-K1 cells, as judged by Western blotting. ADR-3 cells were hypersensitive to cumene hydroperoxide but cross-resistant to hydrogen peroxide, suggesting possible abnormality in the detoxification of peroxides by glutathione peroxidase or catalase. Glutathione peroxidase activity against hydroperoxide was elevated to a small but significant extent in mutant cells. Catalase levels were not significantly different in ADR-3 and CHO-K1 cells. ADR-3 cells were recessive in hybrids with parental CHO-K1 cells with respect to sensitivity to topoisomerase II inhibitors and X-rays, and represent a different genetic complementation group from the previously reported adriamycin-sensitive mutant, ADR-1. (author). 34 refs.; 5 figs.; 3 tabs

  14. Role for DNA topoisomerase II in prostatic growth

    International Nuclear Information System (INIS)

    Nelson, W.G. V.

    1987-01-01

    In the studies presented the role of the mammalian type II topoisomerase in the proliferation of normal and neoplastic rat prostate cells in vitro and in vivo was evaluated. First, the utility of mammalian type II topoisomerase inhibitors for the study of the biologic functions of the enzyme was assessed. Novobiocin inhibited rat topoisomerase II, but also interacted directly with chromatin in rat ventral prostate nuclei as well. Teniposide and amsacrine both trapped topoisomerase II in a covalent enzyme-DNA reaction intermediate that could be recovered using a K-SDS precipitation assay. The specific trapping of covalent topoisomerase II-DNA complexes by teniposide was exploited to implicate topoisomerase II in DNA replication in cultured Dunning R3327-G rat prostatic adenocarcinoma cells. In 3 H-thymidine pulse and pulse-chase labelling experiments, newly replicated DNA was found to be enriched among DNA linked topoisomerase II following teniposide treatment. Additional experiments demonstrated that topoisomerase II formed covalent complexes in the presence of teniposide directly with nascent DNA chains. On the basis of this data, a model for topoisomerase II function in untangling intertwined daughter DNA strands during replication by acting in the wake of the DNA replication fork near the site of DNA synthesis was proposed

  15. The importance of topoisomerases for chromatin regulated genes

    DEFF Research Database (Denmark)

    Fredsøe, Jacob Christian; Pedersen, Jakob Madsen; Rødgaard, Morten Terpager

    2013-01-01

    DNA topoisomerases are enzymes, which function to relieve torsional stress in the DNA helix by introducing transient breaks into the DNA molecule. By use of Saccharomyces cerevisiae and microarray technology we have previously shown that topoisomerases are required for the activation of chromatin...... topoisomerases for optimal activation, but in contrast to the PHO5 gene, topoisomerases are not required for chromatin remodeling of the GAL1/10 promoter region, indicating a different role of the enzymes. We are currently performing a detailed investigation of the GAL genes to elucidate the precise role...

  16. Flavonoids in Helichrysum pamphylicum inhibit mammalian type I DNA topoisomerase.

    Science.gov (United States)

    Topcu, Zeki; Ozturk, Bintug; Kucukoglu, Ozlem; Kilinc, Emrah

    2008-01-01

    DNA topoisomerases are important targets for cancer chemotherapy. We investigated the effects of a methanolic extract of Helichrysum pamphylicum on mammalian DNA topoisomerase I via in vitro plasmid supercoil relaxation assays. The extracts manifested a considerable inhibition of the enzyme's activity in a dose-dependent manner. We also performed a HPLC analysis to identify the flavonoid content of the H. pamphylicum extract and tested the identified flavonoids; luteolin, luteolin-4-glucoside, naringenin, helichrysinA and isoquercitrin, on DNA topoisomerase I activity. The measurement of the total antioxidant capacity of the flavonoid standards suggested that the topoisomerase inhibition might be correlated with the antioxidant capacity of the plant.

  17. 6 Tips: IBS and Complementary Health Practices

    Science.gov (United States)

    ... health practice for IBS, here are 6 tips: Hypnotherapy (hypnosis). This practice involves the power of suggestion by ... IBS. According to reviews of the scientific literature, hypnotherapy may be a helpful treatment for managing IBS ...

  18. Effects of an unusual poison identify a lifespan role for Topoisomerase 2 in Saccharomyces cerevisiae

    OpenAIRE

    Tombline, Gregory; Millen, Jonathan I.; Polevoda, Bogdan; Rapaport, Matan; Baxter, Bonnie; Van Meter, Michael; Gilbertson, Matthew; Madrey, Joe; Piazza, Gary A.; Rasmussen, Lynn; Wennerberg, Krister; White, E. Lucile; Nitiss, John L.; Goldfarb, David S.

    2017-01-01

    A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates...

  19. 3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

    Science.gov (United States)

    Bansal, Sandhya; Sinha, Devapriya; Singh, Manish; Cheng, Bokun; Tse-Dinh, Yuk-Ching; Tandon, Vibha

    2012-01-01

    Objectives Antibiotic resistance in bacterial pathogens is a serious clinical problem. Novel targets are needed to combat increasing drug resistance in Escherichia coli. Our objective is to demonstrate that 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA) inhibits E. coli DNA topoisomerase I more strongly than human topoisomerase I. In addition, DMA is non-toxic to mammalian cells at antibiotic dosage level. Methods In the present study, we have established DMA as an antibacterial compound by determining MICs, post-antibiotic effects (PAEs) and MBCs for different standard as well as clinical strains of E. coli. We have described the differential catalytic inhibitory mechanism of bis-benzimidazole, DMA, for human and E. coli topoisomerase I and topoisomerase II by performing different assays, including relaxation assays, cleavage–religation assays, DNA unwinding assays, ethidium bromide displacement assays, decatenation assays and DNA gyrase supercoiling assays. Results DMA significantly inhibited bacterial growth at a very low concentration, but did not affect human cell viability at higher concentrations. Activity assays showed that it preferentially targeted E. coli topoisomerase I over human topoisomerase I, topoisomerase II and gyrase. Cleavage–religation assays confirmed DMA as a poison inhibitor of E. coli topoisomerase I. This study illuminates new properties of DMA, which may be further modified to develop an efficient topoisomerase inhibitor that is selective towards bacterial topoisomerase I. Conclusions This is the first report of a bis-benzimidazole acting as an E. coli topoisomerase I inhibitor. DMA is a safe, non-cytotoxic molecule to human cells at concentrations that are needed for antibacterial activity. PMID:22945915

  20. Medications (for IBS)

    Medline Plus

    Full Text Available ... lifestyle changes and careful use of medications should consider being evaluated by a physician who specializes in ... concerns. If you found this article helpful, please consider supporting IFFGD with a small tax- deductible donation. ...

  1. Medications (for IBS)

    Science.gov (United States)

    ... helpful, please consider supporting IFFGD with a small tax- deductible donation. Make Donation Adapted from IFFGD Publication # ... arises requiring an expert’s care. © Copyright 1998-2018 International Foundation for Functional Gastrointestinal Disorders, Inc. (IFFGD). All ...

  2. Medications (for IBS)

    Medline Plus

    Full Text Available ... specifically for IFFGD readers, in response to your questions and concerns. If you found this article helpful, please consider supporting IFFGD with a small tax- deductible donation. Make Donation Adapted from IFFGD Publication # ...

  3. Medications (for IBS)

    Medline Plus

    Full Text Available ... conditions which may respond to treatment. Did This Article Help You? IFFGD is a nonprofit education and ... your questions and concerns. If you found this article helpful, please consider supporting IFFGD with a small ...

  4. Medications (for IBS)

    Medline Plus

    Full Text Available ... article helpful, please consider supporting IFFGD with a small tax- deductible donation. Make Donation Adapted from IFFGD ... Diet What to Do and What to Avoid Foods That Cause Cramping and Diarrhea Foods that Cause ...

  5. Topoisomerase II poisoning by indazole and imidazole complexes ...

    Indian Academy of Sciences (India)

    Unknown

    These molecules constitute two of the few most effective anticancer ruthenium compounds. ... however was hindered due to toxic side effects on the human body. Our ... cells. The catalytic cycle of topoisomerase II (topo II) typically involves ...

  6. Anti-topoisomerase drugs as potent inducers of chromosomal aberrations

    Directory of Open Access Journals (Sweden)

    Loredana Bassi

    2000-12-01

    Full Text Available DNA topoisomerases catalyze topological changes in DNA that are essential for normal cell cycle progression and therefore they are a preferential target for the development of anticancer drugs. Anti-topoisomerase drugs can be divided into two main classes: "cleavable complex" poisons and catalytic inhibitors. The "cleavable complex" poisons are very effective as anticancer drugs but are also potent inducers of chromosome aberrations so they can cause secondary malignancies. Catalytic inhibitors are cytotoxic but they do not induce chromosome aberrations. Knowledge about the mechanism of action of topoisomerase inhibitors is important to determine the best anti-topoisomerase combinations, with a reduced risk of induction of secondary malignancies.As topoisomerases de DNA catalisam alterações topológicas no DNA que são essenciais para a progressão do ciclo celular normal e, portanto, são um alvo preferencial para o desenvolvimento de drogas anticâncer. Drogas anti-topoisomerases podem ser divididas em duas classes principais: drogas anti-"complexos cliváveis" e inibidores catalíticos. As drogas anti-"complexos cliváveis" são muito eficazes como drogas anticancerígenas, mas são também potentes indutores de aberrações cromossômicas, podendo causar neoplasias malignas secundárias. Inibidores catalíticos são citotóxicos mas não induzem aberrações cromossômicas. Conhecimento a respeito do mecanismo de ação de inibidores de topoisomerases é importante para determinar as melhores combinações anti-topoisomerases, com um reduzido risco de indução de neoplasias malignas secundárias.

  7. The Insight of Industrialised Building System (IBS By Bumiputera Construction Players

    Directory of Open Access Journals (Sweden)

    Muhammad W. M. N. W.

    2016-01-01

    Full Text Available The term Industrialised Building System (IBS is widely recognised by construction players in Malaysia since its first implementation since 1960s for IBS pilot projects of Pekeliling Flats and Rifle Range Flats. The aim for the implementation is to promote better system in delivering construction end-products which offers efficiency and effectiveness. At the same time, Bumiputera construction players are the majority of parties in construction industry especially in Small and Medium Enterprises (SMEs. Therefore, the purpose of this paper is to identify the perception and awareness of IBS implementation among Bumiputera players. It is found that, Bumiputera construction players have sound knowledge on the IBS and optimistic towards further implementation for future projects. Nonetheless, issues on payment methods and coordination of IBS project delivery are found to be the negative perceptions which are considered as hindrance for Bumiputera construction players’ involvement in IBS project.

  8. Medications (for IBS)

    Medline Plus

    Full Text Available ... helpful, please consider supporting IFFGD with a small tax- deductible donation. Make Donation Adapted from IFFGD Publication # ... arises requiring an expert’s care. © Copyright 1998-2018 International Foundation for Functional Gastrointestinal Disorders, Inc. (IFFGD). All ...

  9. IB Offering Certificate for Careers

    Science.gov (United States)

    Robelen, Erik W.

    2012-01-01

    The International Baccalaureate (IB) organization, best known in the United States for its prestigious two-year diploma program for juniors and seniors, will enter new terrain this fall as it formally rolls out an initiative centered on a variety of career pathways that includes engineering, culinary arts, and automotive technology. The move comes…

  10. IBS and Non-GI Functional Disorders

    Science.gov (United States)

    ... of IBS patients have at least one coexisting somatic symptom and many IBS patients meet diagnostic criteria ... up-to-date on the latest news, stories, tips, research highlights, and more! Sign up for eNewsletter: ...

  11. The dynamic interplay between DNA topoisomerases and DNA topology.

    Science.gov (United States)

    Seol, Yeonee; Neuman, Keir C

    2016-11-01

    Topological properties of DNA influence its structure and biochemical interactions. Within the cell, DNA topology is constantly in flux. Transcription and other essential processes, including DNA replication and repair, not only alter the topology of the genome but also introduce additional complications associated with DNA knotting and catenation. These topological perturbations are counteracted by the action of topoisomerases, a specialized class of highly conserved and essential enzymes that actively regulate the topological state of the genome. This dynamic interplay among DNA topology, DNA processing enzymes, and DNA topoisomerases is a pervasive factor that influences DNA metabolism in vivo. Building on the extensive structural and biochemical characterization over the past four decades that has established the fundamental mechanistic basis of topoisomerase activity, scientists have begun to explore the unique roles played by DNA topology in modulating and influencing the activity of topoisomerases. In this review we survey established and emerging DNA topology-dependent protein-DNA interactions with a focus on in vitro measurements of the dynamic interplay between DNA topology and topoisomerase activity.

  12. A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol

    International Nuclear Information System (INIS)

    Elharrar, Xavier; Barbolosi, Dominique; Ciccolini, Joseph; Meille, Christophe; Faivre, Christian; Lacarelle, Bruno; André, Nicolas; Barlesi, Fabrice

    2016-01-01

    Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile. This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0–2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib. An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial. This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer

  13. [Validation of the IBS-SSS].

    Science.gov (United States)

    Betz, C; Mannsdörfer, K; Bischoff, S C

    2013-10-01

    Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterised by abdominal pain, associated with stool abnormalities and changes in stool consistency. Diagnosis of IBS is based on characteristic symptoms and exclusion of other gastrointestinal diseases. A number of questionnaires exist to assist diagnosis and assessment of severity of the disease. One of these is the irritable bowel syndrome - severity scoring system (IBS-SSS). The IBS-SSS was validated 1997 in its English version. In the present study, the IBS-SSS has been validated in German language. To do this, a cohort of 60 patients with IBS according to the Rome III criteria, was compared with a control group of healthy individuals (n = 38). We studied sensitivity and reproducibility of the score, as well as the sensitivity to detect changes of symptom severity. The results of the German validation largely reflect the results of the English validation. The German version of the IBS-SSS is also a valid, meaningful and reproducible questionnaire with a high sensitivity to assess changes in symptom severity, especially in IBS patients with moderate symptoms. It is unclear if the IBS-SSS is also a valid questionnaire in IBS patients with severe symptoms because this group of patients was not studied. © Georg Thieme Verlag KG Stuttgart · New York.

  14. The dual topoisomerase inhibitor A35 preferentially and specially targets topoisomerase 2? by enhancing pre-strand and post-strand cleavage and inhibiting DNA religation

    OpenAIRE

    Zhao, Wuli; Jiang, Guohua; Bi, Chongwen; Li, Yangbiao; Liu, Jingbo; Ye, Cheng; He, Hongwei; Li, Liang; Song, Danqing; Shao, Rongguang

    2015-01-01

    DNA topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2?. Here, we validated cyclizing-berberine A35, which is a dual t...

  15. Conversion of DNA gyrase into a conventional type II topoisomerase

    DEFF Research Database (Denmark)

    Kampranis, S C; Maxwell, A

    1996-01-01

    DNA gyrase is unique among topoisomerases in its ability to introduce negative supercoils into closed-circular DNA. We have demonstrated that deletion of the C-terminal DNA-binding domain of the A subunit of gyrase gives rise to an enzyme that cannot supercoil DNA but relaxes DNA in an ATP-depend...

  16. Platelet Glycoprotein Ib-IX and Malignancy

    Science.gov (United States)

    2010-09-01

    provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin - rich network produced by coagulation...process and can initiate the formation of a platelet - rich thrombus by tethering the platelet to a thrombogenic surface. Several ligands binding to GP Ib... Platelet Glycoprotein Ib-IX and Malignancy PRINCIPAL INVESTIGATOR: Jerry Ware, Ph.D

  17. 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.

  18. IBS for non-gaussian distributions

    International Nuclear Information System (INIS)

    Fedotov, A.; Sidorin, A.O.; Smirnov, A.V.

    2010-01-01

    In many situations distribution can significantly deviate from Gaussian which requires accurate treatment of IBS. Our original interest in this problem was motivated by the need to have an accurate description of beam evolution due to IBS while distribution is strongly affected by the external electron cooling force. A variety of models with various degrees of approximation were developed and implemented in BETACOOL in the past to address this topic. A more complete treatment based on the friction coefficient and full 3-D diffusion tensor was introduced in BETACOOL at the end of 2007 under the name 'local IBS model'. Such a model allowed us calculation of IBS for an arbitrary beam distribution. The numerical benchmarking of this local IBS algorithm and its comparison with other models was reported before. In this paper, after briefly describing the model and its limitations, they present its comparison with available experimental data.

  19. Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations

    Science.gov (United States)

    Kristoffersen, Emil L.; Jørgensen, Line A.; Franch, Oskar; Etzerodt, Michael; Frøhlich, Rikke; Bjergbæk, Lotte; Stougaard, Magnus; Ho, Yi-Ping; Knudsen, Birgitta R.

    2015-05-01

    Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using

  20. Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha

    DEFF Research Database (Denmark)

    Mönnich, Maren; Hess, Isabell; Wiest, Waltraud

    2010-01-01

    All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure-specific "dissolvasome," also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans, the hetero......All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure-specific "dissolvasome," also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans...

  1. Genotoxicity of topoisomerase II inhibitors: An anti-infective perspective

    International Nuclear Information System (INIS)

    Smart, Daniel J.

    2008-01-01

    At present, an inevitable consequence of a chemical's inhibitory activity on key regulators of DNA topology in bacteria, the type II topoisomerases, is a less pronounced effect on their eukaryotic counterparts. In the context of anti-infectives drug development, this may pose a risk to patient safety as inhibition of eukaryotic type II topoisomerases (TOPO II) can result in the generation of DNA double-strand breaks (DSBs), which have the potential to manifest as mutations, chromosome breakage or cell death. The biological effects of several TOPO II inhibitors in mammalian cells are described herein; their modulation of DSB damage response parameters is examined and evidence for the existence of a threshold concept for genotoxicity and its relevance in safety assessment is discussed. The potential utility of γH2AX, a promising and highly sensitive molecular marker for DSBs, in a novel genotoxicity 'pre-screen' to conventional assays is also highlighted

  2. DNA topoisomerase II enzyme activity appears in mouse sperm ...

    African Journals Online (AJOL)

    Sperm suspensions of 4 male mice (A, B, C and D), having an initial motility grade of 3.5 were used to examine the presence of DNA topoisomerase II (top 2) activity in sperm heads. The initial percentage motile of male A was 75%, male B was 80%, male C was 70% and male D was 60%. Top 2 activity was examined by ...

  3. Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations.

    Science.gov (United States)

    Kristoffersen, Emil L; Jørgensen, Line A; Franch, Oskar; Etzerodt, Michael; Frøhlich, Rikke; Bjergbæk, Lotte; Stougaard, Magnus; Ho, Yi-Ping; Knudsen, Birgitta R

    2015-06-07

    Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.

  4. Topoisomerase 3alpha and RMI1 suppress somatic crossovers and are essential for resolution of meiotic recombination intermediates in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Frank Hartung

    2008-12-01

    Full Text Available Topoisomerases are enzymes with crucial functions in DNA metabolism. They are ubiquitously present in prokaryotes and eukaryotes and modify the steady-state level of DNA supercoiling. Biochemical analyses indicate that Topoisomerase 3alpha (TOP3alpha functions together with a RecQ DNA helicase and a third partner, RMI1/BLAP75, in the resolution step of homologous recombination in a process called Holliday Junction dissolution in eukaryotes. Apart from that, little is known about the role of TOP3alpha in higher eukaryotes, as knockout mutants show early lethality or strong developmental defects. Using a hypomorphic insertion mutant of Arabidopsis thaliana (top3alpha-2, which is viable but completely sterile, we were able to define three different functions of the protein in mitosis and meiosis. The top3alpha-2 line exhibits fragmented chromosomes during mitosis and sensitivity to camptothecin, suggesting an important role in chromosome segregation partly overlapping with that of type IB topoisomerases. Furthermore, AtTOP3alpha, together with AtRECQ4A and AtRMI1, is involved in the suppression of crossover recombination in somatic cells as well as DNA repair in both mammals and A. thaliana. Surprisingly, AtTOP3alpha is also essential for meiosis. The phenotype of chromosome fragmentation, bridges, and telophase I arrest can be suppressed by AtSPO11 and AtRAD51 mutations, indicating that the protein is required for the resolution of recombination intermediates. As Atrmi1 mutants have a similar meiotic phenotype to Attop3alpha mutants, both proteins seem to be involved in a mechanism safeguarding the entangling of homologous chromosomes during meiosis. The requirement of AtTOP3alpha and AtRMI1 in a late step of meiotic recombination strongly hints at the possibility that the dissolution of double Holliday Junctions via a hemicatenane intermediate is indeed an indispensable step of meiotic recombination.

  5. A systematic review on topoisomerase 1 inhibition in the treatment of metastatic breast cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Brünner, Nils; Stenvang, Jan

    2013-01-01

    as standard treatment for the disease. We performed a systematic review on topoisomerase 1 inhibitors in MBC and found 22 prospective trials and three retrospective ones. No phase III trials were identified. Only one study was randomized, and generally studies were small. Response rates (RR) for irinotecan...... monotherapy varied from 5 to 23 %, whereas RRs for etirinotecan were 26-32 %. Only four trials on topotecan monotherapy were reported with RRs of 6-31 %. Combination therapy with irinotecan and various chemotherapeutics resulted in RRs ranging from 14 to 64 %, whereas irinotecan combined with biologic agents...... and taxanes. RRs of 23 % for irinotecan and 32 % for etirinotecan are comparable to some of the more commonly used treatments for MBC. However, a large proportion of patients do not respond, thus emphasizing the need for a biomarker predictive of response to irinotecan in order to introduce this drug...

  6. Effects of Olive Metabolites on DNA Cleavage Mediated by Human Type II Topoisomerases

    Science.gov (United States)

    2016-01-01

    Several naturally occurring dietary polyphenols with chemopreventive or anticancer properties are topoisomerase II poisons. To identify additional phytochemicals that enhance topoisomerase II-mediated DNA cleavage, a library of 341 Mediterranean plant extracts was screened for activity against human topoisomerase IIα. An extract from Phillyrea latifolia L., a member of the olive tree family, displayed high activity against the human enzyme. On the basis of previous metabolomics studies, we identified several polyphenols (hydroxytyrosol, oleuropein, verbascoside, tyrosol, and caffeic acid) as potential candidates for topoisomerase II poisons. Of these, hydroxytyrosol, oleuropein, and verbascoside enhanced topoisomerase II-mediated DNA cleavage. The potency of these olive metabolites increased 10–100-fold in the presence of an oxidant. Hydroxytyrosol, oleuropein, and verbascoside displayed hallmark characteristics of covalent topoisomerase II poisons. (1) The activity of the metabolites was abrogated by a reducing agent. (2) Compounds inhibited topoisomerase II activity when they were incubated with the enzyme prior to the addition of DNA. (3) Compounds were unable to poison a topoisomerase IIα construct that lacked the N-terminal domain. Because hydroxytyrosol, oleuropein, and verbascoside are broadly distributed across the olive family, extracts from the leaves, bark, and fruit of 11 olive tree species were tested for activity against human topoisomerase IIα. Several of the extracts enhanced enzyme-mediated DNA cleavage. Finally, a commercial olive leaf supplement and extra virgin olive oils pressed from a variety of Olea europea subspecies enhanced DNA cleavage mediated by topoisomerase IIα. Thus, olive metabolites appear to act as topoisomerase II poisons in complex formulations intended for human dietary consumption. PMID:26132160

  7. Integrals for IBS and Beam Cooling

    International Nuclear Information System (INIS)

    Burov, A.

    2005-01-01

    Simulation of beam cooling usually requires performing certain integral transformations every time step or so, which is a significant burden on the CPU. Examples are the dispersion integrals (Hilbert transforms) in the stochastic cooling, wake fields and IBS integrals. An original method is suggested for fast and sufficiently accurate computation of the integrals. This method is applied for the dispersion integral. Some methodical aspects of the IBS analysis are discussed

  8. Maternal topoisomerase II alpha, not topoisomerase II beta, enables embryonic development of zebrafish top2a-/- mutants

    LENUS (Irish Health Repository)

    Sapetto-Rebow, Beata

    2011-11-23

    Abstract Background Genetic alterations in human topoisomerase II alpha (TOP2A) are linked to cancer susceptibility. TOP2A decatenates chromosomes and thus is necessary for multiple aspects of cell division including DNA replication, chromosome condensation and segregation. Topoisomerase II alpha is also required for embryonic development in mammals, as mouse Top2a knockouts result in embryonic lethality as early as the 4-8 cell stage. The purpose of this study was to determine whether the extended developmental capability of zebrafish top2a mutants arises from maternal expression of top2a or compensation from its top2b paralogue. Results Here, we describe bloody minded (blm), a novel mutant of zebrafish top2a. In contrast to mouse Top2a nulls, zebrafish top2a mutants survive to larval stages (4-5 day post fertilization). Developmental analyses demonstrate abundant expression of maternal top2a but not top2b. Inhibition or poisoning of maternal topoisomerase II delays embryonic development by extending the cell cycle M-phase. Zygotic top2a and top2b are co-expressed in the zebrafish CNS, but endogenous or ectopic top2b RNA appear unable to prevent the blm phenotype. Conclusions We conclude that maternal top2a enables zebrafish development before the mid-zygotic transition (MZT) and that zebrafish top2a and top2b are not functionally redundant during development after activation of the zygotic genome.

  9. Maternal topoisomerase II alpha, not topoisomerase II beta, enables embryonic development of zebrafish top2a-/- mutants

    Directory of Open Access Journals (Sweden)

    Sapetto-Rebow Beata

    2011-11-01

    Full Text Available Abstract Background Genetic alterations in human topoisomerase II alpha (TOP2A are linked to cancer susceptibility. TOP2A decatenates chromosomes and thus is necessary for multiple aspects of cell division including DNA replication, chromosome condensation and segregation. Topoisomerase II alpha is also required for embryonic development in mammals, as mouse Top2a knockouts result in embryonic lethality as early as the 4-8 cell stage. The purpose of this study was to determine whether the extended developmental capability of zebrafish top2a mutants arises from maternal expression of top2a or compensation from its top2b paralogue. Results Here, we describe bloody minded (blm, a novel mutant of zebrafish top2a. In contrast to mouse Top2a nulls, zebrafish top2a mutants survive to larval stages (4-5 day post fertilization. Developmental analyses demonstrate abundant expression of maternal top2a but not top2b. Inhibition or poisoning of maternal topoisomerase II delays embryonic development by extending the cell cycle M-phase. Zygotic top2a and top2b are co-expressed in the zebrafish CNS, but endogenous or ectopic top2b RNA appear unable to prevent the blm phenotype. Conclusions We conclude that maternal top2a enables zebrafish development before the mid-zygotic transition (MZT and that zebrafish top2a and top2b are not functionally redundant during development after activation of the zygotic genome.

  10. Camptothecins inhibit the utilization of hydrogen peroxide in the ligation step of topoisomerase I catalysis

    DEFF Research Database (Denmark)

    Lisby, M; Krogh, B O; Boege, F

    1998-01-01

    of topoisomerase I to couple non-DNA nucleophiles to the cleaved strand of the covalent enzyme-DNA complexes. This reaction of topoisomerase I was originally observed at moderate basic pH where active cleavage complexes mediate hydrolysis or alcoholysis by accepting water or polyhydric alcohol compounds...

  11. DNA Topoisomerases Maintain Promoters in a State Competent for Transcriptional Activation in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Pedersen, Jakob Madsen; Fredsøe, Jacob Christian; Rødgaard, Morten Terpager

    2012-01-01

    To investigate the role of DNA topoisomerases in transcription, we have studied global gene expression in Saccharomyces cerevisiae cells deficient for topoisomerases I and II and performed single-gene analyses to support our findings. The genome-wide studies show a general transcriptional down......-regulation upon lack of the enzymes, which correlates with gene activity but not gene length. Furthermore, our data reveal a distinct subclass of genes with a strong requirement for topoisomerases. These genes are characterized by high transcriptional plasticity, chromatin regulation, TATA box presence......-depth analysis of the inducible PHO5 gene reveals that topoisomerases are essential for binding of the Pho4p transcription factor to the PHO5 promoter, which is required for promoter nucleosome removal during activation. In contrast, topoisomerases are dispensable for constitutive transcription initiation...

  12. 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...

  13. Potentiation of radiation lethality by Topotecan, a Topoisomerase I inhibitor

    International Nuclear Information System (INIS)

    Lamond, J.P.; Kinsella, T.J.; Boothman, D.A.

    1995-01-01

    Purpose/Objective: Topotecan is a water soluble Topoisomerase I (Topo I) inhibitor that has demonstrated antineoplastic activity in phase I/II trials of solid tumors (such as non-small cell lung, small cell lung, ovarian, esophageal and head and neck primaries) and leukemias. We sought to determine (1) if Topotecan potentiated the lethal effects of ionizing radiation, and (2) the characteristics of the synergistic effect. Materials and Methods: Human radioresistant melanoma (U1-Mel) and glioma (D54) cells were grown in Dulbecco's modified Eagle's medium (DME) with 10% fetal calf serum (FCS) until confluence-arrest. Cells were x-irradiated (0-700 cGy) and exposed to various Topotecan concentrations (2-100μM), either before (for 4 hours), during, or after (for 4 hours) irradiation. Appropriate controls were also performed. Survival was determined via colony forming assays. Survival curves were normalized to correct for drug cytotoxicities and variations in initial viable cells plated. In another set of experiments, U1-Mel cells were exposed to 10 μM Topotecan either before, during or after 400 cGy, as described above. A modification of the SDS and KCl assay was used to quantify Topo I-DNA complexes via glass fiber filter binding. All experiments were performed at least 7 times in duplicate. Results: Potentiation of radiation lethality was seen in the U1-Mel and D54 cell lines. The synergistic effects were (1) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 μM range (2) dependent on timing, with synergy present only when the drug was present at the time of, or shortly after irradiation, and (3) irreversible, with inhibition of potential lethal damage repair (PLDR). The dose enhancement ratios (DER) for 4 μM Topotecan in the U1-Mel cells was 1.7 - 2.4, depending on the survival endpoints that were used. The DER for 2 μM Topotecan in D54 cells was 3.0 - 4.0. The U1-Mel cells that were exposed to Topotecan

  14. Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II.

    Directory of Open Access Journals (Sweden)

    Rachael E Hawtin

    2010-04-01

    Full Text Available Topoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available topoisomerase II-targeting drugs or encounter unacceptable toxicities. Voreloxin is an anticancer quinolone derivative, a chemical scaffold not used previously for cancer treatment. Voreloxin is completing Phase 2 clinical trials in acute myeloid leukemia and platinum-resistant ovarian cancer. This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research.Biochemical and cell-based studies established that voreloxin intercalates DNA and poisons topoisomerase II, causing DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin is differentiated both structurally and mechanistically from other topoisomerase II poisons currently in use as chemotherapeutics. In cell-based studies, voreloxin poisoned topoisomerase II and caused dose-dependent, site-selective DNA fragmentation analogous to that of quinolone antibacterials in prokaryotes; in contrast etoposide, the nonintercalating epipodophyllotoxin topoisomerase II poison, caused extensive DNA fragmentation. Etoposide's activity was highly dependent on topoisomerase II while voreloxin and the intercalating anthracycline topoisomerase II poison, doxorubicin, had comparable dependence on this enzyme for inducing G2 arrest. Mechanistic interrogation with voreloxin analogs revealed that intercalation is required for voreloxin's activity; a nonintercalating analog did not inhibit proliferation or induce G2 arrest, while an analog with enhanced intercalation was 9.5-fold more potent.As a first-in-class anticancer

  15. Regulation of Xenopus laevis DNA topoisomerase I activity by phosphorylation in vitro

    International Nuclear Information System (INIS)

    Kaiserman, H.B.; Ingebritsen, T.S.; Benbow, R.M.

    1988-01-01

    DNA topoisomerase I has been purified to electrophoretic homogeneity from ovaries of the frog Xenopus laevis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the most purified fraction revealed a single major band at 110 kDa and less abundant minor bands centered at 62 kDa. Incubation of the most purified fraction with immobilized calf intestinal alkaline phosphatase abolished all DNA topoisomerase enzymatic activity in a time-dependent reaction. Treatment of the dephosphorylated X. laevis DNA topoisomerase I with a X. laevis casein kinase type II activity and ATP restored DNA topoisomerase activity to a level higher than that observed in the most purified fraction. In vitro labeling experiments which employed the most purified DNA topoisomerase I fraction, [γ- 32 P]ATP, and the casein kinase type II enzyme showed that both the 110- and 62-kDa bands became phosphorylated in approximately molar proportions. Phosphoamino acid analysis showed that only serine residues became phosphorylated. Phosphorylation was accompanied by an increase in DNA topoisomerase activity in vitro. Dephosphorylation of DNA topoisomerase I appears to block formation of the initial enzyme-substrate complex on the basis of the failure of the dephosphorylated enzyme to nick DNA in the presence of camptothecin. The authors conclude that X. laevis DNA topoisomerase I is partially phosphorylated as isolated and that this phosphorylation is essential for expression of enzymatic activity in vitro. On the basis of the ability of the casein kinase type II activity to reactivate dephosphorylated DNA topoisomerase I, they speculate that this kinase may contribute to the physiological regulation of DNA topoisomerase I activity

  16. Transcription facilitated genome-wide recruitment of topoisomerase I and DNA gyrase.

    Science.gov (United States)

    Ahmed, Wareed; Sala, Claudia; Hegde, Shubhada R; Jha, Rajiv Kumar; Cole, Stewart T; Nagaraja, Valakunja

    2017-05-01

    Movement of the transcription machinery along a template alters DNA topology resulting in the accumulation of supercoils in DNA. The positive supercoils generated ahead of transcribing RNA polymerase (RNAP) and the negative supercoils accumulating behind impose severe topological constraints impeding transcription process. Previous studies have implied the role of topoisomerases in the removal of torsional stress and the maintenance of template topology but the in vivo interaction of functionally distinct topoisomerases with heterogeneous chromosomal territories is not deciphered. Moreover, how the transcription-induced supercoils influence the genome-wide recruitment of DNA topoisomerases remains to be explored in bacteria. Using ChIP-Seq, we show the genome-wide occupancy profile of both topoisomerase I and DNA gyrase in conjunction with RNAP in Mycobacterium tuberculosis taking advantage of minimal topoisomerase representation in the organism. The study unveils the first in vivo genome-wide interaction of both the topoisomerases with the genomic regions and establishes that transcription-induced supercoils govern their recruitment at genomic sites. Distribution profiles revealed co-localization of RNAP and the two topoisomerases on the active transcriptional units (TUs). At a given locus, topoisomerase I and DNA gyrase were localized behind and ahead of RNAP, respectively, correlating with the twin-supercoiled domains generated. The recruitment of topoisomerases was higher at the genomic loci with higher transcriptional activity and/or at regions under high torsional stress compared to silent genomic loci. Importantly, the occupancy of DNA gyrase, sole type II topoisomerase in Mtb, near the Ter domain of the Mtb chromosome validates its function as a decatenase.

  17. Molecular characterization of a nuclear topoisomerase II from Nicotiana tabacum that functionally complements a temperature-sensitive topoisomerase II yeast mutant.

    Science.gov (United States)

    Singh, B N; Mudgil, Yashwanti; Sopory, S K; Reddy, M K

    2003-07-01

    We have successfully expressed enzymatically active plant topoisomerase II in Escherichia coli for the first time, which has enabled its biochemical characterization. Using a PCR-based strategy, we obtained a full-length cDNA and the corresponding genomic clone of tobacco topoisomerase II. The genomic clone has 18 exons interrupted by 17 introns. Most of the 5' and 3' splice junctions follow the typical canonical consensus dinucleotide sequence GU-AG present in other plant introns. The position of introns and phasing with respect to primary amino acid sequence in tobacco TopII and Arabidopsis TopII are highly conserved, suggesting that the two genes are evolved from the common ancestral type II topoisomerase gene. The cDNA encodes a polypeptide of 1482 amino acids. The primary amino acid sequence shows a striking sequence similarity, preserving all the structural domains that are conserved among eukaryotic type II topoisomerases in an identical spatial order. We have expressed the full-length polypeptide in E. coli and purified the recombinant protein to homogeneity. The full-length polypeptide relaxed supercoiled DNA and decatenated the catenated DNA in a Mg(2+)- and ATP-dependent manner, and this activity was inhibited by 4'-(9-acridinylamino)-3'-methoxymethanesulfonanilide (m-AMSA). The immunofluorescence and confocal microscopic studies, with antibodies developed against the N-terminal region of tobacco recombinant topoisomerase II, established the nuclear localization of topoisomerase II in tobacco BY2 cells. The regulated expression of tobacco topoisomerase II gene under the GAL1 promoter functionally complemented a temperature-sensitive TopII(ts) yeast mutant.

  18. A critical role for topoisomerase IIb and DNA double strand breaks in transcription.

    Science.gov (United States)

    Calderwood, Stuart K

    2016-05-26

    Recent studies have indicated a novel role for topoisomerase IIb in transcription. Transcription of heat shock genes, serum-induced immediate early genes and nuclear receptor-activated genes, each required DNA double strands generated by topoisomerase IIb. Such strand breaks seemed both necessary and sufficient for transcriptional activation. In addition, such transcription was associated with initiation of the DNA damage response pathways, including the activation of the enzymes: ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase and poly (ADP ribose) polymerase 1. DNA damage response signaling was involved both in transcription and in repair of DNA breaks generated by topoisomerase IIb.

  19. Prevalence of mood and anxiety disorder in self reported irritable bowel syndrome (IBS). An epidemiological population based study of women

    OpenAIRE

    Mykletun, Arnstein; Jacka, Felice; Williams, Lana; Pasco, Julie; Henry, Margaret; Nicholson, Geoffrey C.; Kotowicz, Mark A.; Berk, Michael

    2010-01-01

    Abstract Background Irritable bowel syndrome (IBS) is commonly regarded as a functional disorder, and is hypothesized to be associated with anxiety and depression. This evidence mainly rests on population-based studies utilising self-report screening instruments for psychopathology. Other studies applying structured clinical interviews are generally based on small clinical samples, which are vulnerable to biases. The extant evidence base for an association between IBS and psychopathology is h...

  20. TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib)†

    OpenAIRE

    Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William; Koscielniak, Nikolas; Kottler, Marie-Laure; Agretti, Patrizia; De Marco, Giuseppina; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

    2015-01-01

    Hypocalcemia and hyperphosphatemia because of resistance towards parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder that is caused by GNAS methylation changes, resistance can occur towards other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are...

  1. The IB Diploma and UK University Degree Qualifications

    Science.gov (United States)

    Frank-Gemmill, Gerda

    2013-01-01

    In recent years the International Baccalaureate (IB) Diploma has become widely accepted as a university-entry qualification in the UK, but there has been little quantitative research into the achievements of IB students at degree level. This study investigates IB students from one selective independent school who entered UK universities between…

  2. Small bowel bacterial overgrowth

    Science.gov (United States)

    ... Surgical procedures that create a loop of small intestine where excess bacteria can grow. An example is a Billroth II type of stomach removal ( gastrectomy ). Some cases of irritable bowel syndrome (IBS).

  3. Randomised controlled trial of mesalazine in IBS.

    Science.gov (United States)

    Barbara, Giovanni; Cremon, Cesare; Annese, Vito; Basilisco, Guido; Bazzoli, Franco; Bellini, Massimo; Benedetti, Antonio; Benini, Luigi; Bossa, Fabrizio; Buldrini, Paola; Cicala, Michele; Cuomo, Rosario; Germanà, Bastianello; Molteni, Paola; Neri, Matteo; Rodi, Marcello; Saggioro, Alfredo; Scribano, Maria Lia; Vecchi, Maurizio; Zoli, Giorgio; Corinaldesi, Roberto; Stanghellini, Vincenzo

    2016-01-01

    Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. ClincialTrials.gov number, NCT00626288. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  4. Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold.

    Science.gov (United States)

    Tan, Kemin; Cao, Nan; Cheng, Bokun; Joachimiak, Andrzej; Tse-Dinh, Yuk-Ching

    2016-01-16

    The DNA topoisomerase I enzyme of Mycobacterium tuberculosis (MtTOP1) is essential for the viability of the organism and survival in a murine model. This topoisomerase is being pursued as a novel target for the discovery of new therapeutic agents for the treatment of drug-resistant tuberculosis. In this study, we succeeded in obtaining a structure of MtTOP1 by first predicting that the C-terminal region of MtTOP1 contains four repeated domains that do not involve the Zn-binding tetracysteine motifs seen in the C-terminal domains of Escherichia coli topoisomerase I. A construct (amino acids A2-T704), MtTOP1-704t, that includes the N-terminal domains (D1-D4) and the first predicted C-terminal domain (D5) of MtTOP1 was expressed and found to retain DNA cleavage-religation activity and catalyze single-stranded DNA catenation. MtTOP1-704t was crystallized, and a structure of 2.52Å resolution limit was obtained. The structure of the MtTOP1 N-terminal domains has features that have not been observed in other previously available bacterial topoisomerase I crystal structures. The first C-terminal domain D5 forms a novel protein fold of a four-stranded antiparallel β-sheet stabilized by a crossing-over α-helix. Since there is only one type IA topoisomerase present in Mycobacteriaceae and related Actinobacteria, this subfamily of type IA topoisomerase may be required for multiple functions in DNA replication, transcription, recombination, and repair. The unique structural features observed for MtTOP1 may allow these topoisomerase I enzymes to carry out physiological functions associated with topoisomerase III enzyme in other bacteria. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Distinct Mechanism Evolved for Mycobacterial RNA Polymerase and Topoisomerase I Protein-Protein Interaction.

    Science.gov (United States)

    Banda, Srikanth; Cao, Nan; Tse-Dinh, Yuk-Ching

    2017-09-15

    We report here a distinct mechanism of interaction between topoisomerase I and RNA polymerase in Mycobacterium tuberculosis and Mycobacterium smegmatis that has evolved independently from the previously characterized interaction between bacterial topoisomerase I and RNA polymerase. Bacterial DNA topoisomerase I is responsible for preventing the hyper-negative supercoiling of genomic DNA. The association of topoisomerase I with RNA polymerase during transcription elongation could efficiently relieve transcription-driven negative supercoiling. Our results demonstrate a direct physical interaction between the C-terminal domains of topoisomerase I (TopoI-CTDs) and the β' subunit of RNA polymerase of M. smegmatis in the absence of DNA. The TopoI-CTDs in mycobacteria are evolutionarily unrelated in amino acid sequence and three-dimensional structure to the TopoI-CTD found in the majority of bacterial species outside Actinobacteria, including Escherichia coli. The functional interaction between topoisomerase I and RNA polymerase has evolved independently in mycobacteria and E. coli, with distinctively different structural elements of TopoI-CTD utilized for this protein-protein interaction. Zinc ribbon motifs in E. coli TopoI-CTD are involved in the interaction with RNA polymerase. For M. smegmatis TopoI-CTD, a 27-amino-acid tail that is rich in basic residues at the C-terminal end is responsible for the interaction with RNA polymerase. Overexpression of recombinant TopoI-CTD in M. smegmatis competed with the endogenous topoisomerase I for protein-protein interactions with RNA polymerase. The TopoI-CTD overexpression resulted in decreased survival following treatment with antibiotics and hydrogen peroxide, supporting the importance of the protein-protein interaction between topoisomerase I and RNA polymerase during stress response of mycobacteria. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses

    OpenAIRE

    Pépin, Geneviève; Nejad, Charlotte; Ferrand, Jonathan; Thomas, Belinda J.; Stunden, H. James; Sanij, Elaine; Foo, Chwan-Hong; Stewart, Cameron R.; Cain, Jason E.; Bardin, Philip G.; Williams, Bryan R. G.; Gantier, Michael P.

    2017-01-01

    ABSTRACT Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through c...

  7. Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Kemin; Cao, Nan; Cheng, Bokun; Joachimiak, Andrzej; Tse-Dinh, Yuk-Ching

    2016-01-16

    The DNA topoisomerase I enzyme of Mycobacterium tuberculosis (MtTOP1) is essential for the viability of the organism and survival in a murine model. This topoisomerase is being pursued as a novel target for the discovery of new therapeutic agents for the treatment of drug-resistant tuberculosis. In this study, we succeeded in obtaining a structure of MtTOP1 by first predicting that the C-terminal region of MtTOP1 contains four repeated domains that do not involve the Zn-binding tetracysteine motifs seen in the C-terminal domains of Escherichia coli topoisomerase I. A construct (amino acids A2-T704), MtTOP1-704t, that includes the N-terminal domains (D1-D4) and the first predicted C-terminal domain (D5) of MtTOP1 was expressed and found to retain DNA cleavage-religation activity and catalyze single-stranded DNA catenation. MtTOP1-704t was crystallized, and a structure of 2.52 angstrom resolution limit was obtained. The structure of the MtTOP1 N-terminal domains has features that have not been observed in other previously available bacterial topoisomerase I crystal structures. The first C-terminal domain D5 forms a novel protein fold of a four-stranded antiparallel beta-sheet stabilized by a crossing-over alpha-helix. Since there is only one type IA topoisomerase present in Mycobacteriaceae and related Actinobacteria, this subfamily of type IA topoisomerase may be required for multiple functions in DNA replication, transcription, recombination, and repair. The unique structural features observed for MtTOP1 may allow these topoisomerase I enzymes to carry out physiological functions associated with topoisomerase III enzyme in other bacteria.

  8. Prevalence of mood and anxiety disorder in self reported irritable bowel syndrome (IBS). An epidemiological population based study of women.

    Science.gov (United States)

    Mykletun, Arnstein; Jacka, Felice; Williams, Lana; Pasco, Julie; Henry, Margaret; Nicholson, Geoffrey C; Kotowicz, Mark A; Berk, Michael

    2010-08-05

    Irritable bowel syndrome (IBS) is commonly regarded as a functional disorder, and is hypothesized to be associated with anxiety and depression. This evidence mainly rests on population-based studies utilising self-report screening instruments for psychopathology. Other studies applying structured clinical interviews are generally based on small clinical samples, which are vulnerable to biases. The extant evidence base for an association between IBS and psychopathology is hence not conclusive. The aim of this study was therefore to re-examine the hypothesis using population-based data and psychiatric morbidity established with a structured clinical interview. Data were derived from a population-based epidemiological study (n = 1077). Anxiety and mood disorders were established using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP) and the General Health Questionnaire (GHQ-12). Current and lifetime IBS was self-reported. Hypertension and diabetes were employed as comparison groups as they are expected to be unrelated to mental health. Current IBS (n = 69, 6.4%) was associated with an increased likelihood of current mood and/or anxiety disorders (OR = 2.62, 95%CI 1.49 - 4.60). Half the population reporting a lifetime IBS diagnosis also had a lifetime mood or anxiety disorder. Exploratory analyses demonstrated an increased prevalence of IBS across most common anxiety and mood disorders, the exception being bipolar disorder. The association with IBS and symptoms load (GHQ-12) followed a curved dose response pattern. In contrast, hypertension and diabetes were consistently unrelated to psychiatric morbidity. IBS is significantly associated with anxiety and mood disorders. This study provides indicative evidence for IBS as a disorder with a psychosomatic aspect.

  9. Prevalence of mood and anxiety disorder in self reported irritable bowel syndrome (IBS. An epidemiological population based study of women

    Directory of Open Access Journals (Sweden)

    Mykletun Arnstein

    2010-08-01

    Full Text Available Abstract Background Irritable bowel syndrome (IBS is commonly regarded as a functional disorder, and is hypothesized to be associated with anxiety and depression. This evidence mainly rests on population-based studies utilising self-report screening instruments for psychopathology. Other studies applying structured clinical interviews are generally based on small clinical samples, which are vulnerable to biases. The extant evidence base for an association between IBS and psychopathology is hence not conclusive. The aim of this study was therefore to re-examine the hypothesis using population-based data and psychiatric morbidity established with a structured clinical interview. Methods Data were derived from a population-based epidemiological study (n = 1077. Anxiety and mood disorders were established using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP and the General Health Questionnaire (GHQ-12. Current and lifetime IBS was self-reported. Hypertension and diabetes were employed as comparison groups as they are expected to be unrelated to mental health. Results Current IBS (n = 69, 6.4% was associated with an increased likelihood of current mood and/or anxiety disorders (OR = 2.62, 95%CI 1.49 - 4.60. Half the population reporting a lifetime IBS diagnosis also had a lifetime mood or anxiety disorder. Exploratory analyses demonstrated an increased prevalence of IBS across most common anxiety and mood disorders, the exception being bipolar disorder. The association with IBS and symptoms load (GHQ-12 followed a curved dose response pattern. In contrast, hypertension and diabetes were consistently unrelated to psychiatric morbidity. Conclusions IBS is significantly associated with anxiety and mood disorders. This study provides indicative evidence for IBS as a disorder with a psychosomatic aspect.

  10. Cytotoxicity and inhibitory properties against topoisomerase II of doxorubicin and its formamidine derivatives.

    Science.gov (United States)

    Kik, Krzysztof; Studzian, Kazimierz; Wasowska-Łukawska, Małgorzata; Oszczapowicz, Irena; Szmigiero, Leszek

    2009-01-01

    This work was undertaken to compare cytotoxicity, DNA damaging properties and effect on DNA cleavage by topoisomerase II of the anthracycline drug doxorubicin (DOX) and its two derivatives with a formamidino group containing a cyclic amine moiety such as morpholine (DOXM) or hexamethyleneimine (DOXH). The tetrazolium dye colorimetric assay was used to determine the cytotoxic activity of anthracyclines toward L1210 leukemia cells. DNA damage was measured by alkaline elution technique. The effect of anthracyclines on DNA cleavage was studied in a cell-free system containing supercoiled pBR322 DNA and purified human topoisomerase II. The cytotoxicity data and the results of studies on the mechanism of DNA break formation by anthracyclines at the cellular level and in the cell-free system showed that the presence of the formamidino group in the doxorubicin molecule reduced its ability to stimulate DNA cleavage by DNA topoisomerase II. DNA topoisomerase II is not a primary cellular target for DOXM or DOXH. An advantageous feature of formamidinoanthracyclines is their mechanism of cytotoxic action which is not related to the inhibition of DNA topoisomerase II. Therefore this class of anthracyclines seems to be a good source for selection of an anticancer drug directed toward cancer cells with the developed multidrug resistance attributed to the presence of altered DNA topoisomerase II.

  11. Influence of microstructure on laser damage threshold of IBS coatings

    International Nuclear Information System (INIS)

    Stolz, C.J.; Genin, F.Y.; Kozlowski, M.R.; Long, D.; Lalazari, R.; Wu, Z.L.; Kuo, P.K.

    1996-01-01

    Ion-beam sputtering (IBS) coatings were developed for the laser gyro industry to meet significantly different requirements than those of fusion lasers. Laser gyro mirrors are small ( 26 J/cm 2 at 1,064 nm with 3-ns pulses). As part of the National Ignition Facility (NIF) coating development effort, IBS coatings are being studied to explore the possible benefits of this technology to NIF optics. As an initial step to achieving the NIF size and damage threshold requirements, the coating process is being scaled to uniformly coat a 20 x 40 cm 2 area with reduced spectral, reflected wavefront, and laser damage threshold requirements. Here, multilayer coatings deposited by ion-beam sputtering with amorphous layers were found to have lower damage thresholds at 1,064 nm than similar coatings with crystalline layers. Interestingly, at higher fluences the damage was less severe for the amorphous coatings. The magnitude of the difference in damage thresholds between the two different microstructures was strongly influenced by the size of the tested area. To better understand the microstructure effects, single layers of HfO 2 with different microstructures were studied using transmission electron microscopy, ellipsometry, and a photothermal deflection technique. Since the laser damage initiated at defects, the influence of thermal diffusivity on thermal gradients in nodular defects is also presented

  12. Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy

    DEFF Research Database (Denmark)

    Martin, E.; Thougaard, A.V.; Grauslund, M.

    2009-01-01

    of topoisomerase II, resulting in the risk of additional myelosuppression in patients receiving ICRF-187 as a cardioprotectant in combination with doxorubicin. The development of a topoisomerase II-inactive iron chelating compound thus appeared attractive. In the present paper we evaluate the topoisomerase II...... chelation alone does not appear to be sufficient for protection against anthracycline-induced cardiomyopathy Udgivelsesdato: 2009/1/8...

  13. Innovative Approach for IBS Vendor Selection Problem

    Directory of Open Access Journals (Sweden)

    Omar Mohd Faizal

    2016-01-01

    Full Text Available Supply chain management in Industrialised Building System (IBS construction management has significantly determined the successful of company and project performance. Due to the wide variety of criteria and vendor available, the vendor selection process for a specific project needs is becoming more difficult. The need of decision aid for vendor selection in other areas is widely discussed in previous research. However, study on vendor selection for IBS project is largely neglected. Decision Support System (DSS is proposed for this purpose. Yet, most of the DSS models are impractical since they are complicated and difficult for a layman such as project managers to use. Research indicates that the rapid development of ICT has highly potential towards simple and effective DSS. Thus, this paper highlights the importance and research approach for vendor selection in IBS project management. The study is based on Design Science Research Methodology with combination of case studies. It is anticipates that this study will yield an effective value-for-money decision making platform to manage vendor selection process.

  14. ATM deficiency results in accumulation of DNA-topoisomerase I covalent intermediates in neural cells.

    Directory of Open Access Journals (Sweden)

    Meryem Alagoz

    Full Text Available Accumulation of peptide-linked DNA breaks contributes to neurodegeration in humans. This is typified by defects in tyrosyl DNA phosphodiesterase 1 (TDP1 and human hereditary ataxia. TDP1 primarily operates at single-strand breaks (SSBs created by oxidative stress or by collision of transcription machinery with topoisomerase I intermediates (Top1-CCs. Cellular and cell-free studies have shown that Top1 at stalled Top1-CCs is first degraded to a small peptide resulting in Top1-SSBs, which are the primary substrates for TDP1. Here we established an assay to directly compare Top1-SSBs and Top1-CCs. We subsequently employed this assay to reveal an increased steady state level of Top1-CCs in neural cells lacking Atm; the protein mutated in ataxia telangiectasia. Our data suggest that the accumulation of endogenous Top1-CCs in Atm-/- neural cells is primarily due to elevated levels of reactive oxygen species. Biochemical purification of Top1-CCs from neural cell extract and the use of Top1 poisons further confirmed a role for Atm during the formation/resolution of Top1-CCs. Finally, we report that global transcription is reduced in Atm-/- neural cells and fails to recover to normal levels following Top1-mediated DNA damage. Together, these data identify a distinct role for ATM during the formation/resolution of neural Top1-CCs and suggest that their accumulation contributes to the neuropathology of ataxia telangiectasia.

  15. Effects of an unusual poison identify a lifespan role for Topoisomerase 2 in Saccharomyces cerevisiae.

    Science.gov (United States)

    Tombline, Gregory; Millen, Jonathan I; Polevoda, Bogdan; Rapaport, Matan; Baxter, Bonnie; Van Meter, Michael; Gilbertson, Matthew; Madrey, Joe; Piazza, Gary A; Rasmussen, Lynn; Wennerberg, Krister; White, E Lucile; Nitiss, John L; Goldfarb, David S

    2017-01-05

    A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in Saccharomyces cerevisiae (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as potentially manageable cause of aging.

  16. Effects of gut-directed hypnotherapy on IBS in different clinical settings-results from two randomized, controlled trials.

    Science.gov (United States)

    Lindfors, Perjohan; Unge, Peter; Arvidsson, Patrik; Nyhlin, Henry; Björnsson, Einar; Abrahamsson, Hasse; Simrén, Magnus

    2012-02-01

    Gut-directed hypnotherapy has been found to be effective in irritable bowel syndrome (IBS). However, randomized, controlled studies are rare and few have been performed outside highly specialized research centers. The objective of this study was to study the effect of gut-directed hypnotherapy in IBS in different clinical settings outside the traditional research units. The study population included IBS patients refractory to standard management. In study 1, patients were randomized to receive gut-directed hypnotherapy (12 sessions, 1 h/week) in psychology private practices or supportive therapy, whereas patients were randomized to receive gut-directed hypnotherapy in a small county hospital or to serve as waiting list controls in study 2. Gastrointestinal symptom severity and quality of life were evaluated at baseline, at 3 months follow-up and after 1 year. We randomized 138 IBS patients refractory to standard management, 90 in study 1 and 48 in study 2. In both the studies, IBS-related symptoms were improved at 3 months in the gut-directed hypnotherapy groups (Phypnotherapy group than in the control group (Phypnotherapy is an effective treatment alternative for patients with refractory IBS, but the effectiveness is lower when the therapy is given outside the highly specialized research centers.

  17. Integrated Baseline Bystem (IBS) Version 1.03: Models guide

    Energy Technology Data Exchange (ETDEWEB)

    1993-01-01

    The Integrated Baseline System)(IBS), operated by the Federal Emergency Management Agency (FEMA), is a system of computerized tools for emergency planning and analysis. This document is the models guide for the IBS and explains how to use the emergency related computer models. This document provides information for the experienced system user, and is the primary reference for the computer modeling software supplied with the system. It is designed for emergency managers and planners, and others familiar with the concepts of computer modeling. Although the IBS manual set covers basic and advanced operations, it is not a complete reference document set. Emergency situation modeling software in the IBS is supported by additional technical documents. Some of the other IBS software is commercial software for which more complete documentation is available. The IBS manuals reference such documentation where necessary.

  18. Pea DNA topoisomerase I is phosphorylated and stimulated by casein kinase 2 and protein kinase C.

    Science.gov (United States)

    Tuteja, Narendra; Reddy, Malireddy Kodandarami; Mudgil, Yashwanti; Yadav, Badam Singh; Chandok, Meena Rani; Sopory, Sudhir Kumar

    2003-08-01

    DNA topoisomerase I catalyzes the relaxation of superhelical DNA tension and is vital for DNA metabolism; therefore, it is essential for growth and development of plants. Here, we have studied the phosphorylation-dependent regulation of topoisomerase I from pea (Pisum sativum). The purified enzyme did not show autophosphorylation but was phosphorylated in an Mg(2+)-dependent manner by endogenous protein kinases present in pea nuclear extracts. This phosphorylation was abolished with calf intestinal alkaline phosphatase and lambda phosphatase. It was also phosphorylated by exogenous casein kinase 2 (CK2), protein kinase C (PKC; from animal sources), and an endogenous pea protein, which was purified using a novel phorbol myristate acetate affinity chromatography method. All of these phosphorylations were inhibited by heparin (inhibitor of CK2) and calphostin (inhibitor of PKC), suggesting that pea topoisomerase I is a bona fide substrate for these kinases. Spermine and spermidine had no effect on the CK2-mediated phosphorylation, suggesting that it is polyamine independent. Phospho-amino acid analysis showed that only serine residues were phosphorylated, which was further confirmed using antiphosphoserine antibody. The topoisomerase I activity increased after phosphorylation with exogenous CK2 and PKC. This study shows that these kinases may contribute to the physiological regulation of DNA topoisomerase I activity and overall DNA metabolism in plants.

  19. Dynamic investigation of DNA bending and wrapping by type II topoisomerases

    Science.gov (United States)

    Shao, Qing; Finzi, Laura; Dunlap, David

    2009-11-01

    Type II topoisomerases catalyze DNA decatenation and unwinding which is crucial for cell division, and therefore type II topoisomerases are some of the main targets of anti-cancer drugs. A recent crystal structure shows that, during the catalytic cycle, a yeast type II topoimerase can bend a 10 base pair DNA segment by up to 150 degrees. Bacterial gyrase, another type II topoisomerase, can wrap DNA into a tight 180 degree turn. Bending a stiff polymer like DNA requires considerable energy and could represent the rate limiting step in the catalytic (topological) cycle. Using modified deoxyribonucleotides in PCR reactions, stiffer DNA fragments have been produced and used as substrates for topoisomerase II-mediated relaxation of plectonemes introduced in single molecules using magnetic tweezers. The wrapping ability of gyrase decreases for diamino-purine-substituted DNA in which every base pair has three hydrogen-bonds. The overall rate of relaxation of plectonemes by recombinant human topoisomerase II alpha also decreases. These results reveal the dynamic properties of DNA bending and wrapping by type II topisomerases and suggest that A:T base pair melting is a rate determining step for bending and wrapping.

  20. Involvement of DNA topoisomerase I in transcription of human ribosomal RNA genes

    International Nuclear Information System (INIS)

    Zhang, H.; Wang, J.C.; Liu, L.F.

    1988-01-01

    Treatment of HeLa cells with a DNA topoisomerase I-specific inhibitor, camptothecin, results in rapid cessation of the synthesis of the 45S rRNA precursor. The inhibition of rRNA synthesis is reversible following drug removal and correlates with the presence of camptothecin-trapped topoisomerase I-DNA abortive complexes, which can be detected as topoisomerase I-linked DNA breaks upon lysis with sodium dodecyl sulfate. These breaks were found to be concentrated within the transcribed region of human rRNA genes. No such sites can be detected in the inactive human rRNA genes in mouse-human hybrid cells, suggesting a preferential association of topoisomerase I with actively transcribed genes. The distribution of RNA polymerase molecules along the transcription unit of human rRNA genes in camptothecin-treated HeLa cells, as assayed by nuclear run-on transcription, shows a graded decrease of the RNA polymerase density toward the 3' end of the transcription unit; the density is minimally affected near the 5' start of the transcription unit. These results suggest that DNA topoisomerase I is normally involved in the elongation step of transcription, especially when the transcripts are long, and that camptothecin interferes with this role

  1. 3D visualization software to analyze topological outcomes of topoisomerase reactions

    Science.gov (United States)

    Darcy, I. K.; Scharein, R. G.; Stasiak, A.

    2008-01-01

    The action of various DNA topoisomerases frequently results in characteristic changes in DNA topology. Important information for understanding mechanistic details of action of these topoisomerases can be provided by investigating the knot types resulting from topoisomerase action on circular DNA forming a particular knot type. Depending on the topological bias of a given topoisomerase reaction, one observes different subsets of knotted products. To establish the character of topological bias, one needs to be aware of all possible topological outcomes of intersegmental passages occurring within a given knot type. However, it is not trivial to systematically enumerate topological outcomes of strand passage from a given knot type. We present here a 3D visualization software (TopoICE-X in KnotPlot) that incorporates topological analysis methods in order to visualize, for example, knots that can be obtained from a given knot by one intersegmental passage. The software has several other options for the topological analysis of mechanisms of action of various topoisomerases. PMID:18440983

  2. The phosphoCTD-interacting domain of Topoisomerase I

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Jianhong; Phatnani, Hemali P.; Hsieh, Tao-Shih [Department of Biochemistry, Duke University Medical Center, Durham, NC 27710 (United States); Greenleaf, Arno L., E-mail: arno.greenleaf@duke.edu [Department of Biochemistry, Duke University Medical Center, Durham, NC 27710 (United States)

    2010-06-18

    The N-terminal domain (NTD) of Drosophila melanogaster (Dm) Topoisomerase I has been shown to bind to RNA polymerase II, but the domain of RNAPII with which it interacts is not known. Using bacterially-expressed fusion proteins carrying all or half of the NTDs of Dm and human (Homo sapiens, Hs) Topo I, we demonstrate that the N-terminal half of each NTD binds directly to the hyperphosphorylated C-terminal repeat domain (phosphoCTD) of the largest RNAPII subunit, Rpb1. Thus, the amino terminal segment of metazoan Topo I (1-157 for Dm and 1-114 for Hs) contains a novel phosphoCTD-interacting domain that we designate the Topo I-Rpb1 interacting (TRI) domain. The long-known in vivo association of Topo I with active genes presumably can be attributed, wholly or in part, to the TRI domain-mediated binding of Topo I to the phosphoCTD of transcribing RNAPII.

  3. Resveratrol: A novel type of topoisomerase II inhibitor.

    Science.gov (United States)

    Lee, Joyce H; Wendorff, Timothy J; Berger, James M

    2017-12-22

    Resveratrol, a polyphenol found in various plant sources, has gained attention as a possible agent responsible for the purported health benefits of certain foods, such as red wine. Despite annual multi-million dollar market sales as a nutriceutical, there is little consensus about the physiological roles of resveratrol. One suggested molecular target of resveratrol is eukaryotic topoisomerase II (topo II), an enzyme essential for chromosome segregation and DNA supercoiling homeostasis. Interestingly, resveratrol is chemically similar to ICRF-187, a clinically approved chemotherapeutic that stabilizes an ATP-dependent dimerization interface in topo II to block enzyme activity. Based on this similarity, we hypothesized that resveratrol may antagonize topo II by a similar mechanism. Using a variety of biochemical assays, we find that resveratrol indeed acts through the ICRF-187 binding locus, but that it inhibits topo II by preventing ATPase domain dimerization rather than stabilizing it. This work presents the first comprehensive analysis of the biochemical effects of both ICRF-187 and resveratrol on the human isoforms of topo II, and reveals a new mode for the allosteric regulation of topo II through modulation of ATPase status. Natural polyphenols related to resveratrol that have been shown to impact topo II function may operate in a similar manner. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. The phosphoCTD-interacting domain of Topoisomerase I

    International Nuclear Information System (INIS)

    Wu, Jianhong; Phatnani, Hemali P.; Hsieh, Tao-Shih; Greenleaf, Arno L.

    2010-01-01

    The N-terminal domain (NTD) of Drosophila melanogaster (Dm) Topoisomerase I has been shown to bind to RNA polymerase II, but the domain of RNAPII with which it interacts is not known. Using bacterially-expressed fusion proteins carrying all or half of the NTDs of Dm and human (Homo sapiens, Hs) Topo I, we demonstrate that the N-terminal half of each NTD binds directly to the hyperphosphorylated C-terminal repeat domain (phosphoCTD) of the largest RNAPII subunit, Rpb1. Thus, the amino terminal segment of metazoan Topo I (1-157 for Dm and 1-114 for Hs) contains a novel phosphoCTD-interacting domain that we designate the Topo I-Rpb1 interacting (TRI) domain. The long-known in vivo association of Topo I with active genes presumably can be attributed, wholly or in part, to the TRI domain-mediated binding of Topo I to the phosphoCTD of transcribing RNAPII.

  5. TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib).

    Science.gov (United States)

    Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William; Koscielniak, Nikolas; Kottler, Marie-Laure; Agretti, Patrizia; De Marco, Giuseppina; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

    2015-05-01

    Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications. © 2014 American Society for Bone and Mineral Research.

  6. TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib)†

    Science.gov (United States)

    Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William; Koscielniak, Nikolas; Kottler, Marie-Laure; Agretti, Patrizia; De Marco, Giuseppina; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

    2014-01-01

    Hypocalcemia and hyperphosphatemia because of resistance towards parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder that is caused by GNAS methylation changes, resistance can occur towards other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3-20 years later. Although anti-TPO antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL and A/B, and gain of methylation at exon NESP55, i.e. findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications. PMID:25403028

  7. Identification and localization of a gene that specifies production of Escherichia coli DNA topoisomerase I

    International Nuclear Information System (INIS)

    Trucksis, M.; Depew, R.E.

    1981-01-01

    A gene that specifies production of Escherichia coli DNA topoisomerase I (ω protein) was identified with the aid of a radioimmunoassay for this protein. E. coli DNA topoisomerase I was produced by Salmonella typhimurium merodiploids that harbored E. coli plasmid F' 123, but not by strains that lost this plasmid. Analysis of strains with spontaneous deletions of F' 123 showed that the gene, topA, required for production of the E. coli ω protein was between the trp operon and the cysB gene. Deletions that eliminated topA also eliminated the supX gene. We suggest that topA is the structural gene of E. coli DNA topoisomerase I and that topA is identical to supX

  8. Real-Time Label-Free Direct Electronic Monitoring of Topoisomerase Enzyme Binding Kinetics on Graphene.

    Science.gov (United States)

    Zuccaro, Laura; Tesauro, Cinzia; Kurkina, Tetiana; Fiorani, Paola; Yu, Hak Ki; Knudsen, Birgitta R; Kern, Klaus; Desideri, Alessandro; Balasubramanian, Kannan

    2015-11-24

    Monolayer graphene field-effect sensors operating in liquid have been widely deployed for detecting a range of analyte species often under equilibrium conditions. Here we report on the real-time detection of the binding kinetics of the essential human enzyme, topoisomerase I interacting with substrate molecules (DNA probes) that are immobilized electrochemically on to monolayer graphene strips. By monitoring the field-effect characteristics of the graphene biosensor in real-time during the enzyme-substrate interactions, we are able to decipher the surface binding constant for the cleavage reaction step of topoisomerase I activity in a label-free manner. Moreover, an appropriate design of the capture probes allows us to distinctly follow the cleavage step of topoisomerase I functioning in real-time down to picomolar concentrations. The presented results are promising for future rapid screening of drugs that are being evaluated for regulating enzyme activity.

  9. Increased topoisomerase IIalpha expression in colorectal cancer is associated with advanced disease and chemotherapeutic resistance via inhibition of apoptosis.

    LENUS (Irish Health Repository)

    Coss, Alan

    2012-02-01

    Topoisomerase IIalpha is a nuclear enzyme that regulates the tertiary structure of DNA. The influence of topoisomerase IIalpha gene (TOP2A) or protein alterations on disease progression and treatment response in colorectal cancer (CRC) is unknown. The study investigated the clinical relevance of topoisomerase IIalpha in CRC using in vivo and in vitro models. Differentially expressed genes in early and late-stage CRC were identified by array comparative genomic hybridization (CGH). Cellular location of gene amplifications was determined by fluorescence in situ hybridization (FISH). Topoisomerase IIalpha levels, proliferation index, and HER2 expression were examined in 228 colorectal tumors by immunohistochemistry. Overexpression of topoisomerase IIalpha in vitro was achieved by liposome-based transfection. Cell growth inhibition and apoptosis were quantified using the crystal violet assay and flow cytometry, respectively, in response to drug treatment. Amplification of TOP2A was identified in 3 (7.7%) tumors using array CGH and confirmed using FISH. At the protein level, topoisomerase IIalpha staining was observed in 157 (69%) tumors, and both staining and intensity levels were associated with an aggressive tumor phenotype (p values 0.04 and 0.005, respectively). Using logistic regression analysis, topoisomerase IIalpha remained significantly associated with advanced tumor stage when corrected for tumor proliferation (p=0.007) and differentiation (p=0.001). No association was identified between topoisomerase IIalpha and HER2. In vitro, overexpression of topoisomerase IIalpha was associated with resistance to irinotecan (p=0.001) and etoposide chemotherapy (p=0.03), an effect mediated by inhibition of apoptosis. Topoisomerase IIalpha overexpression is significantly associated with alterations in tumor behavior and response to drug treatment in CRC. Our results suggest that gene amplification may represent an important mechanism underlying these changes.

  10. A Measure of Suffering in relation to Anxiety and Quality of Life in IBS Patients: Preliminary Results

    Directory of Open Access Journals (Sweden)

    Sanda Pletikosić Tončić

    2017-01-01

    Full Text Available Irritable bowel syndrome (IBS is a chronic gastrointestinal (GI disorder with a severe impact on quality of life (QoL. We explored the relationship of a visual measure of suffering, the PRISM-RII, with quality of life (QoL and anxiety measures in IBS patients. Participants were 44 IBS patients who completed several questionnaires and kept a symptom diary for two weeks. The measures used were PRISM-RII (self-illness separation (SIS; illness perception measure (IPM; IBS-36 (IBS health related QoL; SF-36 (physical and mental health related QoL; State-Trait Anxiety Inventory (STAI-T; Visceral Sensitivity Index (VSI; GI-specific anxiety; and a symptom diary. SIS was negatively correlated to VSI, while IPM was negatively correlated to SIS and the physical component of SF-36 and positively to VSI and symptom severity. We found significant differences between participants who perceive their illness as small and those who perceive it as medium in SIS, symptom severity, VSI, and the mental component of SF-36. Participants, who perceived their illness as small, represented their illness as more distant, showed lower average symptom severity, and had lower GI-specific anxiety and higher QoL. The results indicate that IPM and SIS can be useful in discriminating patients with more prominent psychological difficulties and QoL impairment.

  11. Streptococcus sanguinis Class Ib Ribonucleotide Reductase

    Science.gov (United States)

    Makhlynets, Olga; Boal, Amie K.; Rhodes, DeLacy V.; Kitten, Todd; Rosenzweig, Amy C.; Stubbe, JoAnne

    2014-01-01

    Streptococcus sanguinis is a causative agent of infective endocarditis. Deletion of SsaB, a manganese transporter, drastically reduces S. sanguinis virulence. Many pathogenic organisms require class Ib ribonucleotide reductase (RNR) to catalyze the conversion of nucleotides to deoxynucleotides under aerobic conditions, and recent studies demonstrate that this enzyme uses a dimanganese-tyrosyl radical (MnIII2-Y•) cofactor in vivo. The proteins required for S. sanguinis ribonucleotide reduction (NrdE and NrdF, α and β subunits of RNR; NrdH and TrxR, a glutaredoxin-like thioredoxin and a thioredoxin reductase; and NrdI, a flavodoxin essential for assembly of the RNR metallo-cofactor) have been identified and characterized. Apo-NrdF with FeII and O2 can self-assemble a diferric-tyrosyl radical (FeIII2-Y•) cofactor (1.2 Y•/β2) and with the help of NrdI can assemble a MnIII2-Y• cofactor (0.9 Y•/β2). The activity of RNR with its endogenous reductants, NrdH and TrxR, is 5,000 and 1,500 units/mg for the Mn- and Fe-NrdFs (Fe-loaded NrdF), respectively. X-ray structures of S. sanguinis NrdIox and MnII2-NrdF are reported and provide a possible rationale for the weak affinity (2.9 μm) between them. These streptococcal proteins form a structurally distinct subclass relative to other Ib proteins with unique features likely important in cluster assembly, including a long and negatively charged loop near the NrdI flavin and a bulky residue (Thr) at a constriction in the oxidant channel to the NrdI interface. These studies set the stage for identifying the active form of S. sanguinis class Ib RNR in an animal model for infective endocarditis and establishing whether the manganese requirement for pathogenesis is associated with RNR. PMID:24381172

  12. TRPA1 is functionally expressed primarily by IB4-binding, non-peptidergic mouse and rat sensory neurons.

    Directory of Open Access Journals (Sweden)

    Marie E Barabas

    Full Text Available Subpopulations of somatosensory neurons are characterized by functional properties and expression of receptor proteins and surface markers. CGRP expression and IB4-binding are commonly used to define peptidergic and non-peptidergic subpopulations. TRPA1 is a polymodal, plasma membrane ion channel that contributes to mechanical and cold hypersensitivity during tissue injury, making it a key target for pain therapeutics. Some studies have shown that TRPA1 is predominantly expressed by peptidergic sensory neurons, but others indicate that TRPA1 is expressed extensively within non-peptidergic, IB4-binding neurons. We used FURA-2 calcium imaging to define the functional distribution of TRPA1 among peptidergic and non-peptidergic adult mouse (C57BL/6J DRG neurons. Approximately 80% of all small-diameter (<27 µm neurons from lumbar 1-6 DRGs that responded to TRPA1 agonists allyl isothiocyanate (AITC; 79% or cinnamaldehyde (84% were IB4-positive. Retrograde labeling via plantar hind paw injection of WGA-Alexafluor594 showed similarly that most (81% cutaneous neurons responding to TRPA1 agonists were IB4-positive. Additionally, we cultured DRG neurons from a novel CGRP-GFP mouse where GFP expression is driven by the CGRPα promoter, enabling identification of CGRP-expressing live neurons. Interestingly, 78% of TRPA1-responsive neurons were CGRP-negative. Co-labeling with IB4 revealed that the majority (66% of TRPA1 agonist responders were IB4-positive but CGRP-negative. Among TRPA1-null DRGs, few small neurons (2-4% responded to either TRPA1 agonist, indicating that both cinnamaldehyde and AITC specifically target TRPA1. Additionally, few large neurons (≥27 µm diameter responded to AITC (6% or cinnamaldehyde (4%, confirming that most large-diameter somata lack functional TRPA1. Comparison of mouse and rat DRGs showed that the majority of TRPA1-responsive neurons in both species were IB4-positive. Together, these data demonstrate that TRPA1 is

  13. TRPA1 Is Functionally Expressed Primarily by IB4-Binding, Non-Peptidergic Mouse and Rat Sensory Neurons

    Science.gov (United States)

    Stucky, Cheryl L.

    2012-01-01

    Subpopulations of somatosensory neurons are characterized by functional properties and expression of receptor proteins and surface markers. CGRP expression and IB4-binding are commonly used to define peptidergic and non-peptidergic subpopulations. TRPA1 is a polymodal, plasma membrane ion channel that contributes to mechanical and cold hypersensitivity during tissue injury, making it a key target for pain therapeutics. Some studies have shown that TRPA1 is predominantly expressed by peptidergic sensory neurons, but others indicate that TRPA1 is expressed extensively within non-peptidergic, IB4-binding neurons. We used FURA-2 calcium imaging to define the functional distribution of TRPA1 among peptidergic and non-peptidergic adult mouse (C57BL/6J) DRG neurons. Approximately 80% of all small-diameter (neurons from lumbar 1–6 DRGs that responded to TRPA1 agonists allyl isothiocyanate (AITC; 79%) or cinnamaldehyde (84%) were IB4-positive. Retrograde labeling via plantar hind paw injection of WGA-Alexafluor594 showed similarly that most (81%) cutaneous neurons responding to TRPA1 agonists were IB4-positive. Additionally, we cultured DRG neurons from a novel CGRP-GFP mouse where GFP expression is driven by the CGRPα promoter, enabling identification of CGRP-expressing live neurons. Interestingly, 78% of TRPA1-responsive neurons were CGRP-negative. Co-labeling with IB4 revealed that the majority (66%) of TRPA1 agonist responders were IB4-positive but CGRP-negative. Among TRPA1-null DRGs, few small neurons (2–4%) responded to either TRPA1 agonist, indicating that both cinnamaldehyde and AITC specifically target TRPA1. Additionally, few large neurons (≥27 µm diameter) responded to AITC (6%) or cinnamaldehyde (4%), confirming that most large-diameter somata lack functional TRPA1. Comparison of mouse and rat DRGs showed that the majority of TRPA1-responsive neurons in both species were IB4-positive. Together, these data demonstrate that TRPA1 is functionally expressed

  14. Treatment of cancer of cervix stages IB1 and IB2 in the Hospital Calderon Guardia (2000-2003)

    International Nuclear Information System (INIS)

    Saenz, Oscar; Picans, Serafin

    2004-01-01

    The types of treatment applied in patients with stages of cancer of cervix IB1 and IB2, your evolution and prognosis were determined. Different methods of treatment were compared. It was a prospective descriptive and observational study of the patients of Servicio de Ginecologia Oncologica of the Hospital Calderon Guardia, San Jose, Costa Rica. It was carried out from August 2000 to November 2002. The study included all female patients with proved histological diagnosis of cervical cancer IB1 and IB2. All of them had pre-operative studies: plate of thorax, abdomen ultrasound, computerized axial tomography of pelvis and abdomen, at least received primary treatment (surgery) and the following monitoring. The statistical analysis was realized with chi-square evidences, through epi-info software. Of 24 patients only 19 got complete information. It was found a 22% of patients with positives adenopatias to level of histological study with a ganglionic compromise of 32% in general form, a 36% in the stages IB1 and a 25% in stages IB2. Of all the patients that presented ganglionic metastasis illness, did not get to show with the computerized axial tomography and it is concluded that TAC is a bad method for detection of the microscopic metastasis illness, or at least to 2 cm. None of the patients in stages IB1 presented relapse data in the observed period, founding a 100% of survival to 24 months. The patients in stages IB2 presented relapses, with a 75% of survival [es

  15. The involvement of topoisomerases and DNA polymerase I in the mechanism of induced thermal and radiation resistance in yeast

    International Nuclear Information System (INIS)

    Boreham, D.R.; Trivedi, A.; Weinberger, P.; Mitchel, R.E.

    1990-01-01

    Either an ionizing radiation exposure or a heat shock is capable of inducing both thermal tolerance and radiation resistance in yeast. Yeast mutants, deficient in topoisomerase I, in topoisomerase II, or in DNA polymerase I, were used to investigate the mechanism of these inducible resistances. The absence of either or both topoisomerase activities did not prevent induction of either heat or radiation resistance. However, if both topoisomerase I and II activities were absent, the sensitivity of yeast to become thermally tolerant (in response to a heat stress) was markedly increased. The absence of only topoisomerase I activity (top1) resulted in the constitutive expression of increased radiation resistance equivalent to that induced by a heat shock in wild-type cells, and the topoisomerase I-deficient cells were not further inducible by heat. This heat-inducible component of radiation resistance (or its equivalent constitutive expression in top1 cells) was, in turn, only a portion of the full response inducible by radiation. The absence of polymerase I activity had no detectable effect on either response. Our results indicate that the actual systems that confer resistance to heat or radiation are independent of either topoisomerase activity or DNA polymerase function, but suggest that topoisomerases may have a regulatory role during the signaling of these mechanisms. The results of our experiments imply that maintenance of correct DNA topology prevents induction of the heat-shock response, and that heat-shock induction of a component of the full radiation resistance in yeast may be the consequence of topoisomerase I inactivation

  16. An Archaebacterial Topoisomerase Homolog Not Present in Other Eukaryotes Is Indispensable for Cell Proliferation of Plants

    Czech Academy of Sciences Publication Activity Database

    Hartung, F.; Angelis, Karel; Meister, A.

    2002-01-01

    Roč. 12, - (2002), s. 1787-1791 ISSN 0960-9822 R&D Projects: GA AV ČR IAA6038201; GA ČR GA521/01/1418 Institutional research plan: CEZ:AV0Z5038910 Keywords : Archaebacterial Topoisomerase * Cell Proliferation Subject RIV: GE - Plant Breeding Impact factor: 7.007, year: 2002

  17. Consistent rationalization of type-2 topoisomerases' unknotting, decatenating, supercoil-relaxing actions and their scaling relation.

    Science.gov (United States)

    Liu, Zhirong; Chan, Hue Sun

    2015-09-09

    How type-2 topoisomerases discern global topology from local properties of DNA is not known precisely but the hypothesis that the enzymes selectively pass double-helix strands at hook-like juxtapositions is promising. Building upon an investigation of unknotting and decatenating using an improved wormlike DNA model, here we focus primarily on the enzymes' action in narrowing the distribution of linking number (Lk) in supercoiled DNA. Consistent with experiments, with selective passage at a hooked juxtaposition, the simulated narrowing factor RLk diminishes with decreasing DNA circle size but approaches an asymptotic RLk ≈ 1.7-1.8 for circle size ≳3.5 kb. For the larger DNA circles, we found that (RLk - 1) ≈ 0.42log10RK ≈ 0.68log10RL and thus RK ≈ (RL)(1.6) holds for the computed RLk and knot and catenane reduction factors RK and RL attained by selective passage at different juxtaposition geometries. Remarkably, this general scaling relation is essentially identical to that observed experimentally for several type-2 topoisomerases from a variety of organisms, indicating that the different disentangling powers of the topoisomerases likely arise from variations in the hooked geometries they select. Taken together, our results suggest strongly that type-2 topoisomerases recognize not only the curvature of the G-segment but also that of the T-segment.

  18. Collaborating functions of BLM and DNA topoisomerase I in regulating human rDNA transcription

    International Nuclear Information System (INIS)

    Grierson, Patrick M.; Acharya, Samir; Groden, Joanna

    2013-01-01

    Bloom's syndrome (BS) is an inherited disorder caused by loss of function of the recQ-like BLM helicase. It is characterized clinically by severe growth retardation and cancer predisposition. BLM localizes to PML nuclear bodies and to the nucleolus; its deficiency results in increased intra- and inter-chromosomal recombination, including hyper-recombination of rDNA repeats. Our previous work has shown that BLM facilitates RNA polymerase I-mediated rRNA transcription in the nucleolus (Grierson et al., 2012 [18]). This study uses protein co-immunoprecipitation and in vitro transcription/translation (IVTT) to identify a direct interaction of DNA topoisomerase I with the C-terminus of BLM in the nucleolus. In vitro helicase assays demonstrate that DNA topoisomerase I stimulates BLM helicase activity on a nucleolar-relevant RNA:DNA hybrid, but has an insignificant effect on BLM helicase activity on a control DNA:DNA duplex substrate. Reciprocally, BLM enhances the DNA relaxation activity of DNA topoisomerase I on supercoiled DNA substrates. Our study suggests that BLM and DNA topoisomerase I function coordinately to modulate RNA:DNA hybrid formation as well as relaxation of DNA supercoils in the context of nucleolar transcription

  19. Collaborating functions of BLM and DNA topoisomerase I in regulating human rDNA transcription

    Energy Technology Data Exchange (ETDEWEB)

    Grierson, Patrick M. [Department of Microbiology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, OH 43210 (United States); Acharya, Samir, E-mail: samir.acharya@osumc.edu [Department of Microbiology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, OH 43210 (United States); Groden, Joanna [Department of Microbiology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, OH 43210 (United States)

    2013-03-15

    Bloom's syndrome (BS) is an inherited disorder caused by loss of function of the recQ-like BLM helicase. It is characterized clinically by severe growth retardation and cancer predisposition. BLM localizes to PML nuclear bodies and to the nucleolus; its deficiency results in increased intra- and inter-chromosomal recombination, including hyper-recombination of rDNA repeats. Our previous work has shown that BLM facilitates RNA polymerase I-mediated rRNA transcription in the nucleolus (Grierson et al., 2012 [18]). This study uses protein co-immunoprecipitation and in vitro transcription/translation (IVTT) to identify a direct interaction of DNA topoisomerase I with the C-terminus of BLM in the nucleolus. In vitro helicase assays demonstrate that DNA topoisomerase I stimulates BLM helicase activity on a nucleolar-relevant RNA:DNA hybrid, but has an insignificant effect on BLM helicase activity on a control DNA:DNA duplex substrate. Reciprocally, BLM enhances the DNA relaxation activity of DNA topoisomerase I on supercoiled DNA substrates. Our study suggests that BLM and DNA topoisomerase I function coordinately to modulate RNA:DNA hybrid formation as well as relaxation of DNA supercoils in the context of nucleolar transcription.

  20. The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation

    DEFF Research Database (Denmark)

    Andersen, Félicie Faucon; Tange, Thomas Ø.; Sinnathamby, Thayaline

    2002-01-01

    Human topoisomerase I interacts with and phosphorylates the SR-family of RNA splicing factors, including ASF/SF2, and has been suggested to play an important role in the regulation of RNA splicing. Here we present evidence to support the theory that the regulation can go the other way around...

  1. Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1

    DEFF Research Database (Denmark)

    Bocquet, Nicolas; Bizard, Anna H; Abdulrahman, Wassim

    2014-01-01

    to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase...

  2. Suppression of topoisomerase IIα expression and function in human cells decreases chromosomal radiosensitivity

    International Nuclear Information System (INIS)

    Terry, Samantha Y.A.; Riches, Andrew C.; Bryant, Peter E.

    2009-01-01

    The mechanism behind chromatid break formation is as yet unclear, although it is known that DNA double-strand breaks (DSBs) are the initiating lesions. Chromatid breaks formed in cells in the G2-phase of the cell-cycle disappear ('rejoin') as a function of time between radiation exposure and cell fixation. However, the kinetics of disappearance of chromatid breaks does not correspond to those of DSB rejoining, leading us to seek alternative models. We have proposed that chromatid breaks could be formed indirectly from DSB and that the mechanism involves topoisomerase IIα. In support of this hypothesis we have recently shown that frequencies of radiation-induced chromatid breaks are lower in two variant human promyelocytic leukaemic cell lines with reduced topoisomerase IIα expression. Here we report that suppression of topoisomerase IIα in human hTERT-RPE1 cells, either by its abrogation using specific siRNA or by inhibition of its catalytic activity with the inhibitor ICRF-193, causes a reduction in frequency of chromatid breaks in radiation-exposed cells. The findings support our hypothesis for the involvement of topoisomerase IIα in the formation of radiation-induced chromatid breaks, and could help explain inter-individual variation in human chromosomal radiosensitivity; elevation of which has been linked with cancer susceptibility.

  3. Methanosarcina acetivorans C2A topoisomerase IIIα, an archaeal enzyme with promiscuity in divalent cation dependence.

    Directory of Open Access Journals (Sweden)

    Raymond Morales

    Full Text Available Topoisomerases play a fundamental role in genome stability, DNA replication and repair. As a result, topoisomerases have served as therapeutic targets of interest in Eukarya and Bacteria, two of the three domains of life. Since members of Archaea, the third domain of life, have not been implicated in any diseased state to-date, there is a paucity of data on archaeal topoisomerases. Here we report Methanosarcina acetivorans TopoIIIα (MacTopoIIIα as the first biochemically characterized mesophilic archaeal topoisomerase. Maximal activity for MacTopoIIIα was elicited at 30-35°C and 100 mM NaCl. As little as 10 fmol of the enzyme initiated DNA relaxation, and NaCl concentrations above 250 mM inhibited this activity. The present study also provides the first evidence that a type IA Topoisomerase has activity in the presence of all divalent cations tested (Mg(2+, Ca(2+, Sr(2+, Ba(2+, Mn(2+, Fe(2+, Co(2+, Ni(2+, Cu(2+, Zn(2+ and Cd(2+. Activity profiles were, however, specific to each metal. Known type I (ssDNA and camptothecin and type II (etoposide, novobiocin and nalidixic acid inhibitors with different mechanisms of action were used to demonstrate that MacTopoIIIα is a type IA topoisomerase. Alignment of MacTopoIIIα with characterized topoisomerases identified Y317 as the putative catalytic residue, and a Y317F mutation ablated DNA relaxation activity, demonstrating that Y317 is essential for catalysis. As the role of Domain V (C-terminal domain is unclear, MacTopoIIIα was aligned with the canonical E. coli TopoI 67 kDa fragment in order to construct an N-terminal (1-586 and a C-terminal (587-752 fragment for analysis. Activity could neither be elicited from the fragments individually nor reconstituted from a mixture of the fragments, suggesting that native folding is impaired when the two fragments are expressed separately. Evidence that each of the split domains plays a role in Zn(2+ binding of the enzyme is also provided.

  4. A CMMS Expert using BIM for IBS Building Maintenance

    Directory of Open Access Journals (Sweden)

    Hamzah Noraini

    2016-01-01

    Full Text Available In the IBS building maintenance, the conventional methods to the project delivery and its failure to form effective communication channel between complementary knowledge on IBS construction and related members that is conducted in the sequential manner has resulted in ineffectiveness for managing building maintenance, where a paradigm shift within the IBS traditional approach is necessary. The research results described are concerned with i an integrated system to record, diagnose and analyse information for IBS building maintenance to detect patent or latent defect, select an effective repair method, provide appropriate planning decision and reduce risks of defect throughout the building lifetime. ii building a decision making support in diagnosis in IBS building maintenance based on robust data collection about concrete defects and causes including in the selection of a durable replacement design and material or the proper rehabilitation method. The system development was based on analysis of number of interviews and case studies conducted with professional engineers working in IBS building maintenance departments. The paper concludes that implementing a CMMS Expert using BIM can help improve the performance of IBS building design, construction and maintenance operations.

  5. Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Barros, Francisco W.A. [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil); Bezerra, Daniel P., E-mail: danielpbezerra@gmail.com [Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe (Brazil); Ferreira, Paulo M.P. [Department of Biological Sciences, Federal University of Piauí, Picos, Piauí (Brazil); Cavalcanti, Bruno C. [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil); Silva, Teresinha G.; Pitta, Marina G.R.; Lima, Maria do C.A. de; Galdino, Suely L.; Pitta, Ivan da R. [Department of Antibiotics, Federal, University of Pernambuco, Recife, Pernembuco (Brazil); Costa-Lotufo, Letícia V.; Moraes, Manoel O. [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil); Burbano, Rommel R. [Institute of Biological Sciences, Federal University of Pará, Belém, Pará (Brazil); Guecheva, Temenouga N.; Henriques, João A.P. [Biotechnology Center, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul (Brazil); Pessoa, Cláudia, E-mail: cpessoa@ufc.br [Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará (Brazil)

    2013-04-01

    Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl) -1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2, 4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. - Highlights: ► Thiazacridine derivatives induce mitochondrial-dependent apoptotic cell death. ► Thiazacridine derivatives inhibit DNA topoisomerase I action. ► Thiazacridine derivatives failed to cause genotoxicity on human lymphocytes.

  6. Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

    International Nuclear Information System (INIS)

    Barros, Francisco W.A.; Bezerra, Daniel P.; Ferreira, Paulo M.P.; Cavalcanti, Bruno C.; Silva, Teresinha G.; Pitta, Marina G.R.; Lima, Maria do C.A. de; Galdino, Suely L.; Pitta, Ivan da R.; Costa-Lotufo, Letícia V.; Moraes, Manoel O.; Burbano, Rommel R.; Guecheva, Temenouga N.; Henriques, João A.P.; Pessoa, Cláudia

    2013-01-01

    Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione — AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione — AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl) -1,3-thiazolidine-2,4-dione — AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2, 4-dione — AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin–eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. - Highlights: ► Thiazacridine derivatives induce mitochondrial-dependent apoptotic cell death. ► Thiazacridine derivatives inhibit DNA topoisomerase I action. ► Thiazacridine derivatives failed to cause genotoxicity on human lymphocytes

  7. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters.

    Directory of Open Access Journals (Sweden)

    Walid Fayad

    Full Text Available BACKGROUND: Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS: A library of natural products (NCI Natural Product set was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine, an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS: The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  8. Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters.

    Science.gov (United States)

    Fayad, Walid; Fryknäs, Mårten; Brnjic, Slavica; Olofsson, Maria Hägg; Larsson, Rolf; Linder, Stig

    2009-10-02

    Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  9. Key factors of successful JIT integration with IBS - An overview

    Science.gov (United States)

    Asri, Mohammad Azwanie Naim Mohammad; Nawi, Mohd Nasrun Mohd; Nadarajan, Santhirasegaran

    2016-08-01

    The Just-In-Time (JIT) philosophy has been used for many decades to increase productivity through waste elimination process. The purpose of this paper is to contribute to the knowledge by addressing the transportation and material delivery activities in Industrialized Building System (IBS) and integrating JIT to improve the performance of those activities. The literature review has been conducted through relevant database. It was found that there is a need for more holistic approach to be adopted to integrate JIT in IBS project. This paper discusses the key success factors for effective integration between JIT and IBS in the context of transportation and material delivery activities.

  10. Integrated Baseline System (IBS) Version 1.03: Utilities guide

    Energy Technology Data Exchange (ETDEWEB)

    Burford, M.J.; Downing, T.R.; Pottier, M.C.; Schrank, E.E.; Williams, J.R.

    1993-01-01

    The Integrated Baseline System (IBS) is an emergency management planning and analysis tool that was developed under the direction of the Federal Emergency Management Agency (FEMA). This Utilities Guide explains how to operate utility programs that are supplied as a part of the IBS. These utility programs are chiefly for managing and manipulating various kinds of IBS data and system administration files. Many of the utilities are for creating, editing, converting, or displaying map data and other data that are related to geographic location.

  11. Integrated Baseline System (IBS) Version 2.0: Utilities Guide

    Energy Technology Data Exchange (ETDEWEB)

    Burford, M.J.; Downing, T.R.; Williams, J.R. [Pacific Northwest Lab., Richland, WA (United States); Bower, J.C. [Bower Software Services, Kennewick, WA (United States)

    1994-03-01

    The Integrated Baseline System (IBS) is an emergency management planning and analysis tool being developed under the direction of the US Army Nuclear and Chemical Agency. This Utilities Guide explains how you can use the IBS utility programs to manage and manipulate various kinds of IBS data. These programs include utilities for creating, editing, and displaying maps and other data that are referenced to geographic location. The intended audience for this document are chiefly data managers but also system managers and some emergency management planners and analysts.

  12. Invasive cervical carcinoma (Stages IB-IIB)

    International Nuclear Information System (INIS)

    Sironi, S.; Zanello, A.; Rodighiero, M.G.; Vanzulli, A.; Del Maschio, A.; Taccagni, G.L.; Belloni, C.

    1991-01-01

    In the patients with invasive cervical carcinoma, the accurate assessment of parametrial invasion greatly affects the therapeutic choice between surgery and radiation therapy. As a matter of fact, surgery is usually performed only in the patients with carcinoma confined to the cervix, whereas those with parametrial involvement, or more advanced stages, are treated with radiation therapy. This prospective study was aimed at investigating the comparative adequecy of CT and MR imaging in assessing parametrial status in the patients with invasive cervical cancer. Twenty-one consecutive patients, with histologic diagnosis of cervical carcinoma, were investigated. All of them were clinically considered as having invasive cervical cancer (FIGO stage IB-IIB) and subsequently underwent surgery. In all cases, detailed histology of the parametrium was obtained. Pathological data were compared with CT and MR findings in all cases. As for assessing parametrial involvement by cancer, CT had 62% accuracy, 63% sensitivity, and 60% specificity, versus MR imaging 81% accuracy, 69% sensitivity, and 80% specificify. Therefore, MR imaging appears to be superior to CT in assessing the parametrial status of patients with invasive cervical carcinoma; the method yields valuable information for treatment planning

  13. Experience with IBS-suppression lattice in RHIC

    International Nuclear Information System (INIS)

    Litvinenko, V.N.; Luo, Y.; Ptitsyn, V.; Satogata, T.; Tepikian, S.; Bai, M.; Bruno, D.; Cameron, P.; Connolly, R.; Della Penna, A.; Drees, A.; Fedotov, A.; Ganetis, G.; Hoff, L.; Louie, W.; Malitsky, N.; Marr, G.; Marusic, A.; Montag, C.; Pilat, F.; Roser, T.; Trbojevic, D.; Tsoupas, N.

    2008-01-01

    An intra-beam scattering (IBS) is the limiting factor of the luminosity lifetime for RHIC operating with heavy ions. In order to suppress the IBS we designed and implemented new lattice with higher betatron tunes. This lattice had been developed during last three years and had been used for gold ions in yellow ring of the RHIC during d-Au part of the RHIC Run-8. The use of this lattice allowed both significant increases in the luminosity lifetime and the luminosity levels via reduction of beta-stars in the IPS. In this paper we report on the development, the tests and the performance of IBS-suppression lattice in RHIC, including the resulting increases in the peak and the average luminosity. We also report on our plans for future steps with the IBS suppression

  14. DNA-Based Sensor for Real-Time Measurement of the Enzymatic Activity of Human Topoisomerase I

    DEFF Research Database (Denmark)

    Marcussen, Lærke Bay; Jepsen, Morten Leth; Kristoffersen, Emil Laust

    2013-01-01

    Sensors capable of quantitative real-time measurements may present the easiest and most accurate way to study enzyme activities. Here we present a novel DNA-based sensor for specific and quantitative real-time measurement of the enzymatic activity of the essential human enzyme, topoisomerase I....... The basic design of the sensor relies on two DNA strands that hybridize to form a hairpin structure with a fluorophore-quencher pair. The quencher moiety is released from the sensor upon reaction with human topoisomerase I thus enabling real-time optical measurement of enzymatic activity. The sensor....... The cytotoxic effect of camptothecins correlates directly with the intracellular topoisomerase I activity. We therefore envision that the presented sensor may find use for the prediction of cellular drug response. Moreover, inhibition of topoisomerase I by camptothecin is readily detectable using the presented...

  15. The identification and characterisation of a functional interaction between arginyl-tRNA-protein transferase and topoisomerase II

    International Nuclear Information System (INIS)

    Barker, Catherine R.; Mouchel, Nathalie A.P.; Jenkins, John R.

    2006-01-01

    Topoisomerase II is required for the viability of all eukaryotic cells. It plays important roles in DNA replication, recombination, chromosome segregation, and the maintenance of the nuclear scaffold. Proteins that interact with and regulate this essential enzyme are of great interest. To investigate the role of proteins interacting with the N-terminal domain of the Saccharomyces cerevisiae topoisomerase II, we used a yeast two-hybrid protein interaction screen. We identified an interaction between arginyl-tRNA-protein transferase (Ate1) and the N-terminal domain of the S. cerevisiae topoisomerase II, including the potential site of interaction. Ate1 is a component of the N-end rule protein degradation pathway which targets proteins for degradation. We also propose a previously unidentified role for Ate1 in modulating the level of topoisomerase II through the cell cycle

  16. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

    Directory of Open Access Journals (Sweden)

    Jakub Fichna

    Full Text Available AIMS: Irritable bowel syndrome (IBS is a functional gastrointestinal (GI disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. METHODS: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D and constipation-predominant (IBS-C patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. RESULTS: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. CONCLUSION: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.

  17. Genetic recombination and Cryptosporidium hominis virulent subtype IbA10G2.

    Science.gov (United States)

    Li, Na; Xiao, Lihua; Cama, Vitaliano A; Ortega, Ynes; Gilman, Robert H; Guo, Meijin; Feng, Yaoyu

    2013-10-01

    Little is known about the emergence and spread of virulent subtypes of Cryptosporidium hominis, the predominant species responsible for human cryptosporidiosis. We conducted sequence analyses of 32 genetic loci of 53 C. hominis specimens isolated from a longitudinally followed cohort of children living in a small community. We identified by linkage disequilibrium and recombination analyses only limited genetic recombination, which occurred exclusively within the 60-kDa glycoprotein gene subtype IbA10G2, a predominant subtype for outbreaks in industrialized nations and a virulent subtype in the study community. Intensive transmission of virulent subtype IbA10G2 in the study area might have resulted in genetic recombination with other subtypes. Moreover, we identified selection for IbA10G2 at a 129-kb region around the 60-kDa glycoprotein gene in chromosome 6. These findings improve our understanding of the origin and evolution of C. hominis subtypes and the spread of virulent subtypes.

  18. Effects on gastrointestinal transit and antroduodenojejunal manometry after gut-directed hypnotherapy in irritable bowel syndrome (IBS).

    Science.gov (United States)

    Lindfors, Perjohan; Törnblom, Hans; Sadik, Riadh; Björnsson, Einar S; Abrahamsson, Hasse; Simrén, Magnus

    2012-12-01

    Gut-directed hypnotherapy is an effective treatment in irritable bowel syndrome (IBS) but little is known about the mechanisms of action. In this study we aimed to investigate the effects on gastrointestinal motility when treating IBS with gut-directed hypnotherapy. We randomized 90 patients with IBS, refractory to standard management to receive gut-directed hypnotherapy 1 h/week for 12 weeks or supportive treatment for the same time period. Eighty-one subjects (40 hypnotherapy, 41 controls) could be evaluated by one or more of the following investigations, both before and after the intervention: gastric emptying time, small bowel transit time, colonic transit time, and antroduodenojejunal manometry. No significant differences in gastric emptying time, small bowel transit time, or colonic transit time was found when comparing the baseline and post-intervention measurements in the hypnotherapy group or in the control group. The same was true concerning the results of the antroduodenojejunal manometry. However, there was a numerical trend toward a higher number of migrating motor complexes at manometry and an accelerated gastric emptying time after hypnotherapy that did not reach statistical significance. In this study, we were not able to find evidence for long-standing effects on gastrointestinal motility as a mediator of the effects on IBS when treating the condition with gut-directed hypnotherapy. Further research to understand the mechanism of action is needed.

  19. Chromatin structure and dynamics in hot environments: architectural proteins and DNA topoisomerases of thermophilic archaea.

    Science.gov (United States)

    Visone, Valeria; Vettone, Antonella; Serpe, Mario; Valenti, Anna; Perugino, Giuseppe; Rossi, Mosè; Ciaramella, Maria

    2014-09-25

    In all organisms of the three living domains (Bacteria, Archaea, Eucarya) chromosome-associated proteins play a key role in genome functional organization. They not only compact and shape the genome structure, but also regulate its dynamics, which is essential to allow complex genome functions. Elucidation of chromatin composition and regulation is a critical issue in biology, because of the intimate connection of chromatin with all the essential information processes (transcription, replication, recombination, and repair). Chromatin proteins include architectural proteins and DNA topoisomerases, which regulate genome structure and remodelling at two hierarchical levels. This review is focussed on architectural proteins and topoisomerases from hyperthermophilic Archaea. In these organisms, which live at high environmental temperature (>80 °C <113 °C), chromatin proteins and modulation of the DNA secondary structure are concerned with the problem of DNA stabilization against heat denaturation while maintaining its metabolic activity.

  20. Chromatin Structure and Dynamics in Hot Environments: Architectural Proteins and DNA Topoisomerases of Thermophilic Archaea

    Directory of Open Access Journals (Sweden)

    Valeria Visone

    2014-09-01

    Full Text Available In all organisms of the three living domains (Bacteria, Archaea, Eucarya chromosome-associated proteins play a key role in genome functional organization. They not only compact and shape the genome structure, but also regulate its dynamics, which is essential to allow complex genome functions. Elucidation of chromatin composition and regulation is a critical issue in biology, because of the intimate connection of chromatin with all the essential information processes (transcription, replication, recombination, and repair. Chromatin proteins include architectural proteins and DNA topoisomerases, which regulate genome structure and remodelling at two hierarchical levels. This review is focussed on architectural proteins and topoisomerases from hyperthermophilic Archaea. In these organisms, which live at high environmental temperature (>80 °C <113 °C, chromatin proteins and modulation of the DNA secondary structure are concerned with the problem of DNA stabilization against heat denaturation while maintaining its metabolic activity.

  1. Flexibility of Supply Chain in Industrialised Building System (IBS

    Directory of Open Access Journals (Sweden)

    Kassim U.

    2014-01-01

    Full Text Available It is irrefutable that the construction industry is in need of a highly technological construction method or system for the simple aim of giving it a push it deserves. In Malaysia this technologically enhanced method is known as the Indutrialised Building System (IBS. Concerted efforts have been made for the past decade by various responsible parties especially by the government. Therefore, the IBS ‘Road Map’ 2003–2010 was introduced and now continues with the IBS ‘road map’ 2011-2015. However, its performance is still at its infancy, which target is only at an initial stage. This study seeks to identify and analyse the factor of the IBS’ system’s supply chain flexibility as a factor on the success of the system itself. It has been a suspicion that there exists a condition and situation where the supply chain is too rigid and is not flexible in fulfilling the needs and demands of the IBS development in Malaysia. This inflexible situation has brought about a broad range of problems and has stood in the way of the development of the industrialised building system, despite it being introduced since 1964, or 49 years ago. Flexibility in the IBS supply chain is very important and is associated with other industries like transportation, manufacturing industry, and others. Up until now, we have yet to discover any special studies related to the flexibility in the IBS supply chain in this country. Responding to this challenge, this research is hoped to be able to provide sufficient feedback to the solution to the IBS supply chain flexibility issue. The researcher is confident that the poor system flow of supply chain has impeded the advancement of the Industrialised Building System that has long been open to debate.

  2. HMGB1 interacts with human topoisomerase IIalpha and stimulates its catalytic activity

    Czech Academy of Sciences Publication Activity Database

    Štros, Michal; Bačíková, Alena; Muselíková Polanská, Eva; Štokrová, Jitka; Strauss, F.

    2007-01-01

    Roč. 35, č. 15 (2007), s. 5001-5013 ISSN 0305-1048 R&D Projects: GA ČR(CZ) GA204/05/2031; GA AV ČR(CZ) IAA400040702 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702; CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : HMGB1 * DNA topoisomerase IIalpha * DNA repair Subject RIV: BO - Biophysics Impact factor: 6.954, year: 2007

  3. Secondary Leukemia Associated with the Anti-Cancer Agent, Etoposide, a Topoisomerase II Inhibitor

    OpenAIRE

    Sachiko Ezoe

    2012-01-01

    Etoposide is an anticancer agent, which is successfully and extensively used in treatments for various types of cancers in children and adults. However, due to the increases in survival and overall cure rate of cancer patients, interest has arisen on the potential risk of this agent for therapy-related secondary leukemia. Topoisomerase II inhibitors, including etoposide and teniposide, frequently cause rearrangements involving the mixed lineage leukemia (MLL<...

  4. More negative self-esteem and inferior coping strategies among patients diagnosed with IBS compared with patients without IBS--a case-control study in primary care.

    Science.gov (United States)

    Grodzinsky, Ewa; Walter, Susanna; Viktorsson, Lisa; Carlsson, Ann-Kristin; Jones, Michael P; Faresjö, Åshild

    2015-01-28

    Irritable Bowel Syndrome (IBS) is a chronic, relapsing gastrointestinal disorder, that affects approximately 10% of the general population and the majority are diagnosed in primary care. IBS has been reported to be associated with altered psychological and cognitive functioning such as mood disturbances, somatization, catastrophizing or altered visceral interoception by negative emotions and stress. The aim was to investigate the psychosocial constructs of self-esteem and sense of coherence among IBS patients compared to non-IBS patients in primary care. A case-control study in primary care setting among IBS patients meeting the ROME III criteria (n = 140) compared to controls i.e. non-IBS patients (n = 213) without any present or previous gastrointestinal complaints. The data were collected through self-reported questionnaires of psychosocial factors. IBS-patients reported significantly more negative self-esteem (p IBS-cases were also less likely to report 'good' health status (p IBS patients remained statistically significant (p = 0.02), as did the lower scores for sense of coherence among IBS cases (p = 0.04). The more frequently reported negative self-esteem and inferior coping strategies among IBS patients found in this study suggest the possibility that psychological therapies might be helpful for these patients. However these data do not indicate the causal direction of the observed associations. More research is therefore warranted to determine whether these psychosocial constructs are more frequent in IBS patients.

  5. Probing Conformational Changes in Human DNA Topoisomerase IIα by Pulsed Alkylation Mass Spectrometry*

    Science.gov (United States)

    Chen, Yu-tsung; Collins, Tammy R. L.; Guan, Ziqiang; Chen, Vincent B.; Hsieh, Tao-Shih

    2012-01-01

    Type II topoisomerases are essential enzymes for solving DNA topological problems by passing one segment of DNA duplex through a transient double-strand break in a second segment. The reaction requires the enzyme to precisely control DNA cleavage and gate opening coupled with ATP hydrolysis. Using pulsed alkylation mass spectrometry, we were able to monitor the solvent accessibilities around 13 cysteines distributed throughout human topoisomerase IIα by measuring the thiol reactivities with monobromobimane. Most of the measured reactivities are in accordance with the predicted ones based on a homology structural model generated from available crystal structures. However, these results reveal new information for both the residues not covered in the structural model and potential differences between the modeled and solution holoenzyme structures. Furthermore, on the basis of the reactivity changes of several cysteines located at the N-gate and DNA gate, we could monitor the movement of topoisomerase II in the presence of cofactors and detect differences in the DNA gate between two closed clamp enzyme conformations locked by either 5′-adenylyl β,γ-imidodiphosphate or the anticancer drug ICRF-193. PMID:22679013

  6. Carbohydrate-based heteronuclear complexes as topoisomerase Iα inhibitor: approach toward anticancer chemotherapeutics.

    Science.gov (United States)

    Afzal, Mohd; Al-Lohedan, Hamad A; Usman, Mohammad; Tabassum, Sartaj

    2018-04-18

    Due to the critical role of cellular enzymes necessary for cell proliferation by deciphering topological hurdles in the process of DNA replication, topoisomerases have been one of the major targets in the anticancer drug development area. A need, therefore, arises for new metallodrugs that specifically recognizes DNA and inhibits the activity of topoisomerase enzymes, herein, we report the synthesis and characterization of new metal-based glycoconjugate entities containing heterobimetallic core Cu II -Sn IV (1) and Ni II -Sn IV (2) derived from N-glycoside ligand (L). The optimized structure of complex 1 and other significant vibrational modes have been explained using dispersion corrected B3LYP/DFT calculations. In vitro DNA binding profile of the L and both the complexes 1 and 2 were done by various biophysical studies. Complex 1 breaks pBR322 DNA via a hydrolytic means which was validated by T4 DNA enzymatic assay. To get a mechanistic insight of mode of action topoisomerase I (Topo I) inhibition assay was carried out. Also, we have taken the help of molecular modeling studies in accordance with experimental findings. In vitro cytotoxicity of the complex 1 was evaluated against a panel of cancer cells which exhibited remarkably good anticancer activity (GI 50 values <10 μg/ml). Moreover, intracellular localization of the complex 1 was visualized by confocal microscopy against HeLa cells.

  7. Molecular modeling of cationic porphyrin-anthraquinone hybrids as DNA topoisomerase IIβ inhibitors.

    Science.gov (United States)

    Arba, Muhammad; Ruslin; Ihsan, Sunandar; Tri Wahyudi, Setyanto; Tjahjono, Daryono H

    2017-12-01

    Human DNA Topoisomerase II has been regarded as a promising target in anticancer drug discovery. In the present study, we designed six porphyrin-anthraquinone hybrids bearing pyrazole or pyridine group as meso substituents and evaluated their potentials as DNA Topoisomerase IIβ inhibitor. First, we investigated the binding orientation of porphyrin hybrids into DNA topoisomerase IIβ employing AutoDock 4.2 and then performed 20-ns molecular dynamics simulations to see the dynamic stability of each porphyrin-Topo IIβ complex using Amber 14. We found that the binding of porphyrin hybrids occured through intercalation and groove binding mode in addition interaction with the amino acid residues constituting the active cavity of Topo IIβ. Each porphyrin-Topo IIβ complex was stabilized during 20-ns dynamics simulations. The MM-PBSA free energy calculation shows that the binding affinities of porphyrin hybrids were modified with the number of meso substituent. Interestingly, the affinity of all porphyrin hybrids to Topo IIβ was stronger than that of native ligand (EVP), indicating the potential of the designed porphyrin to be considered in experimental research. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. [Estimation of small intestinal bacterial overgrowth in patients with constipation and diarrhea irritable bowel syndrome].

    Science.gov (United States)

    Łokieć, Katarzyna; Klupińska, Grazyna; Walecka-Kapica, Ewa; Błońska, Aleksandra

    2014-05-01

    Irritable bowel syndrome (IBS) is one of the most common reason for gastroenterology consultations. The diverse in symptomatology of the disease comes from its rich etiopathogenesis. Recently studies talk about infectious etiology of IBS and because of that it is necessary to expand its diagnostics by small intestinal bacterial overgrowth (SIBO) test. The aim of this study was to evaluate the prevalence of small intestinal bacterial overgrowth in patients with constipation (IBS-C) and diarrhea (IBS-D) irritable bowel syndrome with regard to nutrition. The study involved 46 subjects (33 women and 13 men) in average age of 44 years, which were divided into two groups: diarrhea and constipation IBS. All patients underwent hydrogen breath test studying bacterial overgrowth in the small intestine. In addition, each person had fulfilled a feeding questionnaire. Student's t-test, Pearson test. It has been shown that there is no statistical significances between the prevalence of SIBO in form of diarrheal IBS and constipation IBS and gender. Average value of increments of hydrogen in breath during the test was higher in IBS-C in comparison with IBS-D, which was the highest in the intestine bacterial overgrowth in patients with IBS-C. STATISTICAL ANALYSIS showed that there is no relationship between the type and frequency of consumption of milk, meat, fruit and vegetables, sweets and coffee and the prevalence of SIBO in form of diarrhea and constipation IBS. The occurrence of constipation or diarrhea irritable bowel syndrome is not related to gender. SIBO is more common in patients with IBS-C than in IBS-D group. There is no relationship between the type of food consumed and the amount of SIBO in people with IBS. Type of food intake do not affect the status of the intestinal flora of people with IBS.

  9. DNA topoisomerase 1α promotes transcriptional silencing of transposable elements through DNA methylation and histone lysine 9 dimethylation in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Thanh Theresa Dinh

    2014-07-01

    Full Text Available RNA-directed DNA methylation (RdDM and histone H3 lysine 9 dimethylation (H3K9me2 are related transcriptional silencing mechanisms that target transposable elements (TEs and repeats to maintain genome stability in plants. RdDM is mediated by small and long noncoding RNAs produced by the plant-specific RNA polymerases Pol IV and Pol V, respectively. Through a chemical genetics screen with a luciferase-based DNA methylation reporter, LUCL, we found that camptothecin, a compound with anti-cancer properties that targets DNA topoisomerase 1α (TOP1α was able to de-repress LUCL by reducing its DNA methylation and H3K9me2 levels. Further studies with Arabidopsis top1α mutants showed that TOP1α silences endogenous RdDM loci by facilitating the production of Pol V-dependent long non-coding RNAs, AGONAUTE4 recruitment and H3K9me2 deposition at TEs and repeats. This study assigned a new role in epigenetic silencing to an enzyme that affects DNA topology.

  10. Protein kinase activity associated with the corticosteroid binder IB

    International Nuclear Information System (INIS)

    Vujicic, M.; Djordjevic-Markovic, R.; Radic, O.; Krstic, M.; Kanazir, D.

    1997-01-01

    The physiological effects elicited by glucocorticoids are mediated via glucocorticoid receptors (GR). Analysis of specific glucocorticoid binding to radioactively labelled [ 3 H] triamcinolone acetonide in rat liver cytosol and analysis by ion exchange chromatography have revealed the presence of two distinct molecular species. The major form, designated as binder II appears to correspond to the well characterized glucocorticoid receptor by virtue of its size, charge, steroid binding characteristics and ability to bind to DNA.The second form, designated as corticosteroid binder IB, is a minor binding component in the liver. The binder IB differs from the binder II receptor by virtue of its lower molecular weight and its elution in the pre gradient of DEAE-Sephadex A-50 column which retains the un activated binder II receptor complexes. We examined the kinase activity of partially purified corticosteroid binder IB. Using (γ 3 2 P) ATP we detected kinase activity associated with the IB fraction from the rat liver. This kinase phosphorylate mixed histones and and dose not phosphorylate IB protein in vitro. The kinase activity is completely inhibited by the addition of Mg 2 + ions and is partially inhibited by the addition of Ca 2 +ions. (author)

  11. HLA class Ib in pregnancy and pregnancy-related disorders.

    Science.gov (United States)

    Persson, Gry; Melsted, Wenna Nascimento; Nilsson, Line Lynge; Hviid, Thomas Vauvert F

    2017-08-01

    The HLA class Ib genes, HLA-E, HLA-F, and HLA-G, were discovered long after the classical HLA class Ia genes. The elucidation of their functions had a modest beginning. However, their basic functions and involvement in pathophysiology and a range of diseases are now emerging. Although results from a range of studies support the functional roles for the HLA class Ib molecules in adult life, especially HLA-G and HLA-F have most intensively been, and were also primarily, studied in relation to reproduction and pregnancy. The expression of HLA class Ib proteins at the feto-maternal interface in the placenta seems to be important for the maternal acceptance of the semi-allogenic fetus. In contrast to the functions of HLA class Ia, HLA-G possesses immune-modulatory and tolerogenic functions. Here, we review an accumulating amount of data describing the functions of HLA class Ib molecules in relation to fertility, reproduction, and pregnancy, and a possible role for these molecules in certain pregnancy complications, such as implantation failure, recurrent spontaneous abortions, and pre-eclampsia. The results from different kinds of studies point toward a role for HLA class Ib, especially HLA-G, throughout the reproductive cycle from conception to the birth weight of the child.

  12. Immunohistochemical study of DNA topoisomerase I, DNA topoisomerase II alpha, p53, and Ki-67 in oral preneoplastic lesions and oral squamous cell carcinomas.

    Science.gov (United States)

    Hafian, Hilal; Venteo, Lydie; Sukhanova, Alyona; Nabiev, Igor; Lefevre, Benoît; Pluot, Michel

    2004-06-01

    Human DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of anticancer drugs. Laboratory studies have shown that the cellular response to topo I-targeted drugs depends on the topo I expression and DNA replication rate and the apoptotic pathway activity. In this study, we tested potential indicators of the sensitivity of topo I-targeted drugs in 36 cases of oral squamous cell carcinoma (OSCC). Formalin-fixed, paraffin-embedded tissue sections were immunostained with monoclonal antibodies against Ki-67, p53, and topo I, and with polyclonal antibodies against DNA topoisomerase II-alpha (topo II-alpha). These markers were also tested in 18 epithelial hyperplastic lesions and 18 mild dysplasias. Immunostaining was quantified by the percentage of stained nuclei in each sample (the labeling index); 200 immunoreactive epithelial nuclei were counted per case for each antibody. The results support the possibility of using topo II-alpha staining for assessing the proliferative activity. High expression of topo II-alpha and topo I in OSCCs suggests that they may serve as potential indicators of sensitivity to topo I inhibitors. However, the apoptotic pathway assessed by p53 immunostaining was found to be uninformative. Analysis of the relationship between immunohistochemical results and clinical and pathologic parameters (the T and N stages and differentiation) showed that only the differentiation parameter correlated with the topo I expression rate. Thus, significant increase in the topo I expression in the poorly differentiated OSCCs suggests their higher sensitivity to drug treatment.

  13. Role of the Water–Metal Ion Bridge in Mediating Interactions between Quinolones and Escherichia coli Topoisomerase IV

    Science.gov (United States)

    2015-01-01

    Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water–metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water–metal ion bridge is a general mechanism of quinolone–topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water–metal ion bridge is essential for quinolone activity against E. coli topoisomerase IV. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase IV. The water–metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase IV. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase IV proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates. PMID:25115926

  14. Los materiales hercínicos de la cordillera ibérica en el contexto del macizo ibérico

    Directory of Open Access Journals (Sweden)

    Liñán, E.

    1988-12-01

    Full Text Available The discontinuity observed between the paleozoic outcrops of the Iberian Mountains and the ones of the Iberian Massif, has been the greatest incovenient to include those ones in a general Hercynian Iberian model. Two hypothesis have been proposed to the respect. One initial hypothesis postulates the inclusion of the Iberian Mountains paleozoic racks in the West Asturian-Leonese Zone (Lotze, 1961; Julivert et al., 1974. Other one postulates a double inelusion: the occidental part of the Iberian Chaines into the West Asturian-Leonese Zone and the oriental part of the Iberian Chaines into the Cantabrian Zona (Liñán, 1983. In this work new geological data are provided for the geological conexion between Cantabrian Zone and the oriental part of the Iberian Chains; they can be summarised in three points. One of them is referred to the paralellism between the Narcea and Paracuellos antiforms. Those antiforms are divided by a tectonic accident, wich separates different Precambrian sequences. Another point deals with the close relation of the stratigraphical sequences of the Paleozoic racks between the Cantabrian region and Iberian region at both sides of the Narcea and Paracuellos antiforms. the last point refers to the study of small outcrops located in the northwest of the Iberian Chains, that show a probably more similar geological structure to the Cantabrian Zone wich was defined as a fold and thrust belt.La falta de continuidad de los afloramientos paleozoicos de la Cordillera Ibérica con los del Macizo Ibérico han venido constituyendo un serio obstáculo para la inclusión de aquéllos dentro de un esquema general para el hercínico ibérico. Dos hipótesis han sido hasta ahora planteadas: su conexión con la Zona Asturoccidental-Leonesa, o su doble conexión con esta zona y con la zona Cantábrica. En este trabajo se aportan nuevos datos geológicos que son congruentes con la prolongación tanto de la Zona Cantábrica como de la Zona

  15. Relaxation Techniques to Manage IBS Symptoms

    Science.gov (United States)

    ... for 15–20 seconds and then begin again. Progressive Muscle Relaxation This method of relaxation focuses on ... helpful, please consider supporting IFFGD with a small tax- deductible donation. Make Donation Adapted from IFFGD Publication # ...

  16. FRAGMENTATION ISSUE IN MALAYSIAN INDUSTRIALISED BUILDING SYSTEM (IBS PROJECTS

    Directory of Open Access Journals (Sweden)

    MOHD NASRUN MOHD NAWI

    2014-02-01

    Full Text Available As a developing country, Malaysian is currently driving for implementing a new or modern construction method, the Industrialised Building System (IBS, as an alternative towards enhancing construction performance. Currently, most of the IBS project developments in Malaysia are still conducted by using the traditional construction process approach. This traditional construction process has been widely criticised for its fragmented approach to project delivery and its failure to form effective teams thus created a number of issues such as reworks, time delay, rising costs, lack of communication and coordination, and wastages. This paper through literature review aims to highlight this fragmentation issue and clarify how far it affects the process of IBS implementation. Suggestions on how an integrated approach in design and construction in order to minimise the fragmentation gaps will be concluded.

  17. Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib).

    Science.gov (United States)

    Bastepe, Murat; Altug-Teber, Ozge; Agarwal, Chhavi; Oberfield, Sharon E; Bonin, Michael; Jüppner, Harald

    2011-03-01

    Pseudohypoparathyoridism type Ib (PHP-Ib) typically defines the presence of end-organ resistance to parathyroid hormone in the absence of Albright's hereditary osteodystrophy. Patients affected by this disorder present with imprinting defects in the complex GNAS locus. Microdeletions within STX16 or GNAS have been identified in familial cases with PHP-Ib, but the molecular cause of the GNAS imprinting defects in sporadic PHP-Ib cases remains poorly defined. We now report a case with sporadic PHP-Ib for whom a SNPlex analysis revealed loss of the maternal GNAS allele. Further analysis of the entire genome with a 100K SNP chip identified a paternal uniparental isodisomy affecting the entire chromosome 20 without evidence for another chromosomal abnormality. Our findings explain the observed GNAS methylation changes and the patient's hormone resistance, and furthermore suggest that chromosome 20 harbors, besides GNAS, no additional imprinted region that contributes to the clinical and laboratory phenotype. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Integrated Baseline System (IBS) Version 2.0: Models guide

    Energy Technology Data Exchange (ETDEWEB)

    1994-03-01

    The Integrated Baseline System (IBS) is an emergency management planning and analysis tool being developed under the direction of the US Army Nuclear and Chemical Agency. This Models Guide summarizes the IBS use of several computer models for predicting the results of emergency situations. These include models for predicting dispersion/doses of airborne contaminants, traffic evacuation, explosion effects, heat radiation from a fire, and siren sound transmission. The guide references additional technical documentation on the models when such documentation is available from other sources. The audience for this manual is chiefly emergency management planners and analysts, but also data managers and system managers.

  19. Stimulation of topoisomerase II mediated DNA cleavage at specific sequence elements by the 2-nitroimidazole Ro 15-0216

    International Nuclear Information System (INIS)

    Sorensen, B.S.; Jensen, P.S.; Andersen, A.H.; Christiansen, K.; Alsner, J.; Thomsen, B.; Westergaard, O.

    1990-01-01

    The effect of the 2-nitroimidazole Ro 15-0216 upon the interaction between purified topoisomerase II and its DNA substrate was investigated. The cleavage reaction in the presence of this DNA-nonintercalative drug took place with the hallmarks of a regular topoisomerase II mediated cleavage reaction, including covalent linkage of the enzyme to the cleaved DNA. In the presence of Ro 15-0216, topoisomerase II mediated cleavage was extensively stimulated at major cleavage sites of which only one existed in the 4363 base pair pBR322 molecule. The sites stimulated by Ro 15-0216 shared a pronounced sequence homology, indicating that a specific nucleotide sequence is crucial for the action of this drug. The effect of Ro 15-0216 thus differs from that of the clinically important topoisomerase II targeted agents such as mAMSA, VM26, and VP16, which enhance enzyme-mediated cleavage at a multiple number of sites. In contrast to the previous described drugs, Ro 15-0216 did not exert any inhibitory effect on the enzyme's catalytic activity. This observation might be ascribed to the low stability of the cleavage complexes formed in the presence of Ro 15-0216 as compared to the stability of the ones formed in the presence of traditional topoisomerase II targeted drugs

  20. A murine experimental anthracycline extravasation model: pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

    DEFF Research Database (Denmark)

    Thougaard, Annemette V; Langer, Seppo W; Hainau, Bo

    2010-01-01

    in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin...

  1. Adjuvant Chemotherapy Improves the Probability of Freedom From Recurrence in Patients With Resected Stage IB Lung Adenocarcinoma.

    Science.gov (United States)

    Hung, Jung-Jyh; Wu, Yu-Chung; Chou, Teh-Ying; Jeng, Wen-Juei; Yeh, Yi-Chen; Hsu, Wen-Hu

    2016-04-01

    The benefit of adjuvant chemotherapy remains controversial for patients with stage IB non-small-cell lung cancer (NSCLC). This study investigated the effect of adjuvant chemotherapy and the predictors of benefit from adjuvant chemotherapy in patients with stage IB lung adenocarcinoma. A total of 243 patients with completely resected pathologic stage IB lung adenocarcinoma were included in the study. Predictors of the benefits of improved overall survival (OS) or probability of freedom from recurrence (FFR) from platinum-based adjuvant chemotherapy in patients with resected stage IB lung adenocarcinoma were investigated. Among the 243 patients, 70 (28.8%) had received platinum-based doublet adjuvant chemotherapy. A micropapillary/solid-predominant pattern (versus an acinar/papillary-predominant pattern) was a significantly worse prognostic factor for probability of FFR (p = 0.033). Although adjuvant chemotherapy (versus surgical intervention alone) was not a significant prognostic factor for OS (p = 0.303), it was a significant prognostic factor for a better probability of FFR (p = 0.029) on multivariate analysis. In propensity-score-matched pairs, there was no significant difference in OS between patients who received adjuvant chemotherapy and those who did not (p = 0.386). Patients who received adjuvant chemotherapy had a significantly better probability of FFR than those who did not (p = 0.043). For patients with a predominantly micropapillary/solid pattern, adjuvant chemotherapy (p = 0.033) was a significant prognostic factor for a better probability of FFR on multivariate analysis. Adjuvant chemotherapy is a favorable prognostic factor for the probability of FFR in patients with stage IB lung adenocarcinoma, particularly in those with a micropapillary/solid-predominant pattern. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  2. Current job situation of the alumni from IBS Groningen -2017

    NARCIS (Netherlands)

    Liefers, Jan

    2017-01-01

    Our main question is: what is the current job situation of the alumni from IBS Groningen? The sub questions are: •How many students graduated in the various years? •What are the most popular jobs? •Where do alumni work and what is the career path? •What is their highest degree? •What companies

  3. Al-Shāṭibīs sufismekritik:

    DEFF Research Database (Denmark)

    Riexinger, Martin Thomas

    2016-01-01

    The faqīh (Islamic legal scholar) al-Shāṭibī (d. 1388) from Granada is primarily known for his innovative approach within the field of legal theory (uṣūl al-fiqh). However, he dedicated much attention to the criticism of sufism. But like other Islamic scholars who opposed Sufism he did...

  4. Travel Tips Help IBS Sufferers Enjoy Their Vacations

    Science.gov (United States)

    ... can feel more in control when traveling." IFFGD's travel tips include: Allow enough time in the morning to get to the airport ... Heartache 2004-0929 Norton Honored 2004-0525 IBS Travel Tips ... Real World 2001-1119 Heartburn or Heart Attack Commentary ...

  5. IBS SURVEY 2010: DRIVERS, BARRIERS AND CRITICAL SUCCESS FACTORS IN ADOPTING INDUSTRIALISED BUILDING SYSTEM (IBS CONSTRUCTION BY G7 CONTRACTORS IN MALAYSIA

    Directory of Open Access Journals (Sweden)

    KAMARUL ANUAR MOHAMAD KAMAR

    2014-08-01

    Full Text Available The industrialised building system (IBS survey has become an essential tool for ensuring the IBS Roadmap (2003 to 2010 meets its goals and target. As part of the process review survey, it also records the trend achievement of Malaysia in the usage of IBS in the building construction industry. The first and second IBS surveys were published in 2003 and 2005, respectively. Afterward, the IBS Roadmap’s midterm review was conducted. The third and the most recent IBS surveys were conducted in 2008 and 2010, respectively. This paper aims to highlight a part of the IBS survey report in 2010, which has been conducted to measure the drivers, barriers and the critical success factors of G7 contractors in adopting IBS construction. G7 is a Construction Industry Development Board contractor grade that can apply tender without limit. The importance of this paper is that it guides the policy and implementation strategy of IBS by G7 contractors. The survey shows that the acceptance, adoption, and deployment of IBS in the Malaysian construction industry are still low and do not address the persisting problems, such as productivity, dependency on foreign workers and high level of construction wastage.

  6. El estudio de la Fauna Ibérica

    Directory of Open Access Journals (Sweden)

    Ramos Sánchez, María Ángeles

    2007-10-01

    Full Text Available Since the beginning in 1989, Fauna Ibérica has promoted coordinated research in Taxonomy bringing together more than 100 Spanish and non-Spanish experts. The programme supported by CSIC Presidency is lead by Museo Nacional de Ciencias Naturales. As a result, 30 Fauna Ibérica monographs has been published in addition to a year average of 50-60 scientific papers describing more than 50 new species per year. IBERFAUNA, the Data Bank of the Spanish Fauna, has been created including 38.000 out of the 61.000 species estimated to live in the Iberian Peninsula and Balearic Islands. This area is confirmed as one of the most biodiverse of the European Union with more than 50 % of the European species and more than 50 % of its endemics. Among future plans, a more stable organization is proposed in order to: maintaining dichotomy paper/digital publications, increasing interactivity among taxonomists and training, developing cyber-tools to facilitate public access to the information and increasing the strength of Fauna Ibérica through collaboration with other international initiatives and other areas of knowledge.Desde su inicio en 1989, Fauna Ibérica ha impulsado la investigación coordinada de más de 100 taxónomos españoles y extranjeros. El programa, apoyado por la Presidencia del CSIC, está dirigido por el Museo Nacional de Ciencias Naturales. Como resultado, se han publicado 30 monografías de la serie Fauna Ibérica, y un promedio anual de 50-60 artículos científicos que describen más de 50 nuevas especies por año. Se ha creado el Banco de Datos, IBERFAUNA, que cuenta ya con 38.000 de las aproximadamente 61.000 especies que habitan en la Península Ibérica y Baleares. Se confirma como una de las regiones más ricas en biodiversidad de la Unión Europea, con más del 50 % de las especies y más de un 50 % de sus endemismos. Entre los planes de futuro, se propone una estructura estable para Fauna Ibérica, que mantenga la dicotomía soporte

  7. Inhibition of Topoisomerase IIα and Induction of Apoptosis in Gastric Cancer Cells by 19-Triisopropyl Andrographolide

    Science.gov (United States)

    Monger, Adeep; Boonmuen, Nittaya; Suksen, Kanoknetr; Saeeng, Rungnapha; Kasemsuk, Teerapich; Piyachaturawat, Pawinee; Saengsawang, Witchuda; Chairoungdua, Arthit

    2017-10-26

    Gastric cancer is the most common cancer in Eastern Asia. Increasing chemoresistance and general systemic toxicities have complicated the current chemotherapy leading to an urgent need of more effective agents. The present study reported a potent DNA topoisomerase IIα inhibitory activity of an andrographolide analogue (19-triisopropyl andrographolide, analogue-6) in gastric cancer cells; MKN-45, and AGS cells. The analogue was potently cytotoxic to both gastric cancer cell lines with the half maximal inhibitory concentration (IC50 values) of 6.3±0.7 μM, and 1.7±0.05 μM at 48 h for MKN-45, and AGS cells, respectively. It was more potent than the parent andrographolide and the clinically used, etoposide with the IC50 values of >50 μM in MKN-45 and 11.3±2.9 μM in AGS cells for andrographolide and 28.5±4.4 μM in MKN-45 and 4.08±0.5 μM in AGS cells for etoposide. Analogue-6 at 2 μM significantly inhibited DNA topoisomerase IIα enzyme in AGS cells, induced DNA damage, activated cleaved PARP-1, and Caspase3 leading to late cellular apoptosis. Interestingly, the expression of tumor suppressor p53 was not activated. These results show the importance of 19-triisopropyl-andrographolide in its emerging selectivity to primary target on topoisomerase IIα enzyme, inducing DNA damage and apoptosis by p53- independent mechanism. Thereby, the results provide insights of the potential of 19-triisopropyl andrographolide as an anticancer agent for gastric cancer. The chemical transformation of andrographolide is a promising strategy in drug discovery of a novel class of anticancer drugs from bioactive natural products. Creative Commons Attribution License

  8. The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS.

    Science.gov (United States)

    Staudacher, Heidi M; Whelan, Kevin

    2017-08-01

    There is an intensifying interest in the interaction between diet and the functional GI symptoms experienced in IBS. Recent studies have used MRI to demonstrate that short-chain fermentable carbohydrates increase small intestinal water volume and colonic gas production that, in those with visceral hypersensitivity, induces functional GI symptoms. Dietary restriction of short-chain fermentable carbohydrates (the low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet) is now increasingly used in the clinical setting. Initial research evaluating the efficacy of the low FODMAP diet was limited by retrospective study design and lack of comparator groups, but more recently well-designed clinical trials have been published. There are currently at least 10 randomised controlled trials or randomised comparative trials showing the low FODMAP diet leads to clinical response in 50%-80% of patients with IBS, in particular with improvements in bloating, flatulence, diarrhoea and global symptoms. However, in conjunction with the beneficial clinical impact, recent studies have also demonstrated that the low FODMAP diet leads to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown. This review aims to present recent advances in the understanding of the mechanisms by which the low FODMAP diet impacts on symptoms in IBS, recent evidence for its efficacy, current findings regarding the consequences of the diet on the microbiome and recommendations for areas for future research. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIα in vivo

    DEFF Research Database (Denmark)

    Grauslund, Morten; Vinding, Annemette; Füchtbauer, Annette C.

    2007-01-01

    previously to render the human ortholog of this enzyme highly resistant toward bisdioxopiperazines, was introduced at the TOP2A locus in mouse embryonic stem cells by targeted homologous recombination. These cells were used for the generation of transgenic TOP2AY165S/+ mice, which were demonstrated...... to be resistant toward the general toxicity of both ICRF-187 and ICRF-193. Hematological measurements indicate that this is most likely caused by a decreased ability of these agents to induce myelosuppression in TOP2AY165S/+ mice, highlighting the role of topoisomerase IIα in this process. The biological...

  10. Loss of DNA topoisomerase I activity alters many cellular functions in Salmonella typhimurium

    International Nuclear Information System (INIS)

    Overbye, K.M.; Basu, S.K.; Margolin, P.

    1983-01-01

    In this paper is reported the absence of DNA topoisomerase I in S. typhimurium results in an increased level of the recBC DNase (exonuclease V) enzyme, an almost total abolition of both direct and indirect mutagenesis by alkylating agents, and altered characteristics in the formation of chromosomal tandem duplications. We also present evidence that modifications in DNA superhelicity may strongly affect the pattern of DNA degrafation initiated by treatment of recA mutant cells with bleomycin and mitomycin C. 43 references, 3 figures, 3 tables

  11. Anti-Inflammatory Activities of a Chinese Herbal Formula IBS-20 In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Zhonghan Yang

    2012-01-01

    Full Text Available Irritable bowel syndrome (IBS is a functional bowel disorder and the etiology is not well understood. Currently there is no cure for IBS and no existing medication induces symptom relief in all patients. IBS-20 is a 20-herb Chinese medicinal formula that offers beneficial effects in patients with IBS; however, the underlying mechanisms are largely unknown. This study showed that IBS-20 potently inhibited LPS- or IFNΓ-stimulated expression of pro-inflammatory cytokines, as well as classically activated macrophage marker nitric oxide synthase 2. Similarly, IBS-20 or the component herb Coptis chinensis decreased LPS-stimulated pro-inflammatory cytokine secretion from JAWS II dendritic cells. IBS-20 or the component herbs also blocked or attenuated the IFNΓ-induced drop in transepithelial electric resistance, an index of permeability, in fully differentiated Caco-2 monolayer. Finally, the up-regulation of key inflammatory cytokines in inflamed colon from TNBS-treated mice was suppressed significantly by orally administrated IBS-20, including IFNΓ and IL-12p40. These data indicate that the anti-inflammatory activities of IBS-20 may contribute to the beneficial effects of the herbal extract in patients with IBS, providing a potential mechanism of action for IBS-20. In addition, IBS-20 may be a potential therapeutic agent against other Th1-dominant gut pathologies such as inflammatory bowel disease.

  12. Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II.

    Science.gov (United States)

    Brel, Viviane; Annereau, Jean-Philippe; Vispé, Stéphane; Kruczynski, Anna; Bailly, Christian; Guilbaud, Nicolas

    2011-12-15

    The polyamines transport system (PTS) is usually enhanced in cancer cells and can be exploited to deliver anticancer drugs. The spermine-conjugated epipodophyllotoxin derivative F14512 is a topoisomerase II poison that exploits the PTS to target preferentially tumor cells. F14512 has been characterized as a potent anticancer drug candidate and is currently in phase 1 clinical trials. Here we have analyzed the mechanisms of cell death induced by F14512, compared to the parent drug etoposide lacking the polyamine tail. F14512 proved to be >30-fold more cytotoxic than etoposide against A549 non-small cell lung cancer cells and triggers less but unrecoverable DNA damages. The cytotoxic action of F14512 is extremely rapid (within 3 h) and does not lead to a marked accumulation in the S-phase of the cell cycle, unlike etoposide. Interestingly, A549 cells treated with F14512 were less prone to undergo apoptosis (neither caspases-dependent nor caspases-independent pathways) or autophagy but preferentially entered into senescence. Drug-induced senescence was characterized qualitatively and quantitatively by an increased β-galactosidase activity, both by cytochemical staining and by flow cytometry. A morphological analysis by electron microscopy revealed the presence of numerous multi-lamellar and vesicular bodies and large electron-lucent (methuosis-like) vacuoles in F14512-treated cell samples. The mechanism of drug-induced cell death is thus distinct for F14512 compared to etoposide, and this difference may account for their distinct pharmacological profiles and the markedly superior activity of F14512 in vivo. This study suggests that senescence markers should be considered as potential pharmacodynamic biomarkers of F14512 antitumor activity. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Fragmentation of the CRISPR-Cas Type I-B signature protein Cas8b.

    Science.gov (United States)

    Richter, Hagen; Rompf, Judith; Wiegel, Julia; Rau, Kristina; Randau, Lennart

    2017-11-01

    CRISPR arrays are transcribed into long precursor RNA species, which are further processed into mature CRISPR RNAs (crRNAs). Cas proteins utilize these crRNAs, which contain spacer sequences that can be derived from mobile genetic elements, to mediate immunity during a reoccurring virus infection. Type I CRISPR-Cas systems are defined by the presence of different Cascade interference complexes containing large and small subunits that play major roles during target DNA selection. Here, we produce the protein and crRNA components of the Type I-B CRISPR-Cas complex of Clostridium thermocellum and Methanococcus maripaludis. The C. thermocellum Cascade complexes were reconstituted and analyzed via size-exclusion chromatography. Activity of the heterologous M. maripaludis CRISPR-Cas system was followed using phage lambda plaques assays. The reconstituted Type-I-B Cascade complex contains Cas7, Cas5, Cas6b and the large subunit Cas8b. Cas6b can be omitted from the reconstitution protocol. The large subunit Cas8b was found to be represented by two tightly associated protein fragments and a small C-terminal Cas8b segment was identified in recombinant complexes and C. thermocellum cell lysate. Production of Cas8b generates a small C-terminal fragment, which is suggested to fulfill the role of the missing small subunit. A heterologous, synthetic M. maripaludis Type I-B system is active in E. coli against phage lambda, highlighting a potential for genome editing using endogenous Type-I-B CRISPR-Cas machineries. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses

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    Geneviève Pèépin

    2017-10-01

    Full Text Available Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1 by low-dose camptothecin (CPT can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS detection of cytoplasmic DNA. This argues against CPT having only anti-inflammatory activity. Furthermore, expression of the simian virus 40 (SV40 large T antigen was paramount to the proinflammatory antiviral activity of CPT, as it potentiated cytoplasmic DNA leakage and subsequent cGAS recruitment in human and mouse cell lines. This work suggests that the capacity of Top1 inhibitors to blunt inflammatory responses can be counteracted by viral oncogenes and that this should be taken into account for their therapeutic development.

  15. Pentapeptide-repeat proteins that act as topoisomerase poison resistance factors have a common dimer interface

    International Nuclear Information System (INIS)

    Vetting, Matthew W.; Hegde, Subray S.; Zhang, Yong; Blanchard, John S.

    2011-01-01

    The pentapeptide repeat protein AlbG, provides self-resistance to the nonribosomally encoded hybrid polyketide-peptide termed albicidin. Analysis of the AlbG three-dimensional structure and the sequences of other pentapeptide repeat proteins that confer resistance to topiosomerase poisons suggests they have a similar dimer interface which may be critical to their interaction with topoisomerases. The protein AlbG is a self-resistance factor against albicidin, a nonribosomally encoded hybrid polyketide-peptide with antibiotic and phytotoxic properties produced by Xanthomonas albilineans. Primary-sequence analysis indicates that AlbG is a member of the pentapeptide-repeat family of proteins (PRP). The structure of AlbG from X. albilineans was determined at 2.0 Å resolution by SAD phasing using data collected from a single trimethyllead acetate derivative on a home source. AlbG folds into a right-handed quadrilateral β-helix composed of approximately eight semi-regular coils. The regularity of the β-helix is blemished by a large loop/deviation in the β-helix between coils 4 and 5. The C-terminus of the β-helix is capped by a dimerization module, yielding a dimer with a 110 Å semi-collinear β-helical axis. This method of dimer formation appears to be common to all PRP proteins that confer resistance to topoisomerase poisons and contrasts with most PRP proteins, which are typically monomeric

  16. DNA topoisomerase III localizes to centromeres and affects centromeric CENP-A levels in fission yeast.

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    Ulrika Norman-Axelsson

    Full Text Available Centromeres are specialized chromatin regions marked by the presence of nucleosomes containing the centromere-specific histone H3 variant CENP-A, which is essential for chromosome segregation. Assembly and disassembly of nucleosomes is intimately linked to DNA topology, and DNA topoisomerases have previously been implicated in the dynamics of canonical H3 nucleosomes. Here we show that Schizosaccharomyces pombe Top3 and its partner Rqh1 are involved in controlling the levels of CENP-A(Cnp1 at centromeres. Both top3 and rqh1 mutants display defects in chromosome segregation. Using chromatin immunoprecipitation and tiling microarrays, we show that Top3, unlike Top1 and Top2, is highly enriched at centromeric central domains, demonstrating that Top3 is the major topoisomerase in this region. Moreover, centromeric Top3 occupancy positively correlates with CENP-A(Cnp1 occupancy. Intriguingly, both top3 and rqh1 mutants display increased relative enrichment of CENP-A(Cnp1 at centromeric central domains. Thus, Top3 and Rqh1 normally limit the levels of CENP-A(Cnp1 in this region. This new role is independent of the established function of Top3 and Rqh1 in homologous recombination downstream of Rad51. Therefore, we hypothesize that the Top3-Rqh1 complex has an important role in controlling centromere DNA topology, which in turn affects the dynamics of CENP-A(Cnp1 nucleosomes.

  17. TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription.

    Science.gov (United States)

    Gómez-Herreros, Fernando; Zagnoli-Vieira, Guido; Ntai, Ioanna; Martínez-Macías, María Isabel; Anderson, Rhona M; Herrero-Ruíz, Andrés; Caldecott, Keith W

    2017-08-10

    DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL. Moreover, we find that TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. Interestingly, however, we implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapy-related leukemia and characterized by junction sequences with 4-bp of perfect homology. Collectively, these data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability.DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.

  18. Learning Negotiation Policies Using IB3 and Bayesian Networks

    Science.gov (United States)

    Nalepa, Gislaine M.; Ávila, Bráulio C.; Enembreck, Fabrício; Scalabrin, Edson E.

    This paper presents an intelligent offer policy in a negotiation environment, in which each agent involved learns the preferences of its opponent in order to improve its own performance. Each agent must also be able to detect drifts in the opponent's preferences so as to quickly adjust itself to their new offer policy. For this purpose, two simple learning techniques were first evaluated: (i) based on instances (IB3) and (ii) based on Bayesian Networks. Additionally, as its known that in theory group learning produces better results than individual/single learning, the efficiency of IB3 and Bayesian classifier groups were also analyzed. Finally, each decision model was evaluated in moments of concept drift, being the drift gradual, moderate or abrupt. Results showed that both groups of classifiers were able to effectively detect drifts in the opponent's preferences.

  19. c-erbB2 and topoisomerase IIα protein expression independently predict poor survival in primary human breast cancer: a retrospective study

    International Nuclear Information System (INIS)

    Fritz, Peter; Cabrera, Cristina M; Dippon, Jürgen; Gerteis, Andreas; Simon, Wolfgang; Aulitzky, Walter E; Kuip, Heiko van der

    2005-01-01

    c-erbB2 (also known as HER-2/neu) and topoisomerase IIα are frequently overexpressed in breast cancer. The aim of the study was to analyze retrospectively whether the expression of c-erbB2 and topoisomerase IIα protein influences the long-term outcome of patients with primary breast cancer. In this study c-erbB2 and topoisomerase IIα protein were evaluated by immunohistochemistry in formalin-fixed paraffin-embedded tissue from 225 samples of primary breast cancer, obtained between 1986 and 1998. The prognostic value of these markers was analyzed. Of 225 primary breast tumor samples, 78 (34.7%) showed overexpression of either c-erbB2 (9.8%) or topoisomerase IIα protein (24.9%), whereas in 21 tumors (9.3%) both proteins were found to be overexpressed. Patients lacking both c-erbB2 and topoisomerase IIα overexpression had the best long-term survival. Overexpression of either c-erbB2 or topoisomerase IIα was associated with shortened survival, whereas patients overexpressing both c-erbB2 and topoisomerase IIα showed the worst disease outcome (P < 0.0001). Treatment with anthracyclines was not capable of reversing the negative prognostic impact of topoisomerase IIα or c-erbB2 overexpression. The results of this exploratory study suggest that protein expression of c-erbB2 and topoisomerase IIα in primary breast cancer tissues are independent prognostic factors and are not exclusively predictive factors for anthracycline response in patients with primary breast cancer

  20. Patient educational media preferences for information about irritable bowel syndrome (IBS).

    Science.gov (United States)

    Halpert, Albena; Dalton, Christine B; Palsson, Olafur; Morris, Carolyn; Hu, Yuming; Bangdiwala, Shrikant; Hankins, Jane; Norton, Nancy; Drossman, Douglas A

    2008-12-01

    To identify the educational media preferences of patients with irritable bowel syndrome (IBS). The IBS-Patient Education Questionnaire (PEQ) was administered to a national sample of IBS patients. Frequencies of item endorsements were compared and meaningful clinical differences were used to identify differences among subgroups. 1,242 patients completed the survey, mean age 39.3 years, 85% female, IBS duration 6.9 years, 79% had seen an MD for IBS within 6 months, and 92.6% used the web for medical information. The most desired source of education was "my doctor" (68%), followed by Internet (62%) and brochure (45%). Notably, patients favored an increase in use of media in the future (past vs. future): doctor (43 vs. 68%); Internet (36 vs. 62%); and brochures (26 vs. 45%). IBS patients expect more education than they have received. Understanding IBS patients' learning preferences can be highly valuable in the development or implementation of educational interventions.

  1. The role of stress in IBS symptom severity

    Directory of Open Access Journals (Sweden)

    Sanda Pletikosic

    2016-04-01

    Full Text Available Irritable bowel syndrome is regarded as a biopsychosocial disorder, the result of a complex combination of predisposing, precipitating and perpetuating factors. Personality traits, affective status and stress are some of the relevant factors contributing to lower quality of life and symptom exacerbation in IBS patients. In order to examine the role of stress in IBS symptom exacerbation, the aims of this study were to explore the relationship of daily stressful events and symptom severity in a prospective manner and to explore the roles of neuroticism, anxiety, depression and stress in the vicious circle of symptom perpetuation. A total of 49 patients with IBS reported their symptom severity and daily stressful events intensity each day for 14 consecutive days. They also completed the Big five personality inventory, the Beck Depression Inventory and the State-trait anxiety inventory. Cross-correlation analyses were performed on the time series data for daily stress and symptom severity for each participant separately. Four different patterns of relationships were found in different subgroups of participants: positive cross-correlations of symptom severity and stress intensity on the same day; higher symptom severity on days following stressful days; lower symptom severity on days following stressful days; and lower stress intensity on days following severe symptoms. Using average scores for daily stress and symptom severity, as well as scores for neuroticism, anxiety and depression, we performed a path analysis to test a model of symptom exacerbation. It showed that, on the group level, average stress intensity predicts average symptom severity. Neuroticism and anxiety were not significant predictors of symptom severity, while depression showed a marginally significant relationship with symptom severity, mediated by stress intensity. In conclusion, depression and daily stress seem to be important contributors to the vicious circle of IBS symptom

  2. Molecular cloning and expression of the gene encoding the kinetoplast-associated type II DNA topoisomerase of Crithidia fasciculata.

    Science.gov (United States)

    Pasion, S G; Hines, J C; Aebersold, R; Ray, D S

    1992-01-01

    A type II DNA topoisomerase, topoIImt, was shown previously to be associated with the kinetoplast DNA of the trypanosomatid Crithidia fasciculata. The gene encoding this kinetoplast-associated topoisomerase has been cloned by immunological screening of a Crithidia genomic expression library with monoclonal antibodies raised against the purified enzyme. The gene CfaTOP2 is a single copy gene and is expressed as a 4.8-kb polyadenylated transcript. The nucleotide sequence of CfaTOP2 has been determined and encodes a predicted polypeptide of 1239 amino acids with a molecular mass of 138,445. The identification of the cloned gene is supported by immunoblot analysis of the beta-galactosidase-CfaTOP2 fusion protein expressed in Escherichia coli and by analysis of tryptic peptide sequences derived from purified topoIImt. CfaTOP2 shares significant homology with nuclear type II DNA topoisomerases of other eukaryotes suggesting that in Crithidia both nuclear and mitochondrial forms of topoisomerase II are encoded by the same gene.

  3. Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors

    Science.gov (United States)

    Mamidala, Rajinikanth; Majumdar, Papiya; Jha, Kunal Kumar; Bathula, Chandramohan; Agarwal, Rahul; Chary, M. Thirumala; Mazumdar, H. K.; Munshi, Parthapratim; Sen, Subhabrata

    2016-05-01

    A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.

  4. Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors.

    Science.gov (United States)

    Yamamoto, Kenta; Wang, Jiguang; Sprinzen, Lisa; Xu, Jun; Haddock, Christopher J; Li, Chen; Lee, Brian J; Loredan, Denis G; Jiang, Wenxia; Vindigni, Alessandro; Wang, Dong; Rabadan, Raul; Zha, Shan

    2016-06-15

    Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (Atm(KD/-)) is more oncogenic than loss of ATM (Atm(-/-)) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate Atm(KD/-), but not Atm-proficientor Atm(-/-) leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.

  5. CBFA1 and topoisomerase I mRNA levels decline during cellular aging of human trabecular osteoblasts

    DEFF Research Database (Denmark)

    Christiansen, Mette; Kveiborg, M.; Kassem, M.

    2000-01-01

    In order to understand the reasons for age-related impairment of the function of bone forming osteoblasts, we have examined the steady-state mRNA levels of the transcription factor CBFA1 and topoisomerase I during cellular aging of normal human trabecular osteoblasts, by the use of semiquantitati...

  6. Double-strand break repair and genetic recombination in topoisomerase and primase mutants of bacteriophage T4.

    Science.gov (United States)

    Shcherbakov, Victor P; Kudryashova, Elena

    2014-09-01

    The effects of primase and topoisomerase II deficiency on the double-strand break (DSB) repair and genetic recombination in bacteriophage T4 were studied in vivo using focused recombination. Site-specific DSBs were induced by SegC endonuclease in the rIIB gene of one of the parents. The frequency/distance relationship was determined in crosses of the wild-type phage, topoisomerase II mutant amN116 (gene 39), and primase mutant E219 (gene 61). Ordinary two-factor (i×j) and three-factor (i k×j) crosses between point rII mutations were also performed. These data provide information about the frequency and distance distribution of the single-exchange (splice) and double-exchange (patch) events. In two-factor crosses ets1×i, the topoisomerase and primase mutants had similar recombinant frequencies in crosses at ets1-i distances longer than 1000 bp, comprising about 80% of the corresponding wild-type values. They, however, differ remarkably in crosses at shorter distances. In the primase mutant, the recombinant frequencies are similar to those in the wild-type crosses at distances less than 100 bp, being a bit diminished at longer distances. In two-factor crosses ets1×i of the topoisomerase mutant, the recombinant frequencies were reduced ten-fold at the shortest distances. In three-factor crosses a6 ets1×i, where we measure patch-related recombination, the primase mutant was quite proficient across the entire range of distances. The topoisomerase mutant crosses demonstrated virtually complete absence of rII(+) recombinants at distances up to 33 bp, with the frequencies increasing steadily at longer distances. The data were interpreted as follows. The primase mutant is fully recombination-proficient. An obvious difference from the wild-type state is some shortage of EndoVII function leading to prolonged existence of HJs and thus stretched out ds-branch migration. This is also true for the topoisomerase mutant. However, the latter is deficient in the ss

  7. PREVALENCE OF SMALL INTESTINAL BACTERIAL OVERGROWTH IN IRRITABLE BOWEL SYNDROME

    Directory of Open Access Journals (Sweden)

    Premaletha Narayanan

    2017-12-01

    Full Text Available BACKGROUND Irritable Bowel Syndrome (IBS is a common functional disorder and the pathophysiology of IBS is poorly understood. The aim of the study is to assess the prevalence of SIBO in patients with IBS using Lactulose Hydrogen Breath Test (LHBT. Diagnosis of IBS was made according to the Rome III Criteria and Lactulose Hydrogen Breath Test (LHBT was done. MATERIALS AND METHODS The current hypothesis suggests that altered gastrointestinal motility, disturbance of visceral hypersensitivity and infection may contribute to the symptoms. Gut microbiota and intestinal pathogens are likely to influence the pathogenesis of IBS. Small Intestinal Bacterial Overgrowth (SIBO is defined as an abnormally high bacterial count (≥105 colony-forming units/mL in the proximal small intestine. RESULTS Out of the 120 patients, 9 were LHBT positive (7.5% compared to none in controls (p <0.01. IBS patients with LHBT positivity was correlated well with the increased frequency of stools. There was no correlation noted with LHBT positivity and abdominal pain or flatulence or bloating compared to IBS patients who were LHBT negative. CONCLUSION These findings may suggest that patients with chronic diarrhoea including IBS should be tested for SIBO. Our study also showed that LHBT positivity is associated with increased frequency of stools and diarrhoea. If SIBO is found in patients with chronic diarrhoea, specific treatment with antibiotics may benefit them.

  8. Microbiota, gastrointestinal infections, low-grade inflammation, and antibiotic therapy in irritable bowel syndrome (IBS: an evidence-based review

    Directory of Open Access Journals (Sweden)

    Max Schmulson

    2014-04-01

    Conclusions: Further studies are required to determine the nature of the gut microbiota in IBS and the differences in low-grade inflammation between PI-IBS and non PI-IBS. Rifaximin has shown itself to be an effective treatment for IBS, regardless of prior factors.

  9. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome.

    Science.gov (United States)

    Pyleris, Emmannouil; Giamarellos-Bourboulis, Evangelos J; Tzivras, Dimitrios; Koussoulas, Vassilios; Barbatzas, Charalambos; Pimentel, Mark

    2012-05-01

    Many studies have linked irritable bowel syndrome (IBS) with small intestinal bacterial overgrowth (SIBO), although they have done so on a qualitative basis using breath tests even though quantitative cultures are the hallmark of diagnosis. The purpose of this study was to underscore the frequency of SIBO in a large number of Greeks necessitating upper gastrointestinal (GI) tract endoscopy by using quantitative microbiological assessment of the duodenal aspirate. Consecutive subjects presenting for upper GI endoscopy were eligible to participate. Quantitative culture of aspirates sampled from the third part of the duodenum during upper GI tract endoscopy was conducted under aerobic conditions. IBS was defined by Rome II criteria. Among 320 subjects enrolled, SIBO was diagnosed in 62 (19.4%); 42 of 62 had IBS (67.7%). SIBO was found in 37.5% of IBS sufferers. SIBO was found in 60% of IBS patients with predominant diarrhea compared with 27.3% without diarrhea (P = 0.004). Escherichia coli, Enterococcus spp and Klebsiella pneumoniae were the most common isolates within patients with SIBO. A step-wise logistic regression analysis revealed that IBS, history of type 2 diabetes mellitus and intake of proton pump inhibitors were independently and positively linked with SIBO; gastritis was protective against SIBO. Using culture of the small bowel, SIBO by aerobe bacteria is independently linked with IBS. These results reinforce results of clinical trials evidencing a therapeutic role of non-absorbable antibiotics for the management of IBS symptoms.

  10. Down-regulation of human topoisomerase IIα expression correlates with relative amounts of specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions

    Directory of Open Access Journals (Sweden)

    Isaacs Richard J

    2007-05-01

    Full Text Available Abstract Background Topoisomerase IIα has been shown to be down-regulated in doxorubicin-resistant cell lines. The specificity proteins Sp1 and Sp3 have been implicated in regulation of topoisomerase IIα transcription, although the mechanism by which they regulate expression is not fully understood. Sp1 has been shown to bind specifically to both proximal and distal GC elements of the human topoisomerase IIα promoter in vitro, while Sp3 binds only to the distal GC element unless additional flanking sequences are included. While Sp1 is thought to be an activator of human topoisomerase IIα, the functional significance of Sp3 binding is not known. Therefore, we sought to determine the functional relationship between Sp1 and Sp3 binding to the topoisomerase IIα promoter in vivo. We investigated endogenous levels of Sp1, Sp3 and topoisomerase IIα as well as binding of both Sp1 and Sp3 to the GC boxes of the topoisomerase IIα promoter in breast cancer cell lines in vivo after short term doxorubicin exposure. Results Functional effects of Sp1 and Sp3 were studied using transient cotransfection assays using a topoisomerase IIα promoter reporter construct. The in vivo interactions of Sp1 and Sp3 with the GC elements of the topoisomerase IIα promoter were studied in doxorubicin-treated breast cancer cell lines using chromatin immunoprecipitation assays. Relative amounts of endogenous proteins were measured using immunoblotting. In vivo DNA looping mediated by proteins bound at the GC1 and GC2 elements was studied using the chromatin conformation capture assay. Both Sp1 and Sp3 bound to the GC1 and GC2 regions. Sp1 and Sp3 were transcriptional activators and repressors respectively, with Sp3 repression being dominant over Sp1-mediated activation. The GC1 and GC2 elements are linked in vivo to form a loop, thus bringing distal regulatory elements and their cognate transcription factors into close proximity with the transcription start site

  11. Quantitative analysis of topoisomerase IIα to rapidly evaluate cell proliferation in brain tumors

    International Nuclear Information System (INIS)

    Oda, Masashi; Arakawa, Yoshiki; Kano, Hideyuki; Kawabata, Yasuhiro; Katsuki, Takahisa; Shirahata, Mitsuaki; Ono, Makoto; Yamana, Norikazu; Hashimoto, Nobuo; Takahashi, Jun A.

    2005-01-01

    Immunohistochemical cell proliferation analyses have come into wide use for evaluation of tumor malignancy. Topoisomerase IIα (topo IIα), an essential nuclear enzyme, has been known to have cell cycle coupled expression. We here show the usefulness of quantitative analysis of topo IIα mRNA to rapidly evaluate cell proliferation in brain tumors. A protocol to quantify topo IIα mRNA was developed with a real-time RT-PCR. It took only 3 h to quantify from a specimen. A total of 28 brain tumors were analyzed, and the level of topo IIα mRNA was significantly correlated with its immuno-staining index (p < 0.0001, r = 0.9077). Furthermore, it sharply detected that topo IIα mRNA decreased in growth-inhibited glioma cell. These results support that topo IIα mRNA may be a good and rapid indicator to evaluate cell proliferate potential in brain tumors

  12. Phaeophytins from Thyrsacanthus ramosissimus Moric. with inhibitory activity on human DNA topoisomerase II-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Cabral, Analucia Guedes Silveira; Tenorio-Souza, Fabio Henrique; Moura, Marcelo Dantas; Mota, Sabrina Gondim Ribeiro; Silva Lins, Antonio Claudio da; Dias, Celidarque da Silva; Barbosa-Filho, Jose Maria [Universidade Federal da Paraiba (UFPB), Joao Pessoa, PB (Brazil). Dept. de Ciencias Frmaceuticas; Giulietti, Ana Maria [Universidade Estadual de Feira de Santana, Feira de Santana, BA (Brazil). Dept. de Ciencias Biologicas; Silva, Tania Maria Sarmento da [Universidade Federal Rural de Pernambuco, Recife, PE (Brazil). Dept. de Ciencias Moleculares; Santos, Creusioni Figueredo dos, E-mail: jbarbosa@ltf.ufpb.br [Universidade Federal da Paraiba (UFPB), Joao Pessoa, PB (Brazil). Dept. de Biologia Molecular

    2012-07-01

    Our study reports the extraction and isolation of a new phaeophytin derivative 15{sup 1}-hydroxy-(15{sup 1}-S)-porphyrinolactone, designated anamariaine (1) herein, isolated from the chloroform fraction of aerial parts of Thyrsacanthus ramosissimus Moric. along with the known 15{sup 1}-ethoxy-(15{sup 1}-S)-porphyrinolactone (2). These compounds were identified by usual spectroscopic methods. Both compounds were subjected to in vitro (inhibitory activity) tests by means of supercoiled DNA relaxation techniques and were shown to display inhibitory activity against human DNA topoisomerase II-{alpha} at 50 {mu}M. Interconversion of these two pigments under the mild conditions of the isolation techniques should be highly unlikely but cannot be entirely ruled out. (author)

  13. The connection between BRG1, CTCF and topoisomerases at TAD boundaries.

    Science.gov (United States)

    Barutcu, A Rasim; Lian, Jane B; Stein, Janet L; Stein, Gary S; Imbalzano, Anthony N

    2017-03-04

    The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. Recently, we demonstrated that knockdown of BRG1, an ATPase driving the chromatin remodeling activity of mammalian SWI/SNF enzymes, globally alters long-range genomic interactions and results in a reduction of TAD boundary strength. We provided evidence suggesting that this effect may be due to BRG1 affecting nucleosome occupancy around CTCF sites present at TAD boundaries. In this review, we elaborate on our findings and speculate that BRG1 may contribute to the regulation of the structural and functional properties of chromatin at TAD boundaries by affecting the function or the recruitment of CTCF and DNA topoisomerase complexes.

  14. DNA Topoisomerase-I Inhibition due to Exposure to X-Rays

    International Nuclear Information System (INIS)

    Daudee, R.; Gonen, R.; German, U.; Orion, I.; Priel, E.

    2014-01-01

    In events such as radiological terrorism, accidents involving radioactive materials and occupational exposures, there is a great need to identify exposures to relatively low radiation levels. In many situations, the evaluation of radiation doses is not possible using physical dosimeters as they are not worn, and it is desirable to achieve this based on sensitive biomarkers (1, 2, 3). DNA Topoisomerase-I (Topo-I) is an essential nuclear enzyme that is responsible for the topological state of the DNA. The enzyme is involved in a variety of DNA transactions, including replication, transcription, recombination and DNA repair (4,5). The aim of the present work was to investigate the influence of X-ray radiation on the catalytic activity of this enzyme, and to evaluate its applicability as a biological dosimeter

  15. Deletion of the topoisomerase III gene in the hyperthermophilic archaeon Sulfolobus islandicus results in slow growth and defects in cell cycle control

    DEFF Research Database (Denmark)

    Li, Xiyang; Guo, Li; Deng, Ling

    2011-01-01

    Topoisomerase III (topo III), a type IA topoisomerase, is widespread in hyperthermophilic archaea. In order to interrogate the in vivo role of archaeal topo III, we constructed and characterized a topo III gene deletion mutant of Sulfolobus islandicus. The mutant was viable but grew more slowly...... results suggest that the enzyme may serve roles in chromosomal segregation and control of the level of supercoiling in the cell....

  16. Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning

    International Nuclear Information System (INIS)

    Huang, C.-P.; Fang, W.-H.; Lin, L.-I.; Chiou, Robin Y.; Kan, L.-S.; Chi, N.-H.; Chen, Y.-R.; Lin, T.-Y.; Lin, S.-B.

    2008-01-01

    Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo IIα activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC 50 of 0.9 μM, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC 50 of 9.6 μM, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 μM. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC 50 about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design

  17. Activity of Topotecan toward the DNA/Topoisomerase I Complex: A Theoretical Rationalization.

    Science.gov (United States)

    Bali, Semiha Kevser; Marion, Antoine; Ugur, Ilke; Dikmenli, Ayse Kumru; Catak, Saron; Aviyente, Viktorya

    2018-03-06

    Topotecan (TPT) is a nontoxic anticancer drug characterized by a pH-dependent lactone/carboxyl equilibrium. TPT acts on the covalently bonded DNA/topoisomerase I (DNA/TopoI) complex by intercalating between two DNA bases at the active site. This turns TopoI into a DNA-damaging agent and inhibits supercoil relaxation. Although only the lactone form of the drug is active and effectively inhibits TopoI, both forms have been co-crystallized at the same location within the DNA/TopoI complex. To gain further insights into the pH-dependent activity of TPT, the differences between two TPT:DNA/TopoI complexes presenting either the lactone (acidic pH) or the carboxyl (basic pH) form of TPT were studied by means of molecular dynamic simulations, quantum mechanical/molecular mechanical calculations, and topological analysis. We identified two specific amino acids that have a direct relationship with the activity of the drug, i.e., lysine 532 (K532) and asparagine 722 (N722). K532 forms a stable hydrogen bond bridge between TPT and DNA only when the drug is in its active lactone form. The presence of the active drug triggers the formation of an additional stable interaction between DNA and protein residues, where N722 acts as a bridge between the two fragments, thus increasing the binding affinity of DNA for TopoI and further slowing the release of DNA. Overall, our results provide a clear understanding of the activity of the TPT-like class of molecules and can help in the future design of new anticancer drugs targeting topoisomerase enzymes.

  18. Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses.

    Science.gov (United States)

    Pépin, Geneviève; Nejad, Charlotte; Ferrand, Jonathan; Thomas, Belinda J; Stunden, H James; Sanij, Elaine; Foo, Chwan-Hong; Stewart, Cameron R; Cain, Jason E; Bardin, Philip G; Williams, Bryan R G; Gantier, Michael P

    2017-10-03

    Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS) detection of cytoplasmic DNA. This argues against CPT having only anti-inflammatory activity. Furthermore, expression of the simian virus 40 (SV40) large T antigen was paramount to the proinflammatory antiviral activity of CPT, as it potentiated cytoplasmic DNA leakage and subsequent cGAS recruitment in human and mouse cell lines. This work suggests that the capacity of Top1 inhibitors to blunt inflammatory responses can be counteracted by viral oncogenes and that this should be taken into account for their therapeutic development. IMPORTANCE Recent studies suggest that low-dose DNA-damaging compounds traditionally used in cancer therapy can have opposite effects on antiviral responses, either suppressing (with the example of CPT) or potentiating (with the example of doxorubicin) them. Our work demonstrates that the minor DNA damage promoted by low-dose CPT can also trigger strong antiviral responses, dependent on the presence of viral oncogenes. Taken together, these results call for caution in the therapeutic use of low-dose chemotherapy agents to modulate antiviral responses in humans. Copyright © 2017 Pépin et al.

  19. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy.

    Science.gov (United States)

    Weijer, Ruud; Broekgaarden, Mans; Krekorian, Massis; Alles, Lindy K; van Wijk, Albert C; Mackaaij, Claire; Verheij, Joanne; van der Wal, Allard C; van Gulik, Thomas M; Storm, Gert; Heger, Michal

    2016-01-19

    Photodynamic therapy (PDT) induces tumor cell death by oxidative stress and hypoxia but also survival signaling through activation of hypoxia-inducible factor 1 (HIF-1). Since perihilar cholangiocarcinomas are relatively recalcitrant to PDT, the aims were to (1) determine the expression levels of HIF-1-associated proteins in human perihilar cholangiocarcinomas, (2) investigate the role of HIF-1 in PDT-treated human perihilar cholangiocarcinoma cells, and (3) determine whether HIF-1 inhibition reduces survival signaling and enhances PDT efficacy. Increased expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was confirmed in human perihilar cholangiocarcinomas. PDT with liposome-delivered zinc phthalocyanine caused HIF-1α stabilization in SK-ChA-1 cells and increased transcription of HIF-1α downstream genes. Acriflavine was taken up by SK-ChA-1 cells and translocated to the nucleus under hypoxic conditions. Importantly, pretreatment of SK-ChA-1 cells with acriflavine enhanced PDT efficacy via inhibition of HIF-1 and topoisomerases I and II. The expression of VEGF, CD105, CD31/Ki-67, and GLUT-1 was determined by immunohistochemistry in human perihilar cholangiocarcinomas. In addition, the response of human perihilar cholangiocarcinoma (SK-ChA-1) cells to PDT with liposome-delivered zinc phthalocyanine was investigated under both normoxic and hypoxic conditions. Acriflavine, a HIF-1α/HIF-1β dimerization inhibitor and a potential dual topoisomerase I/II inhibitor, was evaluated for its adjuvant effect on PDT efficacy. HIF-1, which is activated in human hilar cholangiocarcinomas, contributes to tumor cell survival following PDT in vitro. Combining PDT with acriflavine pretreatment improves PDT efficacy in cultured cells and therefore warrants further preclinical validation for therapy-recalcitrant perihilar cholangiocarcinomas.

  20. cDNA cloning of human DNA topoisomerase I. Catalytic activity of a 67.7-kDa carboxyl-terminal fragment

    International Nuclear Information System (INIS)

    D'Arpa, P.; Machlin, P.S.; Ratrie, H. III; Rothfield, N.F.; Cleveland, D.W.; Earnshaw, W.C.

    1988-01-01

    cDNA clones encoding human topoisomerase I were isolated from an expression vector library (λgt11) screened with autoimmune anti-topoisomerase I serum. One of these clones has been expressed as a fusion protein comprised of a 32-kDa fragment of the bacterial TrpE protein linked to 67.7 kDa of protein encoded by the cDNA. Three lines of evidence indicate that the cloned cDNA encodes topoisomerase I. (i) Proteolysis maps of the fusion protein and human nuclear topoisomerase I are essentially identical. (ii) The fusion protein relaxes supercoiled DNA, an activity that can be immunoprecipitated by anti-topoisomerase I serum. (iii) Sequence analysis has revealed that the longest cDNA clone (3645 base pairs) encodes a protein of 765 amino acids that shares 42% identity with Saccharomyces cerevisiae topoisomerase I. The sequence data also show that the catalytically active 67.7-kDa fragment is comprised of the carboxyl terminus

  1. Synthesis and biological evaluation of N-(carbobenzyloxy)-l-phenylalanine and N-(carbobenzyloxy)-l-aspartic acid-β-benzyl ester derivatives as potent topoisomerase IIα inhibitors.

    Science.gov (United States)

    Han, Xiaoyan; Zhong, Yifan; Zhou, Guan; Qi, Hui; Li, Shengbin; Ding, Qiang; Liu, Zhenming; Song, Yali; Qiao, Xiaoqiang

    2017-06-15

    A new series of thirteen N-(carbobenzyloxy)-l-phenylalanine and N-(carbobenzyloxy)-l-aspartic acid-β-benzyl ester compounds were synthesized and evaluated for antiproliferative activity against four different human cancer cell lines: cervical cancer (HeLa), lung cancer (A549), gastric cancer (MGC-803) and breast cancer (MCF-7) as well as topoisomerase I and IIα inhibitory activity. Compounds (5a, 5b, 5e, 8a, 8b) showed significant antiproliferative activity with low IC 50 values against the four cancer cell lines. Equally, compounds 5a, 5b, 5e, 5f, 8a, 8d, 8e and 8f showed topoisomerase IIα inhibitory activity at 100μM with 5b, 5e, 8f exhibiting potential topoisomerase IIα inhibitory activity compared to positive control at 100μM and 20μM, respectively. Conversely compounds 5e, 5f, 5g and 8a showed weaker topoisomerase I inhibitory activity compared to positive control at 100μM. Compound 5b exhibited the most potent topoisomerase IIα inhibitory activity at low concentration and better antiproliferative activity against the four human cancer cell lines. The molecular interactions between compounds 5a-5g, 8a-8f and the topoisomerase IIα (PDB ID: 1ZXM) were further investigated through molecular docking. The results indicated that these compounds could serve as promising leads for further optimization as novel antitumor agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Advantages and Setbacks of Industrialized Building System (IBS) Implementation: A Case Study in Sarawak

    OpenAIRE

    Sing Sing Wong; Ling Kung Lau

    2015-01-01

    Industrialized Building System (IBS) is an innovative technique adopted to increase the efficiency, quality and productivity of projects. However, these advantages are proven mainly for projects located in urban areas only. IBS is not a common practice for projects located in rural areas. Although there were studies about IBS in Malaysia about its advantages and setbacks, these studies were focusing on projects located in urban areas located in West Malaysia only. Hence, this paper aids to cl...

  3. The Significance of Coordination for Industrialised Building System (IBS) Precast Concrete in Construction Industry

    OpenAIRE

    Fitri Othman Mohd Khairul; Wan Muhammad Wan Mohd Nurdden; Abd Hadi Nurulhudaya; Azman Mohd Azrai

    2017-01-01

    IBS precast concrete is construction system which is meant to improve the conventional construction process. However IBS precast concrete projects are suffering from serious problems such as cost overrun, delays and less quality of the end product. The absence of coordination is perceived as the reason for this issue. The purpose of this paper is to review the significance of coordination for IBS precast concrete in the construction industry. It if found that the fragmentation which occurs in...

  4. Data Management Guide: Integrated Baseline System (IBS). Version 2.1

    Energy Technology Data Exchange (ETDEWEB)

    Bower, J.C. [Bower Software Services, Kennewick, Washington (United States); Burford, M.J.; Downing, T.R.; Moise, M.C.; Williams, J.R. [Pacific Northwest Lab., Richland, WA (United States)

    1995-01-01

    The Integrated Baseline System (IBS) is an emergency management planning and analysis tool that is being developed under the direction of the US Army Nuclear and Chemical Agency (USANCA). The IBS Data Management Guide provides the background, as well as the operations and procedures needed to generate and maintain a site-specific map database. Data and system managers use this guide to manage the data files and database that support the administrative, user-environment, database management, and operational capabilities of the IBS. This document provides a description of the data files and structures necessary for running the IBS software and using the site map database.

  5. A unique set of SH3-SH3 interactions controls IB1 homodimerization

    DEFF Research Database (Denmark)

    Kristensen, Ole; Guenat, Sylvie; Dar, Imran

    2006-01-01

    Islet-brain 1 (IB1 or JIP-1) is a scaffold protein that interacts with components of the c-Jun N-terminal kinase (JNK) signal-transduction pathway. IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components...... reduces IB1-dependent basal JNK activity in 293T cells. Impaired dimerization also results in a reduction in glucose transporter type 2 expression and in glucose-dependent insulin secretion in pancreatic beta-cells. Taken together, these results indicate that IB1 homodimerization through its SH3 domain...

  6. A geochemical evaluation of the Ash Sha'ib mineral prospect, Asir quadrangle, Kingdom of Saudi Arabia

    Science.gov (United States)

    Allcott, Glenn H.

    1970-01-01

    The mineralized zone at the remotely located Ash Sha'ib ancient mine contains only a small tonnage of moderately low grade sulfide- bearing rock. Based on present data the gross value of the deposit, with a value of $25.00 or more per ton, is $20,000,000. A belt of metasedimentary rocks, intruded by gabbro to the south and granite to the north, was the host for fissure vein-replacement type mineralization. Most of the mineralization is in a siliceous dolomite transected by fissures. The main sulfide mineral is sphalerite, but minor amounts of chalcopyrlte and argentlferous galena contribute to the value of the mineralized sections.

  7. iB1350 no.3. Passive double confinement and SA population dose evaluation for the iB1350

    International Nuclear Information System (INIS)

    Sato, Takashi; Matsumoto, Keiji; Hosomi, Kenji; Iwasaki, Ryuji

    2017-01-01

    iB1350 stands for an innovative, intelligent and inexpensive BWR 1350. It is the first Generation III.7 reactor after the Fukushima Daiichi accident. The iB1350 uses the Mark W containment and the in-containment filtered venting system (IFVS). The Mark W containment is made of reinforced concrete and has double cylinder FP barriers. There are also IC/iPCCS pools, a fuel pool and a dryer separator (DS) pool on the top slab of the containment. These pools work as water seal for FP leakage through the top slab. Most FP such as CsI are scrubbed in the pools. The containment head is also submerged in the reactor well pool. The pool water works as shielding for radiation from the reactor core during normal operation and water seal for FP scrubbing during a severe accident. The base mat concrete is covered with the S/P and the core catcher that is also submerged with corium flooding water during an accident. Therefore, the Mark W containment has passive double confinement barriers for FP. Moreover, the IFVS works as in-containment filtered venting system that scrubs FP from the wet well (WW) and the dry well (DW). The filtered venting tank is arranged in the outer well (OW) of the Mark W containment. Even noble gases and organic iodine going through the filtered venting system are still confined inside the containment and never released directly to the environment. The IFVS uses the innovative passive containment cooling system (iPCCS) as the pre-stage heat removal system. The iPCCS has a normal open suction line from the WW. Therefore, FP are scrubbed in the S/P at first and then vented into the filtered venting tank. After the DW suction line of the iPCCS is opened all the steam is cooled and condensed in the heat exchanger. Most FP are trapped in the condensate and returned into the WW through the condensate return line of the iPCCS. Therefore, the Mark W containment has excellent FP double confinement barriers and the in-containment filtered venting system that enable

  8. [Abdominal spasms, meteorism, diarrhea: fructose intolerance, lactose intolerance or IBS?].

    Science.gov (United States)

    Litschauer-Poursadrollah, Margaritha; El-Sayad, Sabine; Wantke, Felix; Fellinger, Christina; Jarisch, Reinhart

    2012-12-01

    Meteorism, abdominal spasms, diarrhea, casually obstipation, flatulence and nausea are symptoms of fructose malabsorption (FIT) and/or lactose intolerance (LIT), but are also symptoms of irritable bowel syndrome (IBS). Therefore these diseases should be considered primarily in patients with digestive complaints. For diagnosis an H(2)-breath test is used.In 1,935 patients (526 m, 1,409 f) a fructose intolerance test and in 1,739 patients (518 m,1,221 f) a lactose intolerance test was done.FIT is found more frequently than LIT (57 versus 52 % in adults (p intolerance (HIT). Headache (ca. 10 %), fatigue (ca. 5 %) and dizziness (ca. 3 %) may occur after the test, irrespective whether the test was positive or negative.In more than 2/3 of patients a diet reduced in fructose or lactose may lead to improvement or remission of these metabolic disorders. IBS, which is often correlated with FIT (183/221 patients = 83 %), can be improved by relevant but also not relevant diets indicating that irritable bowel disease seems to be caused primarily by psychological disorders.

  9. Modeling and control simulation of the China CLEAR-IB

    International Nuclear Information System (INIS)

    Yan, Shoujun; Wan, Jiashuang; Wang, Pengfei; Fang, Huawei; Sun, Changyi; Zhao, Fuyu

    2014-01-01

    Highlights: • A model for the reactor for CLEAR-IB was developed. • A PI controller was designed to control the power. • A control strategy was adopted to control the water enthalpy of air cooler. • Dynamic simulation of the whole system was performed. - Abstract: To investigate the dynamic and control characteristics of the plant, a model for the main components of the reactor and the most relevant interactions among them is developed. The system comprises of the primary system with lead bismuth eutectic (LBE) as the coolant, the secondary circuit with steam water mixture as the coolant and the associated air cooling system for an effective rejection of thermal power to the environment as a final heat sink. A Proportional-Integral (PI) controller is designed to keep the power following the set value as quickly as possible. To keep outlet coolant of air coolers and inlet coolant of HXs being saturated water, a control strategy based on a simultaneous feed-forward and feedback scheme has been adopted. Based on the developed model and control strategy, dynamic simulation of the whole system in the cases of step changes of external source and load is performed. The simulation results show that the proposed model is accurate enough to describe the dynamic behaviors of the plant in spite of its simplicity. It has also been demonstrated that the developed controllers for the CLEAR-IB can provide superior reactor control capabilities due to the efficiency of the control strategy adopted

  10. Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex.

    Directory of Open Access Journals (Sweden)

    Giordano Mancini

    Full Text Available BACKGROUND: Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double strand DNA breaks and eventually cell death. METHODOLOGY/PRINCIPAL FINDINGS: Long lasting molecular dynamics simulations of the DNA-topoisomerase I binary complex and of the DNA-topoisomerase-topotecan ternary complex have been performed and compared. The conformational space sampled by the binary complex is reduced by the presence of the drug, as observed by principal component and cluster analyses. This conformational restraint is mainly due to the reduced flexibility of residues 633-643 (the region connecting the linker to the core domain that causes an overall mobility loss in the ternary complex linker domain. During the simulation, DNA/drug stacking interactions are fully maintained, and hydrogen bonds are maintained with the enzyme. Topotecan keeps the catalytic residue Lys532 far from the DNA, making it unable to participate to the religation reaction. Arg364 is observed to interact with both the B and E rings of topotecan with two stable direct hydrogen bonds. An interesting constrain exerted by the protein on the geometrical arrangement of topotecan is also observed. CONCLUSIONS/SIGNIFICANCE: Atomistic-scale understanding of topotecan interactions with the DNA-enzyme complex is fundamental to the explaining of its poisonous effect and of the drug resistance observed in several single residue topoisomerase mutants. We observed significant alterations due to topotecan in

  11. Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: Relationship with DNA binding affinity and cytotoxicity

    International Nuclear Information System (INIS)

    Capranico, G.; Kohn, K.W.; Pommier, Y.; Zunino, F.

    1990-01-01

    Topoisomerase II mediated double-strand breaks produced by anthracycline analogues were studied in SV40 DNA. The compounds included doxorubicin, daunorubicin, two doxorubicin stereoisomers (4'-epimer and β-anomer), and five chromophore-modified derivatives, with a wide range of cytotoxic activity and DNA binding affinity. Cleavage of 32 P-end-labeled DNA fragments was visualized by autoradiography of agarose and polyacrylamide gels. Structure-activity relationships indicated that alterations in the chromophore structure greatly affected drug action on topoisomerase II. In particular, removal of substituents on position 4 of the D ring resulted in more active inducers of cleavage with lower DNA binding affinity. The stereochemistry between the sugar and the chromophore was also essential for activity. All the active anthracyclines induced a single region of prominent cleavage in the entire SV40 DNA, which resulted from a cluster of sites between nucleotides 4237 and 4294. DNA cleavage intensity patterns exhibited differences among analogues and were also dependent upon drug concentration. Intensity at a given site dependent on both stimulatory and suppressive effects depending upon drug concentration and DNA sequence. A good correlation was found between cytotoxicity and intensity of topoisomerase II mediated DNA breakage

  12. Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking.

    Science.gov (United States)

    Taskin, T; Yilmaz, S; Yildiz, I; Yalcin, I; Aki, E

    2012-01-01

    Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.

  13. A flow cytometry-based method for a high-throughput analysis of drug-stabilized topoisomerase II cleavage complexes in human cells.

    Science.gov (United States)

    de Campos-Nebel, Marcelo; Palmitelli, Micaela; González-Cid, Marcela

    2016-09-01

    Topoisomerase II (Top2) is an important target for anticancer therapy. A variety of drugs that poison Top2, including several epipodophyllotoxins, anthracyclines, and anthracenediones, are widely used in the clinic for both hematologic and solid tumors. The poisoning of Top2 involves the formation of a reaction intermediate Top2-DNA, termed Top2 cleavage complex (Top2cc), which is persistent in the presence of the drug and involves a 5' end of DNA covalently bound to a tyrosine from the enzyme through a phosphodiester group. Drug-induced Top2cc leads to Top2 linked-DNA breaks which are the major responsible for their cytotoxicity. While biochemical detection is very laborious, quantification of drug-induced Top2cc by immunofluorescence-based microscopy techniques is time consuming and requires extensive image segmentation for the analysis of a small population of cells. Here, we developed a flow cytometry-based method for the analysis of drug-induced Top2cc. This method allows a rapid analysis of a high number of cells in their cell cycle phase context. Moreover, it can be applied to almost any human cell type, including clinical samples. The methodology is useful for a high-throughput analysis of drugs that poison Top2, allowing not just the discrimination of the Top2 isoform that is targeted but also to track its removal. © 2016 International Society for Advancement of Cytometry. © 2016 International Society for Advancement of Cytometry.

  14. More negative self-esteem and inferior coping strategies among patients diagnosed with IBS compared with patients without IBS - a case-control study in primary care

    OpenAIRE

    Grodzinsky, Ewa; Walter, Susanna; Viktorsson, Lisa; Carlsson, Ann-Kristin; Jones, Michael P.; Olsen Faresjö, Ashild

    2015-01-01

    Background Irritable Bowel Syndrome (IBS) is a chronic, relapsing gastrointestinal disorder,that affects approximately 10% of the general population and the majority are diagnosed  in primary care. IBS has been reported to be associated with altered psychological and cognitive functioning such as mood disturbances, somatization, catastrophizing or altered visceral interoception by negative emotions and stress. The aim was to  investigate the psychosocial constructs of self-esteem and sense of...

  15. Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib?

    Science.gov (United States)

    Fernández-Rebollo, Eduardo; Pérez de Nanclares, Guiomar; Lecumberri, Beatriz; Turan, Serap; Anda, Emma; Pérez-Nanclares, Gustavo; Feig, Denice; Nik-Zainal, Serena; Bastepe, Murat; Jüppner, Harald

    2011-08-01

    Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. Copyright © 2011 American Society for Bone and Mineral Research.

  16. La Inscripción Ibérica en escritura jonia, Serreta IX.

    OpenAIRE

    Silgo Gauche, Luís

    1997-01-01

    S’estudía una nova inscripció sobre làmina de plom, localitzada casualment en l’àrea del poblat ibèric de la Serreta (Alcoi, Cocentaina, Penàguila), en l’escriptura del qual es van emprar caracters greco-ibèrics.

  17. Politics and Pedagogy: Discursive Constructions in the IB "Theory of Knowledge--Guide"

    Science.gov (United States)

    Smith, Nigel V.; Morgan, Mandy

    2010-01-01

    The International Baccalaureate (IB) curriculum is increasingly popular in both national and international secondary education settings. The "Theory of knowledge" (TOK) course is cast as the prime example of the international globalised values the IB Diploma represents. This article argues that such a positioning is contested within the TOK…

  18. Chromosome damage induced by DNA topoisomerase II inhibitors combined with g-radiation in vitro

    Directory of Open Access Journals (Sweden)

    Maria Cristina P. Araújo

    1998-09-01

    Full Text Available Combined radiation and antineoplastic drug treatment have important applications in cancer therapy. In the present work, an evaluation was made of two known topoisomerase II inhibitors, doxorubicin (DXR and mitoxantrone (MXN, with g-radiation. The effects of DXR or MXN on g-radiation-induced chromosome aberrations in Chinese hamster ovary (CHO cells were analyzed. Two concentrations of each drug, 0.5 and 1.0 µg/ml DXR, and 0.02 and 0.04 µg/ml MXN, were applied in combination with two doses of g-radiation (20 and 40 cGy. A significant potentiating effect on chromosomal aberrations was observed in CHO cells exposed to 1.0 µg/ml DXR plus 40 cGy. In the other tests, the combination of g-radiation with DXR or MXN gave approximately additive effects. Reduced mitotic indices reflected higher toxicity of the drugs when combined with radiation.A associação de radiação ionizante com drogas antineoplásicas tem importante aplicação na terapia do câncer. No presente trabalho, foram avaliados os efeitos de dois inibidores de topoisomerase II, doxorubicina (DXR e mitoxantrona (MXN, sobre as aberrações cromossômicas induzidas pelas radiações-g em células do ovário de hamster chinês (CHO. Foram usadas as concentrações 0,5 e 1,0 mg/ml de DXR e 0,02 e 0,04 mg/ml de MXN, combinadas com duas doses de radiações gama (20 e 40 cGy. Um significativo efeito potenciador das aberrações cromossômicas foi observado em células CHO tratadas com 1,0 mg/ml de DXR e expostas a 40 cGy de radiação. Nos outros testes, a combinação da radiação-g com a DXR ou MXN apresentou um efeito próximo ao aditivo. A redução dos índices mitóticos refletiu a alta citotoxicidade das drogas quando combinadas às radiações-g.

  19. Frequent topoisomerase IV mutations associated with fluoroquinolone resistance in Ureaplasma species.

    Science.gov (United States)

    Song, Jingjuan; Qiao, Yingli; Kong, Yingying; Ruan, Zhi; Huang, Jun; Song, Tiejun; Zhang, Jun; Xie, Xinyou

    2015-11-01

    This study aimed to investigate the role of quinolone resistance-determining regions (QRDRs) of DNA gyrase (encoded by gyrA and gyrB) and topoisomerase IV (encoded by parC and parE) associated with fluoroquinolone resistance. A total of 114 Ureaplasma spp. strains, isolated from clinical female patients with symptomatic infection, were tested for species distribution and susceptibility to four fluoroquinolones. Moreover, we analysed the QRDRs and compared these with 14 ATCC reference strains of Ureaplasma spp. serovars to identify mutations that caused antimicrobial resistance. Our study indicated that moxifloxacin was the most effective fluoroquinolone against Ureaplasma spp. (MIC range: 0.125-32 μg ml⁻¹). However, extremely high MICs were estimated for ciprofloxacin (MIC range: 1-256 μg ml⁻¹) and ofloxacin (MIC range: 0.5-128 μg ml⁻¹), followed by levofloxacin (MIC range: 0.5-64 μg ml⁻¹). Seven amino acid substitutions were discovered in GyrB, ParC and ParE, but not in GyrA. Ser-83 → Leu/Trp (C248T/G) in ParC and Arg-448 → Lys (G1343A) in ParE, which were potentially responsible for fluoroquinolone resistance, were observed in 89 (77.2 %) and three (2.6 %) strains, respectively. Pro-462 → Ser (C1384T), Asn-481 → Ser (A1442G) and Ala-493 → Val (C1478T) in GyrB and Met-105 → Ile (G315T) in ParC seemed to be neutral polymorphisms, and were observed and occurred along with the amino acid change of Ser-83 → Leu (C248T) in ParC. Interestingly, two novel mutations of ParC and ParE were independently found in four strains. These observations suggest that amino acid mutation in topoisomerase IV appears to be the leading cause of fluoroquinolone resistance, especially the mutation of Ser-83 → Leu (C248T) in ParC. Moxifloxacin had the best activity against strains with Ser-83 → Leu mutation.

  20. Aportaciones coloniales a las creencias funerarias ibéricas

    Directory of Open Access Journals (Sweden)

    Joaquín García Raya

    1999-01-01

    Full Text Available La «mediterraneidad» de la península ibérica ha producido una serie de contactos con otros pueblos de esta cuenca, atraídos por su riqueza minera o como recurso a la colmatación de sus territorios de origen, lo cual produjo una traslación de ritos funerarios, cuya lectura arqueológica ha significado interpretaciones erróneas básicas.The "Mediterranean style» of the Iberian Península has given way to a series of contacts wth otherpeoples fron this valley, attracted by its mining richness and as an option tgo the overcrowding of their native territories. This brought about the implantation of funeral ceremonies, who archaelogical reading has meant false interpretations.

  1. Clinical evaluation of enalapril maleate and furosemide usage in dogs with degenerative myxomatous mitral valve, CHF functional class Ib

    Directory of Open Access Journals (Sweden)

    Rodrigo P. Franco

    2011-09-01

    Full Text Available Degenerative myxomatous mitral valve (DMMV is a heart disease of high incidence in small animal clinical medicine, affecting mainly older dogs and small breeds. Thus, a scientific investigation was performed in order to evaluate the clinical use of the medicines furosemide and enalapril maleate in dogs with this disease in CHF functional class Ib before and after the treatment was established. For this purpose 16 dogs with the given valve disease were used, separated into two groups: the first received furosemide (n=8 and the second received enalapril maleate (n=8 throughout 56 days. The dogs were evaluated in four stages (T0, T14, T28 and T56 day in relation to clinical signs, hematological, biochemical and serum assessment, which included serum angiotensin converting enzyme (ACE and aldosterone, as well as radiography, electrocardiography, Doppler-echocardiography and blood pressure. The results regarding the clinical, hematological and serum chemistry evaluations revealed no significant changes in both groups, but significant reductions in the values of ACE and aldosterone in the group receiving enalapril maleate were verified. The radiographic examination revealed reductions of VHS values and variable Pms wave of the electrocardiogram in both groups, but no changes in blood pressure values were identified. The echocardiogram showed a significant decrease of the variables LVDd/s in the studied groups and the FS% in animals that received only enalapril. Therefore, analysis of results showed that monotherapy based on enalapril maleate showed better efficiency of symptoms control in patients with CHF functional class Ib.

  2. Detergent-Resistant Membrane Microdomains Facilitate Ib Oligomer Formation and Biological Activity of Clostridium perfringens Iota-Toxin

    National Research Council Canada - National Science Library

    Hale, Martha

    2004-01-01

    ...) were extracted with cold Triton X-100. Western blotting revealed that Ib oligomers localized in DRMs extracted from Vero, but not MRC-5, cells while monomeric Ib was detected in the detergent-soluble fractions of both cell types...

  3. Cloning and characterization of a cell cycle-regulated gene encoding topoisomerase I from Nicotiana tabacum that is inducible by light, low temperature and abscisic acid.

    Science.gov (United States)

    Mudgil, Y; Singh, B N; Upadhyaya, K C; Sopory, S K; Reddy, M K

    2002-05-01

    We have cloned a full-length 2874-bp cDNA coding for tobacco topoisomerase I, with an ORF of 2559 bp encoding a protein of 852 amino acids with a calculated molecular mass of 95 kDa and an estimated pI of 9.51. The deduced amino acid sequence shows homology to other eukaryotic topoisomerases I. Tobacco topoisomerase I was over-expressed in Escherichia coli, and the purified recombinant protein was found to relax both positively and negatively super-coiled DNA in the absence of the divalent cation Mg(2+)and ATP. These characteristic features indicate that the tobacco enzyme is a type I topoisomerase. The recombinant protein could be phosphorylated at (a) threonine residue(s) by protein kinase C. However, phosphorylation did not cause any change in its enzymatic activity. The genomic organization of the topoisomerase I gene revealed the presence of 8 exons and 7 introns in the region corresponding to the ORF and one intron in the 3' UTR region. Transcript analysis using RT-PCR showed basal constitutive expression in all organs examined, and the gene was expressed at all stages of the cell cycle--but the level of expression increased during the G1-S phase. The transcript level also increased following exposure to light, low-temperature stress and abscisic acid, a stress hormone.

  4. Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

    Science.gov (United States)

    Doshi, Kshama A.; Trotta, Rossana; Natarajan, Karthika; Rassool, Feyruz V.; Tron, Adriana E.; Huszar, Dennis; Perrotti, Danilo; Baer, Maria R.

    2016-01-01

    Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD. PMID:27374090

  5. Structure and Chromosomal Organization of Yeast Genes Regulated by Topoisomerase II.

    Science.gov (United States)

    Joshi, Ricky S; Nikolaou, Christoforos; Roca, Joaquim

    2018-01-03

    Cellular DNA topoisomerases (topo I and topo II) are highly conserved enzymes that regulate the topology of DNA during normal genome transactions, such as DNA transcription and replication. In budding yeast, topo I is dispensable whereas topo II is essential, suggesting fundamental and exclusive roles for topo II, which might include the functions of the topo IIa and topo IIb isoforms found in mammalian cells. In this review, we discuss major findings of the structure and chromosomal organization of genes regulated by topo II in budding yeast. Experimental data was derived from short (10 min) and long term (120 min) responses to topo II inactivation in top-2 ts mutants. First, we discuss how short term responses reveal a subset of yeast genes that are regulated by topo II depending on their promoter architecture. These short term responses also uncovered topo II regulation of transcription across multi-gene clusters, plausibly by common DNA topology management. Finally, we examine the effects of deactivated topo II on the elongation of RNA transcripts. Each study provides an insight into the particular chromatin structure that interacts with the activity of topo II. These findings are of notable clinical interest as numerous anti-cancer therapies interfere with topo II activity.

  6. Characterization and immunological identification of cDNA clones encoding two human DNA topoisomerase II isozymes

    International Nuclear Information System (INIS)

    Chung, T.D.Y.; Drake, F.H.; Tan, K.B.; Per, S.R.; Crooke, S.T.; Mirabelli, C.K.

    1989-01-01

    Several DNA topoisomerase II partial cDNA clones obtained from a human Raji-HN2 cDNA library were sequenced and two classes of nucleotide sequences were found. One member of the first class, SP1, was identical to an internal fragment of human HeLa cell Topo II cDNA described earlier. A member of the second class, SP11, shared extensive nucleotide (75%) and predicted peptide (92%) sequence similarities with the first two-thirds of HeLa Topo II. Each class of cDNAs hybridized to unique, nonoverlapping restriction enzyme fragments of genomic DNA from several human cell lines. Synthetic 24-mer oligonucleotide probes specific for each cDNA class hybridized to 6.5-kilobase mRNAs; furthermore, hybridization of probe specific for one class was not blocked by probe specific for the other. Antibodies raised against a synthetic SP1-encoded dodecapeptide specifically recognized the 170-kDa form of Topo II, while antibodies raised against the corresponding SP11-encoded dodecapeptide, or a second unique SP11-encoded tridecapeptide, selectively recognized the 180-kDa form of Topo II. These data provide genetic and immunochemical evidence for two Topo II isozymes

  7. Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion

    Directory of Open Access Journals (Sweden)

    Priya Luthra

    2017-04-01

    Full Text Available Ebola virus (EBOV protein VP35 inhibits production of interferon alpha/beta (IFN by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication.

  8. Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Palshof, Jesper Andreas; Hogdall, Estrid Vilma Solyom; Poulsen, Tim Svenstrup

    2017-01-01

    Background No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients...... were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. Results In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5–9.5) and 2.......00 (range: 0.55–4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82–10.43) and 1.98 (range: 1.22–6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92–2.90) and 2.05 (range: 1.00–6.00), respectively. None...

  9. The DNA topoisomerase II catalytic inhibitor merbarone is genotoxic and induces endoreduplication

    International Nuclear Information System (INIS)

    Pastor, Nuria; Domínguez, Inmaculada; Orta, Manuel Luís; Campanella, Claudia; Mateos, Santiago; Cortés, Felipe

    2012-01-01

    In the last years a number of reports have shown that the so-called topoisomerase II (topo II) catalytic inhibitors are able to induce DNA and chromosome damage, an unexpected result taking into account that they do not stabilize topo II-DNA cleavable complexes, a feature of topo II poisons such as etoposide and amsacrine. Merbarone inhibits the catalytic activity of topo II by blocking DNA cleavage by the enzyme. While it was first reported that merbarone does not induce genotoxic effects in mammalian cells, this has been challenged by reports showing that the topo II inhibitor induces efficiently chromosome and DNA damage, and the question as to a possible behavior as a topo II poison has been put forward. Given these contradictory results, and the as yet incomplete knowledge of the molecular mechanism of action of merbarone, in the present study we have tried to further characterize the mechanism of action of merbarone on cell proliferation, cell cycle, as well as chromosome and DNA damage in cultured CHO cells. Merbarone was cytotoxic as well as genotoxic, inhibited topo II catalytic activity, and induced endoreduplication. We have also shown that merbarone-induced DNA damage depends upon ongoing DNA synthesis. Supporting this, inhibition of DNA synthesis causes reduction of DNA damage and increased cell survival.

  10. Synthesis, DNA Binding and Topoisomerase I Inhibition Activity of Thiazacridine and Imidazacridine Derivatives

    Directory of Open Access Journals (Sweden)

    Elizabeth Almeida Lafayette

    2013-12-01

    Full Text Available Thiazacridine and imidazacridine derivatives have shown promising results as tumors suppressors in some cancer cell lines. For a better understanding of the mechanism of action of these compounds, binding studies of 5-acridin-9-ylmethylidene-3-amino-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-imidazolidin-4-one and 3-acridin-9-ylmethyl-thiazolidin-2,4-dione with calf thymus DNA (ctDNA by electronic absorption and fluorescence spectroscopy and circular dichroism spectroscopy were performed. The binding constants ranged from 1.46 × 104 to 6.01 × 104 M−1. UV-Vis, fluorescence and circular dichroism measurements indicated that the compounds interact effectively with ctDNA, both by intercalation or external binding. They demonstrated inhibitory activities to human topoisomerase I, except for 5-acridin-9-ylmethylidene-2-thioxo-1,3-thiazolidin-4-one. These results provide insight into the DNA binding mechanism of imidazacridines and thiazacridines.

  11. DUPA conjugation of a cytotoxic indenoisoquinoline topoisomerase I inhibitor for selective prostate cancer cell targeting.

    Science.gov (United States)

    Roy, Jyoti; Nguyen, Trung Xuan; Kanduluru, Ananda Kumar; Venkatesh, Chelvam; Lv, Wei; Reddy, P V Narasimha; Low, Philip S; Cushman, Mark

    2015-04-09

    Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA-indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice.

  12. Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells

    Directory of Open Access Journals (Sweden)

    Ying Li

    2014-01-01

    Topoisomerase IIbeta (Top2b is an enzyme that modulates DNA supercoiling by catalyzing the passage of DNA duplexes through one another. It is ubiquitously expressed in postmitotic cells and known to function during the development of neuromuscular junctions in the diaphragm and the proper formation of laminar structure in the cerebral cortex. However, due to the perinatal death phenotype of the traditional constitutive and brain-specific Top2b knockout mice, the precise in vivo function of Top2b, especially during postnatal neural development, remains to be determined. Using both the constitutive and retina-specific knockout mouse models, we showed that Top2b deficiency resulted in delayed neuronal differentiation, degeneration of the plexiform layers and outer segment of photoreceptors, as well as dramatic reduction in cell number in the retina. Genome-wide transcriptome analysis by RNA sequencing revealed that genes involved in neuronal survival and neural system development were preferentially affected in Top2b-deficient retinas. Collectively, our findings have indicated an important function of Top2b in proper development and the maintenance/survival of postmitotic neurons in the retina.

  13. Secondary Leukemia Associated with the Anti-Cancer Agent, Etoposide, a Topoisomerase II Inhibitor

    Directory of Open Access Journals (Sweden)

    Sachiko Ezoe

    2012-07-01

    Full Text Available Etoposide is an anticancer agent, which is successfully and extensively used in treatments for various types of cancers in children and adults. However, due to the increases in survival and overall cure rate of cancer patients, interest has arisen on the potential risk of this agent for therapy-related secondary leukemia. Topoisomerase II inhibitors, including etoposide and teniposide, frequently cause rearrangements involving the mixed lineage leukemia (MLL gene on chromosome 11q23, which is associated with secondary leukemia. The prognosis is extremely poor for leukemias associated with rearrangements in the MLL gene, including etoposide-related secondary leukemias. It is of great importance to gain precise knowledge of the clinical aspects of these diseases and the mechanism underlying the leukemogenesis induced by this agent to ensure correct assessments of current and future therapy strategies. Here, I will review current knowledge regarding the clinical aspects of etoposide-related secondary leukemia, some probable mechanisms, and strategies for treating etoposide-induced leukemia.

  14. Deacetylation of topoisomerase I is an important physiological function of E. coli CobB

    Science.gov (United States)

    Zhou, Qingxuan; Zhou, Yan Ning; Jin, Ding Jun

    2017-01-01

    Abstract Escherichia coli topoisomerase I (TopA), a regulator of global and local DNA supercoiling, is modified by Nε-Lysine acetylation. The NAD+-dependent protein deacetylase CobB can reverse both enzymatic and non-enzymatic lysine acetylation modification in E. coli. Here, we show that the absence of CobB in a ΔcobB mutant reduces intracellular TopA catalytic activity and increases negative DNA supercoiling. TopA expression level is elevated as topA transcription responds to the increased negative supercoiling. The slow growth phenotype of the ΔcobB mutant can be partially compensated by further increase of intracellular TopA level via overexpression of recombinant TopA. The relaxation activity of purified TopA is decreased by in vitro non-enzymatic acetyl phosphate mediated lysine acetylation, and the presence of purified CobB protects TopA from inactivation by such non-enzymatic acetylation. The specific activity of TopA expressed from His-tagged fusion construct in the chromosome is inversely proportional to the degree of in vivo lysine acetylation during growth transition and growth arrest. These findings demonstrate that E. coli TopA catalytic activity can be modulated by lysine acetylation–deacetylation, and prevention of TopA inactivation from excess lysine acetylation and consequent increase in negative DNA supercoiling is an important physiological function of the CobB protein deacetylase. PMID:28398568

  15. Value of urinary topoisomerase-IIA cell-free DNA for diagnosis of bladder cancer.

    Science.gov (United States)

    Kim, Ye-Hwan; Yan, Chunri; Lee, Il-Seok; Piao, Xuan-Mei; Byun, Young Joon; Jeong, Pildu; Kim, Won Tae; Yun, Seok-Joong; Kim, Wun-Jae

    2016-03-01

    Topoisomerase-II alpha (TopoIIA ), a DNA gyrase isoform that plays an important role in the cell cycle, is present in normal tissues and various human cancers, and can show altered expression in both. The aim of the current study was to examine the value of urinary TopoIIA cell-free DNA as a noninvasive diagnosis of bladder cancer (BC). Two patient cohorts were examined. Cohort 1 (73 BC patients and seven controls) provided bladder tissue samples, whereas cohort 2 (83 BC patients, 54 nonmalignant hematuric patients, and 61 normal controls) provided urine samples. Real-time quantitative polymerase chain reaction was used to measure expression of TopoIIA mRNA in tissues and TopoIIA cell-free DNA in urine samples. The results showed that expression of TopoIIA mRNA in BC tissues was significantly higher than that in noncancer control tissues (pbladder cancer (MIBC) when compared with nonmuscle invasive bladder cancer (NMIBC) (p=0.002). Receiver operating characteristics (ROC) curve analysis was performed to examine the sensitivity/specificity of urinary TopoIIA cell-free DNA for diagnosing BC, NMIBC, and MIBC. The areas under the ROC curve for BC, NMIBC, and MIBC were 0.741, 0.701, and 0.838, respectively. In summary, the results of this study provide evidence that cell-free TopoIIA DNA may be a potential biomarker for BC.

  16. Construction, characterization, and complementation of a conditional-lethal DNA topoisomerase IIalpha mutant human cell line.

    Science.gov (United States)

    Carpenter, Adam J; Porter, Andrew C G

    2004-12-01

    DNA Topoisomerase IIalpha (topoIIalpha) is a DNA decatenating enzyme, abundant constituent of mammalian mitotic chromosomes, and target of numerous antitumor drugs, but its exact role in chromosome structure and dynamics is unclear. In a powerful new approach to this important problem, with significant advantages over the use of topoII inhibitors or RNA interference, we have generated and characterized a human cell line (HTETOP) in which >99.5% topoIIalpha expression can be silenced in all cells by the addition of tetracycline. TopoIIalpha-depleted HTETOP cells enter mitosis and undergo chromosome condensation, albeit with delayed kinetics, but normal anaphases and cytokineses are completely prevented, and all cells die, some becoming polyploid in the process. Cells can be rescued by expression of topoIIalpha fused to green fluorescent protein (GFP), even when certain phosphorylation sites have been mutated, but not when the catalytic residue Y805 is mutated. Thus, in addition to validating GFP-tagged topoIIalpha as an indicator for endogenous topoIIalpha dynamics, our analyses provide new evidence that topoIIalpha plays a largely redundant role in chromosome condensation, but an essential catalytic role in chromosome segregation that cannot be complemented by topoIIbeta and does not require phosphorylation at serine residues 1106, 1247, 1354, or 1393.

  17. Mechanistic studies on E. coli DNA topoisomerase I: Divalent ion effects

    International Nuclear Information System (INIS)

    Domanico, P.L.; Tse-Dinh, Y.C.

    1991-01-01

    E. coli DNA topoisomerase I catalyzes the hydrolysis of short, single stranded oligodeoxynucleotides. It also forms a covalent protein-DNA complex with negatively supercoiled DNA in the absence of Mg2+ but requires Mg2+ for the relaxation of negatively supercoiled DNA. In this paper we investigate the effects of various divalent metals on catalysis. For the relaxation reaction, maximum enzyme activity plateaus after 2.5 mM Mg2+. However, the rate of cleavage of short oligodeoxynucleotide increased linearly between 0 and 15 mM Mg2+. In the oligodeoxynucleotide cleavage reaction, Ca2+, Mn2+, Co2+, and Zn2+ inhibit enzymatic activity. When these metals are coincubated with Mg2+ at equimolar concentrations, the normal effect of Mg2+ is not detectable. Of these metals, only Ca2+ can be substituted for Mg2+ as a metal cofactor in the relaxation reaction. And when Mg2+ is coincubated with Mn2+, Co2+, or Zn2+ at equimolar concentrations, the normal effect of Mg2+ on relaxation is not detectable. The authors propose that Mg2+ allows the protein-DNA complex to assume a conformation necessary for strand passage and enhance the rate of enzyme turnover

  18. Topoisomerase I tyrosine phosphorylation site and the DNA-interactive site

    International Nuclear Information System (INIS)

    Roll, D.; Durban, E.

    1986-01-01

    Phosphorylation of topoisomerase I (topo I) at serine by NII kinase is accompanied by stimulation of enzymatic activity. In contrast, phosphorylation at tyrosine by tyrosine kinase seems to inhibit enzymatic activity. This inhibition may be caused by interference of the phosphorylated tyrosine residue with the interaction of topo I with DNA. To test this, topo I was labeled with crude membrane fraction enriched for EGF-receptor kinase in presence of γ-P32-ATP and electrophoresed on SDS-polyacrylamide gels. Stained topo I bands were excised, dried, digested with trypsin and analyzed on a C18 reverse-phase HPLC column. One major peak of radioactivity eluted at fraction 23 with 20% acetonitrile. To obtain the DNA-interactive site, topo I was incubated with pBR322 DNA labeled by nick-translation followed by DNase I treatment, and electrophoresis on SDS-polyacrylamide gels. Tryptic peptides were generated and analyzed by reverse-phase HPLC. A major peak of radioactivity eluted at fraction 16-18 with 15.5-17% acetonitrile. Studies are in progress to resolve whether (a) the two peptides are different, i.e. the tyrosine-P site and DNA-tyrosine interactive site are localized at different regions of the topo I or (b) the peptide sequences are identical but the covalent attachment of deoxynucleotides altered the peptide's elution from the HPLC column

  19. Resveratrol Modulates the Topoisomerase Inhibitory Potential of Doxorubicin in Human Colon Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Anika Schroeter

    2014-12-01

    Full Text Available Resveratrol (RSV is currently being widely discussed as potentially useful for anticancer therapy in combination with classical chemotherapeutics, e.g., the topoisomerase II (TOP II poison doxorubicin (DOX. However, there is still a lack of knowledge of possible interference at the target enzyme, especially since RSV itself has recently been described to act as a TOP poison. We therefore sought to address the question whether RSV affects DOX-induced genotoxic and cytotoxic effects with special emphasis on TOP II in HT-29 colon carcinoma cells. RSV was found to counteract DOX-induced formation of DNA-TOP-intermediates at ≥100 µM for TOP IIα and at 250 µM for TOP IIβ. As a consequence, RSV modulated the DNA-strand breaking potential of DOX by mediating protective effects with an apparent maximum at 100 µM. At higher concentration ranges (≥200 µM RSV diminished the intracellular concentrations of DOX. Nevertheless, the presence of RSV slightly enhanced the cytotoxic effects of DOX after 1.5 h and 24 h of incubation. Taken together, at least in cell culture RSV was found to affect the TOP-poisoning potential of DOX and to modulate its cytotoxic effectiveness. Thus, further studies are needed to clarify the impact of RSV on the therapeutic effectiveness of DOX under in vivo conditions.

  20. Nonsense mutation in the glycoprotein Ibα coding sequence associated with Bernard-Soulier syndrome

    International Nuclear Information System (INIS)

    Ware, J.; Russell, S.R.; Vicente, V.; Scharf, R.E.; Tomer, A.; McMillian, R.; Ruggeri, Z.M.

    1990-01-01

    Three distinct gene products, the α and β chains of glycoprotein (GP) Ib and GP IX, constitute the platelet membrane GP Ib-IX complex, a receptor for von Willebrand factor and thrombin involved in platelet adhesion and aggregation. Defective function of the GP Ib-IX complex is the hallmark of a rare congenital bleeding disorder of still undefined pathogenesis, the Bernard-Soulier syndrome. The authors have analyzed the molecular basis of the disease in one patient in whom immunoblotting of solubilized platelets demonstrated absence of normal GP Ibα but presence of a smaller immunoreactive species. The truncated polypeptide was also present, along with normal protein, in platelets from the patient's mother and two of his four children. Genetic characterization identified a nucleotide transition changing the Trp-343 codon (TGG) to a nonsense codon (TGA). Such a mutation explains the origin of the smaller GP Ibα, which by lacking half of the sequence on the carboxyl-terminal side, including the transmembrane domain, cannot be properly inserted in the platelet membrane. Both normal and mutant codons were found in the patient, suggesting that he is a compound heterozygote with a still unidentified defect in the other GP Ibα allele. Nonsense mutation and truncated GP Ibα polypeptide were found to cosegregate in four individuals through three generations and were associated with either Bernard-Soulier syndrome or carrier state phenotype. The molecular abnormality demonstrated in this family provides evidence that defective synthesis of GP Ibα alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome

  1. Pseudohypoparathyroidism type Ib associated with novel duplications in the GNAS locus.

    Directory of Open Access Journals (Sweden)

    Gustavo Perez-Nanclares

    Full Text Available Pseudohypoparathyroidism type 1b (PHP-Ib is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH and absence of any features of Albright's hereditary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complex GNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype.The aim of the study was to investigate the molecular and imprinting defects in the GNAS locus in two unrelated patients with PHP-Ib.We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Ligation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib.We identified two duplications in the GNAS region in two patients with PHP-Ib: one of them, comprising ∼ 320 kb, occurred 'de novo' in the patient, whereas the other one, of ∼ 179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed.In this article, we describe the to-our-knowledge biggest duplications reported so far in the GNAS region. Both are associated to PHP-Ib, one of them occurring 'de novo' and the other one being maternally inherited.

  2. Migraine, fibromyalgia, and depression among people with IBS: a prevalence study

    Directory of Open Access Journals (Sweden)

    Cabral Howard J

    2006-09-01

    Full Text Available Abstract Background Case descriptions suggest IBS patients are more likely to have other disorders, including migraine, fibromyalgia, and depression. We sought to examine the prevalence of these conditions in cohorts of people with and without IBS. Methods The source of data was a large U.S. health plan from January 1, 1996 though June 30, 2002. We identified all people with a medical claim associated with an ICD-9 code for IBS. A non-IBS cohort was a random sample of people with an ICD-9 code for routine medical care. In the cohorts, we identified all claims for migraine, depression, and fibromyalgia. We estimated the prevalence odds ratios (PORs of each of the three conditions using the Mantel-Haenszel method. We conducted quantitative sensitivity analyses to quantify the impact of residual confounding and in differential outcome identification. Results We identified 97,593 people in the IBS cohort, and a random sample of 27,402 people to compose the non-IBS comparison cohort. With adjustment, there was a 60% higher odds in the IBS cohort of having any one of the three disorders relative to the comparison cohort (POR 1.6, 95% CI 1.5 – 1.7. There was a 40% higher odds of depression in the IBS cohort (POR 1.4, 95% CI 1.3 – 1.4. The PORs for fibromyalgia and migraine were similar (POR for fibromyalgia 1.8, 95% CI 1.7 – 1.9; POR for migraine 1.6, 95% CI 1.4 – 1.7. Differential prevalence of an unmeasured confounder, or imperfect sensitivity or specificity of outcome detection would have impacted the observed results. Conclusion People in the IBS cohort had a 40% to 80% higher prevalence odds of migraine, fibromyalgia, and depression.

  3. Design and docking of novel series of hybrid xanthones as anti-cancer agent to target human DNA topoisomerase 2-alpha

    Directory of Open Access Journals (Sweden)

    Lalit Mohan Nainwal

    2014-06-01

    Full Text Available Topoisomerase (topo IIα is a homodimeric protein catalyzes topological vicissitudes by adding or by soothing super coiling transpiration, occurs in human DNA during DNA replication as an outcome chromosome segregation and condensation occurs during meiosis I and recombination. To prevent the cleavage and religation activity we administered novel hybrid substituted Xanthone series of drugs. The toxicity prediction showed outstanding results which impetus to study its anticancer activities by targeting topoisomerase (topo IIα. We developed the homology model of the topoisomerase (topo IIα due to the unavailability of 3D structure in the Protein Data Bank. Structural assessment of the modeled protein and confirmed the quality of the model. The ligands were docked using Autodock4.2 software and binding energy was reported. The compound XM9, XN2, XM7, XLNU and XNS scored lowest binding energy and highest binding affinity. The interaction sites and the hydrogen bond were observed.

  4. Improving the stability of alpha-conotoxin AuIB through N-to-C cyclization

    DEFF Research Database (Denmark)

    Armishaw, Christopher J; Jensen, Anders A; Balle, Lena D

    2011-01-01

    Modification of alpha-conotoxin frameworks through cyclization via an oligopeptide linker has previously been shown as an effective strategy for improving in vivo stability. We have extended this strategy by investigating cyclic analogs of alpha-conotoxin AuIB, a selective alpha3beta4 nicotinic a......-AuIB. As such, the cAuIB-2 globular isomer could constitute a useful probe for studying the role of the alpha3beta4 nicotinic acetylcholine receptor in a range of in vivo experimental paradigms....

  5. Functional characterization of Brassica napus DNA topoisomerase Iα-1 and its effect on flowering time when expressed in Arabidopsis thaliana

    International Nuclear Information System (INIS)

    Gao, Chenhao; Qi, Shuanghui; Liu, Kaige; Li, Dong; Jin, Changyu; Duan, Shaowei; Zhang, Meng; Chen, Mingxun

    2017-01-01

    Previous studies have shown that DNA topoisomerase Iα (AtTOP1α) has specific developmental functions during growth and development in Arabidopsis thaliana. However, little is known about the roles of DNA topoisomerases in the closely related and commercially important plant, rapeseed (Brassica napus). Here, the full-length BnTOP1α-1 coding sequence was cloned from the A2 subgenome of the Brassica napus inbred line L111. We determine that all BnTOP1α paralogs showed differing patterns of expression in different organs of L111, and that when expressed in tobacco leaves as a fusion protein with green fluorescent protein, BnTOP1α-1 localized to the nucleus. We further showed that ectopic expression of BnTOP1α-1 in the A. thaliana top1α-7 mutant fully complemented the early flowering phenotype of the mutant. Moreover, altered expression levels in top1α-7 seedlings of several key genes controlling flowering time were restored to wild type levels by ectopic expression of BnTOP1α-1. These results provide valuable insights into the roles of rapeseed DNA topoisomerases in flowering time, and provide a promising target for genetic manipulation of this commercially significant process in rapeseed. - Highlights: • BnTOP1α-1 was cloned from the A2 subgenome of Brassica napus inbred line L111. • BnTOP1α-1 rescued the early flowering phenotype of the Attop1α-7 mutant. • BnTOP1α-1 rescued the altered expression of flowering time genes in the Attop1α-mutant. • The functions of BnTOP1α-1 and AtTOP1α are likely conserved.

  6. IB4(+) nociceptors mediate persistent muscle pain induced by GDNF.

    Science.gov (United States)

    Alvarez, Pedro; Chen, Xiaojie; Bogen, Oliver; Green, Paul G; Levine, Jon D

    2012-11-01

    Skeletal muscle is a well-known source of glial cell line-derived neurotrophic factor (GDNF), which can produce mechanical hyperalgesia. Since some neuromuscular diseases are associated with both increased release of GDNF and intense muscle pain, we explored the role of GDNF as an endogenous mediator in muscle pain. Intramuscularly injected GDNF induced a dose-dependent (0.1-10 ng/20 μl) persistent (up to 3 wk) mechanical hyperalgesia in the rat. Once hyperalgesia subsided, injection of prostaglandin E(2) at the site induced a prolonged mechanical hyperalgesia (>72 h) compared with naïve rats (vibration increased muscle GDNF levels at 24 h, a time point where rats also exhibited marked muscle hyperalgesia. Intrathecal antisense oligodeoxynucleotides to mRNA encoding GFRα1, the canonical binding receptor for GDNF, reversibly inhibited eccentric exercise- and mechanical vibration-induced muscle hyperalgesia. Finally, electrophysiological recordings from nociceptors innervating the gastrocnemius muscle in anesthetized rats, revealed significant increase in response to sustained mechanical stimulation after local GDNF injection. In conclusion, these data indicate that GDNF plays a role as an endogenous mediator in acute and induction of chronic muscle pain, an effect likely to be produced by GDNF action at GFRα1 receptors located in IB4(+) nociceptors.

  7. The Role of the MAPK Signaling, Topoisomerase and Dietary Bioactives in Controlling Cancer Incidence

    Directory of Open Access Journals (Sweden)

    Khaled A. Selim

    2017-04-01

    Full Text Available Reactive oxygen species (ROS are common products of mitochondrial oxidative phosphorylation, xenobiotics metabolism and are generated in response to several environmental stress conditions. Some of them play important biochemical roles in cellular signal transduction and gene transcription. On the other hand, ROS are known to be involved in a wide range of human diseases, including cancer. The excessive production of such ROS together with disruption of homeostasis detoxifying mechanisms can mediate a series of cellular oxidative stresses. The oxidative stress of redundant free radicals production can lead to oxidative denaturation of cellular macromolecules including proteins, lipids and DNA. Moreover, oxidative damage is one of the major causes of DNA mutations, replication errors and genomic abnormalities which result in either inhibition or induction of transcription, and end with the disturbance of signal transduction pathways. Among affected signaling pathways are redox-sensitive kinases. The stimulation of these kinases induces several transcription factors through the phosphorylation of their module proteins. The activation of such pathways induces proliferation and cellular transformation. A diet rich in antioxidant compounds has potential health benefits, and there is a growing interest in the role of natural antioxidants in nutrition for prevention and cure of cancer diseases. A controversy has risen regarding the relation between antioxidants and the significant decrease in the risk of cancer incidence. In this review, we will focus on redox-sensitive kinases signaling pathways, highlighting the effects of dietary antioxidant on the prevention, incidence, prognosis or even treatment of human cancers. In addition, we will place emphasis on the chemical classes of pterocarpans as natural anti-oxidants/cancers as well as their underlying mechanisms of action, including their effects on MAPKs and topoisomerase activities.

  8. Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II

    International Nuclear Information System (INIS)

    Kawiak, Anna; Piosik, Jacek; Stasilojc, Grzegorz; Gwizdek-Wisniewska, Anna; Marczak, Lukasz; Stobiecki, Maciej; Bigda, Jacek; Lojkowska, Ewa

    2007-01-01

    Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin

  9. Dynamic Effects of Topoisomerase I Inhibition on R-Loops and Short Transcripts at Active Promoters.

    Directory of Open Access Journals (Sweden)

    Jessica Marinello

    Full Text Available Topoisomerase I-DNA-cleavage complexes (Top1cc stabilized by camptothecin (CPT have specific effects at transcriptional levels. We recently reported that Top1cc increase antisense transcript (aRNAs levels at divergent CpG-island promoters and, transiently, DNA/RNA hybrids (R-loop in nuclear and mitochondrial genomes of colon cancer HCT116 cells. However, the relationship between R-loops and aRNAs was not established. Here, we show that aRNAs can form R-loops in N-TERA-2 cells under physiological conditions, and that promoter-associated R-loops are somewhat increased and extended in length immediately upon cell exposure to CPT. In contrast, persistent Top1ccs reduce the majority of R-loops suggesting that CPT-accumulated aRNAs are not commonly involved in R-loops. The enhancement of aRNAs by Top1ccs is present both in human colon cancer HCT116 cells and WI38 fibroblasts suggesting a common response of cancer and normal cells. Although Top1ccs lead to DSB and DDR kinases activation, we do not detect a dependence of aRNA accumulation on ATM or DNA-PK activation. However, we showed that the cell response to persistent Top1ccs can involve an impairment of aRNA turnover rather than a higher synthesis rate. Finally, a genome-wide analysis shows that persistent Top1ccs also determine an accumulation of sense transcripts at 5'-end gene regions suggesting an increased occurrence of truncated transcripts. Taken together, the results indicate that Top1 may regulate transcription initiation by modulating RNA polymerase-generated negative supercoils, which can in turn favor R-loop formation at promoters, and that transcript accumulation at TSS is a response to persistent transcriptional stress by Top1 poisoning.

  10. TOPOISOMERASE1α Acts through Two Distinct Mechanisms to Regulate Stele and Columella Stem Cell Maintenance.

    Science.gov (United States)

    Zhang, Yonghong; Zheng, Lanlan; Hong, Jing Han; Gong, Ximing; Zhou, Chun; Pérez-Pérez, José Manuel; Xu, Jian

    2016-05-01

    TOPOISOMERASE1 (TOP1), which releases DNA torsional stress generated during replication through its DNA relaxation activity, plays vital roles in animal and plant development. In Arabidopsis (Arabidopsis thaliana), TOP1 is encoded by two paralogous genes (TOP1α and TOP1β), of which TOP1α displays specific developmental functions that are critical for the maintenance of shoot and floral stem cells. Here, we show that maintenance of two different populations of root stem cells is also dependent on TOP1α-specific developmental functions, which are exerted through two distinct novel mechanisms. In the proximal root meristem, the DNA relaxation activity of TOP1α is critical to ensure genome integrity and survival of stele stem cells (SSCs). Loss of TOP1α function triggers DNA double-strand breaks in S-phase SSCs and results in their death, which can be partially reversed by the replenishment of SSCs mediated by ETHYLENE RESPONSE FACTOR115 In the quiescent center and root cap meristem, TOP1α is epistatic to RETINOBLASTOMA-RELATED (RBR) in the maintenance of undifferentiated state and the number of columella stem cells (CSCs). Loss of TOP1α function in either wild-type or RBR RNAi plants leads to differentiation of CSCs, whereas overexpression of TOP1α mimics and further enhances the effect of RBR reduction that increases the number of CSCs Taken together, these findings provide important mechanistic insights into understanding stem cell maintenance in plants. © 2016 American Society of Plant Biologists. All Rights Reserved.

  11. Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery

    Directory of Open Access Journals (Sweden)

    Rafael Balaña-Fouce

    2014-12-01

    Full Text Available The Trypanosomatidae family, composed of unicellular parasites, causes severe vector-borne diseases that afflict human populations worldwide. Chagas disease, sleeping sickness, as well as different sorts of leishmaniases are amongst the most important infectious diseases produced by Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively. All these infections are closely related to weak health care services in low-income populations of less developed and least economically developed countries. Search for new therapeutic targets in order to hit these pathogens is of paramount priority, as no effective vaccine is currently in use against any of these parasites. Furthermore, present-day chemotherapy comprises old-fashioned drugs full of important side effects. Besides, they are prone to produce tolerance and resistance as a consequence of their continuous use for decades. DNA topoisomerases (Top are ubiquitous enzymes responsible for solving the torsional tensions caused during replication and transcription processes, as well as in maintaining genomic stability during DNA recombination. As the inhibition of these enzymes produces cell arrest and triggers cell death, Top inhibitors are among the most effective and most widely used drugs in both cancer and antibacterial therapies. Top relaxation and decatenation activities, which are based on a common nicking–closing cycle involving one or both DNA strands, have been pointed as a promising drug target. Specific inhibitors that bind to the interface of DNA-Top complexes can stabilize Top-mediated transient DNA breaks. In addition, important structural differences have been found between Tops from the Trypanosomatidae family members and Tops from the host. Such dissimilarities make these proteins very interesting for drug design and molecular intervention. The present review is a critical update of the last findings regarding trypanosomatid’s Tops, their new structural features

  12. IB-LBM simulation on blood cell sorting with a micro-fence structure.

    Science.gov (United States)

    Wei, Qiang; Xu, Yuan-Qing; Tian, Fang-bao; Gao, Tian-xin; Tang, Xiao-ying; Zu, Wen-Hong

    2014-01-01

    A size-based blood cell sorting model with a micro-fence structure is proposed in the frame of immersed boundary and lattice Boltzmann method (IB-LBM). The fluid dynamics is obtained by solving the discrete lattice Boltzmann equation, and the cells motion and deformation are handled by the immersed boundary method. A micro-fence consists of two parallel slope post rows which are adopted to separate red blood cells (RBCs) from white blood cells (WBCs), in which the cells to be separated are transported one after another by the flow into the passageway between the two post rows. Effected by the cross flow, RBCs are schemed to get through the pores of the nether post row since they are smaller and more deformable compared with WBCs. WBCs are required to move along the nether post row till they get out the micro-fence. Simulation results indicate that for a fix width of pores, the slope angle of the post row plays an important role in cell sorting. The cells mixture can not be separated properly in a small slope angle, while obvious blockages by WBCs will take place to disturb the continuous cell sorting in a big slope angle. As an optimal result, an adaptive slope angle is found to sort RBCs form WBCs correctly and continuously.

  13. Phenotyping of subjects for large scale studies on patients with IBS

    NARCIS (Netherlands)

    Boeckxstaens, G. E.; Drug, V.; Dumitrascu, D.; Farmer, A. D.; Hammer, J.; Hausken, T.; Niesler, B.; Pohl, D.; Pojskic, L.; Polster, A.; Simren, M.; Goebel-Stengel, M.; van Oudenhove, L.; Vassallo, M.; Wensaas, K.-A.; Aziz, Q.; Houghton, L. A.

    2016-01-01

    Background Irritable bowel syndrome (IBS) is a complex condition with multiple factors contributing to its aetiology and pathophysiology. Aetiologically these include genetics, life-time events and environment, and physiologically, changes in motility, central processing, visceral sensitivity,

  14. Long‐Term Monitoring of a Geosynthetic Reinforced Soil Integrated Bridge System (GRS‐IBS)

    Science.gov (United States)

    2017-11-01

    The geosynthetic reinforced soil integrated bridge system (GRS-IBS) is an innovative alternative to conventional bridge technology that utilizes closely spaced layers of geosynthetic reinforcement and compacted granular fill material to provide direc...

  15. Proteomics analysis of IBS-D with spleen and kidney yang deficiency

    Directory of Open Access Journals (Sweden)

    Yijie Li

    2017-01-01

    Conclusion: These data suggest that SKYD/IBS-D pathophysiology likely involves inflammation, cell growth, apoptosis, stress granule formation, immune activation, loss of epithelial cell integrity, and visceral hypersensitivity.

  16. The ties that bind: perceived social support, stress, and IBS in severely affected patients.

    Science.gov (United States)

    Lackner, J M; Brasel, A M; Quigley, B M; Keefer, L; Krasner, S S; Powell, C; Katz, L A; Sitrin, M D

    2010-08-01

    This study assessed the association between social support and the severity of irritable bowel syndrome (IBS) symptoms in a sample of severely affected IBS patients recruited to an NIH-funded clinical trial. In addition, we examined if the effects of social support on IBS pain are mediated through the effects on stress. Subjects were 105 Rome II diagnosed IBS patients (F = 85%) who completed seven questionnaires which were collected as part of a pretreatment baseline assessment. Partial correlations were conducted to clarify the relationships between social support and clinically relevant variables with baseline levels of psychopathology, holding constant number of comorbid medical diseases, age, gender, marital status, ethnicity, and education. Analyses indicated that social support was inversely related to IBS symptom severity. Social support was positively related with less severe pain. A similar pattern of data was found for perceived stress but not quality of life impairment. Regression analyses examined if the effects of social support on pain are mediated by stress. The effects of social support on bodily pain were mediated by stress such that the greater the social support the less stress and the less pain. This effect did not hold for symptom severity, quality of life, or psychological distress. This study links the perceived adequacy of social support to the global severity of symptoms of IBS and its cardinal symptom (pain). It also suggests that the mechanism by which social support alleviates pain is through a reduction in stress levels.

  17. Critical Success Factors for Lean Thinking in the Application of Industrialised Building System (IBS)

    Science.gov (United States)

    Yunus, Riduan; Noor, Siti Rahimah Mohd; Halid Abdullah, Abd; Nagapan, Sasitharan; Hamid, Abdul Rahim Abdul; Tajudin, Saiful Azhar Ahmad; Rohani Mat Jusof, Siti

    2017-08-01

    Productivity in the manufacturing process of building components can be increased by optimising each advantage that is available in each activity. Identification of critical success factors (CSFs) for lean thinking in the Industrialised Building System (IBS) will be able to minimise cost and reduce time needed to complete a project. The focus of lean thinking in construction is on the production process and the client’s requirement. In developing countries such as Malaysia, the integration of lean thinking in IBS applications is still low and there is a shortage of comprehensive strategies to integrate lean thinking. As key stakeholders, feedback from contractors, manufacturers, developers and the local authority will be able to help the identification of CSFs in integrating lean thinking in IBS applications. The data was collected through a questionnaire survey and analysed quantitatively. There are 31 CSFs for lean thinking in IBS which have been identified in this study. A conceptual model was developed to assist researchers in investigating the influences of CSFs for lean thinking in IBS applications. This study will assist construction players to improvise their manufacturing process in the implementation of IBS to eliminate unnecessary activities and focus instead on significant processes without generating physical and non-physical waste.

  18. The International Baccalaureate (IB programme: An international gateway to higher education and beyond

    Directory of Open Access Journals (Sweden)

    Susan E. Saxton

    2014-09-01

    Full Text Available The aim of this article is to present the International Baccalaureate (IB Programme and briefly outline its core components, followed by a review of what authoritative reports identify as skills for the future, esteemed by universities and the job market. There is a striking match between these skills and IB outcomes; thus, DP graduates perform well in higher education and add to the reputation of those institutions. After a review of the literature, the authors found the IB Diploma Programme has been studied in many countries by both consultants and educational agencies, and also by a wide array of universities themselves; however, there are fewer qualitative studies concerning the degree to which IB graduates display attitudes, values, and behaviours in line with the IB Learner Profile. This is why the authors stress the claims made are supported by examples of significant research, noting that there is a dearth of qualitative longitudinal studies to sufficiently substantiate the affective domain claims that currently rely more on anecdotal evidence. The authors conclude by pointing out more research is needed in order to substantiate anecdotal evidence regarding future employment success for IB Diploma Programme graduates.  DOI: 10.18870/hlrc.v4i3.123

  19. A Preliminary Review on Economies of Scale (EOS Towards Industrialized Building System (IBS Manufacturer

    Directory of Open Access Journals (Sweden)

    Tajul Ariffin Syazwana

    2017-01-01

    Full Text Available Industrialized Building System (IBS is a potential technology to improve productivity of construction industry. Controlled production and minimum generation of construction waste are some of the benefits that can be achieved by replacing conventional construction with IBS. In business, IBS is giving a huge opportunity for manufacturer and supplier to expand their business while contributing to construction development. However, bad strategies will put the company in high risk due to higher initial capital for machines and equipment. Therefore, strategic planning for company’s growth, profit maximization, and enhancement of productivity is undeniable to ensure the success of business in construction industry. This preliminary paper is exploring associated factors that affect Economy of Scale (EOS and their relationships in catalyzing the IBS manufacturer especially precast concrete as the scope of study to continue their business in the construction industry. Thus, a framework of EOS is proposed to assist IBS manufacturers to ensure their company’s growth and stability, competitiveness in term of monopoly or an oligopoly, increasing productivity, leading constant returns to scale, and finally increasing the firm’s efficiency. The refined EOS’s conceptual framework is an important turning point to support the development of decision making tools for IBS manufacturer towards their stability and survival in this highly competitive industry.

  20. The Cytotoxicity of Benzaldehyde Nitrogen Mustard-2-Pyridine Carboxylic Acid Hydrazone Being Involved in Topoisomerase IIα Inhibition

    Directory of Open Access Journals (Sweden)

    Yun Fu

    2014-01-01

    Full Text Available The antitumor property of iron chelators and aromatic nitrogen mustard derivatives has been well documented. Combination of the two pharmacophores in one molecule in drug designation is worth to be explored. We reported previously the syntheses and preliminary cytotoxicity evaluation of benzaldehyde nitrogen mustard pyridine carboxyl acid hydrazones (BNMPH as extended study, more tumor cell lines (IC50 for HepG2: 26.1 ± 3.5 μM , HCT-116: 57.5 ± 5.3 μM, K562: 48.2 ± 4.0 μM, and PC-12: 19.4 ± 2.2 μM were used to investigate its cytotoxicity and potential mechanism. In vitro experimental data showed that the BNMPH chelating Fe2+ caused a large number of ROS formations which led to DNA cleavage, and this was further supported by comet assay, implying that ROS might be involved in the cytotoxicity of BNMPH. The ROS induced changes of apoptosis related genes, but the TFR1 and NDRG1 metastatic genes were not obviously regulated, prompting that BNMPH might not be able to deprive Fe2+ of ribonucleotide reductase. The BNMPH induced S phase arrest was different from that of iron chelators (G1 and alkylating agents (G2. BNMPH also exhibited its inhibition of human topoisomerase IIα. Those revealed that the cytotoxic mechanism of the BNMPH could stem from both the topoisomerase II inhibition, ROS generation and DNA alkylation.

  1. Flavonoids from Annona dioica leaves and their effects in Ehrlich carcinoma cells, DNA-topoisomerase I and II

    International Nuclear Information System (INIS)

    Vega, Maria R.G.; Esteves-Souza, Andressa; Echevarria, Aurea; Vieira, Ivo J.C.; Mathias, Leda; Braz-Filho, Raimundo

    2007-01-01

    Chemical investigation of methanol extract leaves from Annona dioica (Annonaceae) resulted in the identification of flavonoids kaempferol (1), 3-O-[3'',6''-di-O-p-hydroxycinnamoyl]-β- galactopyranosyl-kaempferol (2), 6''-O-p-hydroxycinnamoyl-β-galactopyranosyl-kaempferol (3) and 3-O-β-galactopyranosyl-kaempferol (4). The structures were unequivocally characterized by 1 H and 13 C NMR spectroscopic analyses using 1D and 2D experiments. The cytotoxic effects of the flavonoids and flavonoid fraction (FF) were evaluated by MTT (3-(4,5-dimethylthiazole-2- yl)-2,5-diphenyltetrazolium bromide) assay against Ehrlich carcinoma cells. The results indicated that 1, 2, 3 and FF exhibit significant antiproliferative action when compared to quercetin. The inhibitory action on DNA-topoisomerase I and II of all the flavonoids was evaluated by relaxation assays on pBR322 plasmid DNA. The results indicated the inhibitory and non-selective effects of the flavonoids on DNA-topoisomerase I and II. (author)

  2. Flavonoids from Annona dioica leaves and their effects in Ehrlich carcinoma cells, DNA-topoisomerase I and II

    Energy Technology Data Exchange (ETDEWEB)

    Vega, Maria R.G.; Esteves-Souza, Andressa; Echevarria, Aurea [Universidade Federal Rural do Rio de Janeiro (UFRRJ), Seropedica, RJ (Brazil). Dept. de Quimica]. E-mail: echevarr@ufrrj.br; Vieira, Ivo J.C.; Mathias, Leda; Braz-Filho, Raimundo [Universidade Estadual do Norte Fluminense (UENF), Campos dos Goytacases, RJ (Brazil). Lab. de Ciencias Quimicas

    2007-07-01

    Chemical investigation of methanol extract leaves from Annona dioica (Annonaceae) resulted in the identification of flavonoids kaempferol (1), 3-O-[3'',6''-di-O-p-hydroxycinnamoyl]-{beta}- galactopyranosyl-kaempferol (2), 6''-O-p-hydroxycinnamoyl-{beta}-galactopyranosyl-kaempferol (3) and 3-O-{beta}-galactopyranosyl-kaempferol (4). The structures were unequivocally characterized by {sup 1}H and {sup 13}C NMR spectroscopic analyses using 1D and 2D experiments. The cytotoxic effects of the flavonoids and flavonoid fraction (FF) were evaluated by MTT (3-(4,5-dimethylthiazole-2- yl)-2,5-diphenyltetrazolium bromide) assay against Ehrlich carcinoma cells. The results indicated that 1, 2, 3 and FF exhibit significant antiproliferative action when compared to quercetin. The inhibitory action on DNA-topoisomerase I and II of all the flavonoids was evaluated by relaxation assays on pBR322 plasmid DNA. The results indicated the inhibitory and non-selective effects of the flavonoids on DNA-topoisomerase I and II. (author)

  3. Protection of halogenated DNA from strand breakage and sister-chromatid exchange induced by the topoisomerase I inhibitor camptothecin

    International Nuclear Information System (INIS)

    Orta, Manuel Luis; Mateos, Santiago; Cantero, Gloria; Wolff, Lisa J.; Cortes, Felipe

    2008-01-01

    The fundamental nuclear enzyme DNA topoisomerase I (topo I), cleaves the double-stranded DNA molecule at preferred sequences within its recognition/binding sites. We have recently reported that when cells incorporate halogenated nucleosides analogues of thymidine into DNA, it interferes with normal chromosome segregation, as shown by an extraordinarily high yield of endoreduplication, and results in a protection against DNA breakage induced by the topo II poison m-AMSA [F. Cortes, N. Pastor, S. Mateos, I. Dominguez, The nature of DNA plays a role in chromosome segregation: endoreduplication in halogen-substituted chromosomes, DNA Repair 2 (2003) 719-726; G. Cantero, S. Mateos, N. Pastor; F. Cortes, Halogen substitution of DNA protects from poisoning of topoisomerase II that results in DNA double-strand breaks (DSBs), DNA Repair 5 (2006) 667-674]. In the present investigation, we have assessed whether the presence of halogenated nucleosides in DNA diminishes the frequency of interaction of topo I with DNA and thus the frequency with which the stabilisation of cleavage complexes by the topo I poison camptothecin (CPT) takes place, in such a way that it protects from chromosome breakage and sister-chromatid exchange. This protective effect is shown to parallel a loss in halogen-substituted cells of the otherwise CPT-increased catalytic activity bound to DNA

  4. How the Change in IBS Criteria From Rome III to Rome IV Impacts on Clinical Characteristics and Key Pathophysiological Factors.

    Science.gov (United States)

    Aziz, Imran; Törnblom, Hans; Palsson, Olafur S; Whitehead, William E; Simrén, Magnus

    2018-06-08

    The diagnostic criteria for irritable bowel syndrome (IBS) have recently been updated from Rome III to Rome IV. Whereas in Rome III a diagnosis of IBS entailed chronic abdominal pain or discomfort at least 3 days per month, in Rome IV the term discomfort has been removed and the frequency of abdominal pain increased to at least 1 day per week. We examined how this change in IBS criteria impacts on clinical characteristics and pathophysiological factors. A total of 542 Swedish subjects with Rome III IBS completed a baseline questionnaire enquiring for the number of abdominal pain days in the last 10 days; this was subsequently used as a surrogate marker to identify Rome IV IBS, in that (a) those with 0 or 1 day of pain were classed as Rome IV-negative, and (b) those with ≥2 days of pain were classed as Rome IV-positive. Comparisons were made between Rome IV-positive and -negative IBS groups for demographics, IBS subtype, gastrointestinal and psychological symptoms, somatisation, fatigue, disease-specific quality of life, rectal sensitivity, and oro-anal transit time. Overall, 85% of Rome III IBS patients fulfilled the Rome IV criteria for IBS, but 15% did not. Rome IV-positive subjects were significantly more likely to be female, have poorer quality of life, greater pain severity, bloating, somatisation, fatigue, and rectal sensitivity than Rome IV-negative subjects. There were no differences in severity of anxiety or depression, IBS subtypes, bowel habit dissatisfaction, or oro-anal transit time. Finally, increasing number of pain days correlated positively with symptoms and visceral hypersensitivity. Most Rome III-positive IBS patients seeking healthcare fulfil the Rome IV IBS criteria. They constitute a more severe group than those who lose their IBS diagnosis.

  5. Crystallization and preliminary X-ray diffraction analysis of two N-terminal fragments of the DNA-cleavage domain of topoisomerase IV from Staphylococcus aureus

    Energy Technology Data Exchange (ETDEWEB)

    Carr, Stephen B., E-mail: bmbsbc@bmb.leeds.ac.uk [Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Makris, George [Omega Mediation Hellas Ltd, Clinical and Pharma Consulting, 11525 N. Psychiko, Athens (Greece); Phillips, Simon E. V.; Thomas, Christopher D. [Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)

    2006-11-01

    The crystallization and data collection of topoisomerase IV from S. aureus is described. Phasing by molecular replacement proved difficult owing to the presence of translational NCS and strategies used to overcome this are discussed. DNA topoisomerase IV removes undesirable topological features from DNA molecules in order to help maintain chromosome stability. Two constructs of 56 and 59 kDa spanning the DNA-cleavage domain of the A subunit of topoisomerase IV from Staphylococcus aureus (termed GrlA56 and GrlA59) have been crystallized. Crystals were grown at 291 K using the sitting-drop vapour-diffusion technique with PEG 3350 as a precipitant. Preliminary X-ray analysis revealed that GrlA56 crystals belong to space group P2{sub 1}, diffract to a resolution of 2.9 Å and possess unit-cell parameters a = 83.6, b = 171.5, c = 87.8 Å, β = 90.1°, while crystals of GrlA59 belong to space group P2{sub 1}2{sub 1}2, with unit-cell parameters a = 41.5, b = 171.89, c = 87.9 Å. These crystals diffract to a resolution of 2.8 Å. This is the first report of the crystallization and preliminary X-ray analysis of the DNA-cleavage domain of a topoisomerase IV from a Gram-positive organism.

  6. Crystallization and preliminary X-ray diffraction analysis of two N-terminal fragments of the DNA-cleavage domain of topoisomerase IV from Staphylococcus aureus

    International Nuclear Information System (INIS)

    Carr, Stephen B.; Makris, George; Phillips, Simon E. V.; Thomas, Christopher D.

    2006-01-01

    The crystallization and data collection of topoisomerase IV from S. aureus is described. Phasing by molecular replacement proved difficult owing to the presence of translational NCS and strategies used to overcome this are discussed. DNA topoisomerase IV removes undesirable topological features from DNA molecules in order to help maintain chromosome stability. Two constructs of 56 and 59 kDa spanning the DNA-cleavage domain of the A subunit of topoisomerase IV from Staphylococcus aureus (termed GrlA56 and GrlA59) have been crystallized. Crystals were grown at 291 K using the sitting-drop vapour-diffusion technique with PEG 3350 as a precipitant. Preliminary X-ray analysis revealed that GrlA56 crystals belong to space group P2 1 , diffract to a resolution of 2.9 Å and possess unit-cell parameters a = 83.6, b = 171.5, c = 87.8 Å, β = 90.1°, while crystals of GrlA59 belong to space group P2 1 2 1 2, with unit-cell parameters a = 41.5, b = 171.89, c = 87.9 Å. These crystals diffract to a resolution of 2.8 Å. This is the first report of the crystallization and preliminary X-ray analysis of the DNA-cleavage domain of a topoisomerase IV from a Gram-positive organism

  7. Cloning and characterization of a cDNA encoding topoisomerase II in pea and analysis of its expression in relation to cell proliferation.

    Science.gov (United States)

    Reddy, M K; Nair, S; Tewari, K K; Mudgil, Y; Yadav, B S; Sopory, S K

    1999-09-01

    We have isolated and sequenced four overlapping cDNA clones to identify the full-length cDNA for topoisomerase II (PsTopII) from pea. Using degenerate primers, based on the conserved amino acid sequences of other eukaryotic type II topoisomerases, a 680 bp fragment was PCR-amplified with pea cDNA as template. This fragment was used as a probe to screen an oligo-dT-primed pea cDNA library. A partial cDNA clone was isolated that was truncated at the 3' end. RACE-PCR was employed to isolate the remaining portion of the gene. The total size of PsTopII is 4639 bp with an open reading frame of 4392 bp. The deduced amino acid sequence shows a strong homology to other eukaryotic topoisomerase II (topo II) at the N-terminus end. The topo II transcript was abundant in proliferative tissues. We also show that the level of topo II transcripts could be stimulated by exogenous application of growth factors that induced proliferation in vitro cultures. Light irradiation to etiolated tissue strongly stimulated the expression of topo II. These results suggest that topo II gene expression is up-regulated in response to light and hormones and correlates with cell proliferation. Besides, we have also isolated and analysed the 5'-flanking region of the pea TopII gene. This is first report on the isolation of a putative promoter for topoisomerase II from plants.

  8. Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort

    DEFF Research Database (Denmark)

    Smith, David Hersi; Christensen, Ib Jarle; Jensen, Niels Frank

    2013-01-01

    Topoisomerase I (Top1) is the target of Top1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III C...

  9. Epidermal Growth Factor Receptor (EGFR) and its Cross-Talks with Topoisomerases: Challenges and Opportunities for Multi-Target Anticancer Drugs.

    Science.gov (United States)

    Chauhan, Monika; Sharma, Gourav; Joshi, Gaurav; Kumar, Raj

    2016-01-01

    The interactions of Epidermal Growth Factor Receptor (EGFR) and topoisomerases have been seen in various cancer including brain, breast, ovarian, colorectal, gastric, etc. The studies in adenocarcinoma patients, chromogenic in situ hybridization, western blotting, receptor binding assay and electromobility shift assays, etc. threw light on the biophysical and biochemical features of EGFR and Topoisomerase cross-talks. It has been revealed that both the isomers of topoisomerase (Topo I and Topo II) interact via different mechanisms with EGFR. Topo II and HER2 share the same location i.e. 17q12-21 regions which could be a possible cause of predominant interactions seen between them. Topo I and EGFR interactions are mechanically related to the nucleolar translocation of heparenase by EGF and c-Jun. We compiled literature findings including the mechanistic interventions, signaling pathways, patents, in vitro and in vivo data of tested inhibitors and combinations in clinical trials, which provide convincing confirmations for the interactions of EGFR and topoisomerases. These interactions may be used for deriving a consistent route of mechanism, design and development of standard drug combinations and dual or multi inhibitors.

  10. Novel human topoisomerase I inhibitors, topopyrones A, B, C and D. I. Producing strain, fermentation, isolation, physico-chemical properties and biological activity.

    Science.gov (United States)

    Kanai, Y; Ishiyama, D; Senda, H; Iwatani, W; Takahashi, H; Konno, H; Tokumasu, S; Kanazawa, S

    2000-09-01

    In the course of a screening program for specific inhibitors of human topoisomerase I using a recombinant yeast, we have discovered four new active compounds. All four compounds were isolated from the culture broth of a fungus, Phoma sp. BAUA2861, and two of them were isolated from the culture broth of a fungus, Penicillium sp. BAUA4206. We designated these compounds as topopyrones A, B, C and D. Topopyrones A, B, C and D selectively inhibited recombinant yeast growth dependent on expression of human topoisomerase I with IC50 values of 1.22, 0.15, 4.88 and 19.63 ng/ml, respectively. The activity and selectivity of topopyrone B were comparable to those of camptothecin. The relaxation of supercoiled pBR322 DNA by human DNA topoisomerase I was inhibited by these compounds, however they did not inhibit human DNA topoisomerase II. Topopyrones A, B, C and D were cytotoxic to all tumor cell lines when tested in vitro. Topopyrone B has potent inhibitory activity against herpesvirus, especially varicella zoster virus (VZV). It inhibited VZV growth with EC50 value of 0.038 microg/ml, which is 24-fold stronger than that of acyclovir (0.9 microg/ml). Topopyrones A, B, and C were inhibitory to Gram-positive bacteria.

  11. Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22

    International Nuclear Information System (INIS)

    Tsai-Pflugfelder, M.; Liu, L.F.; Liu, A.A.; Tewey, K.M.; Whang-Peng, J.; Knutsen, T.; Huebner, K.; Croce, C.M.; Wang, J.C.

    1988-01-01

    Two overlapping cDNA clones encoding human DNA topoisomerase II were identified by two independent methods. In one, a human cDNA library in phage λ was screened by hybridization with a mixed oligonucleotide probe encoding a stretch of seven amino acids found in yeast and Drosophila DNA topoisomerase II; in the other, a different human cDNA library in a λgt11 expression vector was screened for the expression of antigenic determinants that are recognized by rabbit antibodies specific to human DNA topoisomerase II. The entire coding sequences of the human DNA topoisomerase II gene were determined from these and several additional clones, identified through the use of the cloned human TOP2 gene sequences as probes. Hybridization between the cloned sequences and mRNA and genomic DNA indicates that the human enzyme is encoded by a single-copy gene. The location of the gene was mapped to chromosome 17q21-22 by in situ hybridization of a cloned fragment to metaphase chromosomes and by hybridization analysis with a panel of mouse-human hybrid cell lines, each retaining a subset of human chromosomes

  12. Topoisomerase 1(TOP1) gene copy number in stage III colorectal cancer patients and its relation to prognosis

    DEFF Research Database (Denmark)

    Rømer, Maria Unni Koefoed; Nygård, Sune Boris; Christensen, Ib Jarle

    2013-01-01

    A Topoisomerase 1 (Top1) poison is frequently included in the treatment regimens for metastatic colorectal cancer (mCRC). However, no predictive biomarkers for Top1 poisons are available. We here report a study on the TOP1 gene copy number in CRC patients and its association with patient prognosis...

  13. The impact of the human DNA topoisomerase II C-terminal domain on activity.

    Directory of Open Access Journals (Sweden)

    Emma L Meczes

    2008-03-01

    Full Text Available Type II DNA topoisomerases (topos are essential enzymes needed for the resolution of topological problems that occur during DNA metabolic processes. Topos carry out an ATP-dependent strand passage reaction whereby one double helix is passed through a transient break in another. Humans have two topoII isoforms, alpha and beta, which while enzymatically similar are differentially expressed and regulated, and are thought to have different cellular roles. The C-terminal domain (CTD of the enzyme has the most diversity, and has been implicated in regulation. We sought to investigate the impact of the CTD domain on activity.We have investigated the role of the human topoII C-terminal domain by creating constructs encoding C-terminally truncated recombinant topoIIalpha and beta and topoIIalpha+beta-tail and topoIIbeta+alpha-tail chimeric proteins. We then investigated function in vivo in a yeast system, and in vitro in activity assays. We find that the C-terminal domain of human topoII isoforms is needed for in vivo function of the enzyme, but not needed for cleavage activity. C-terminally truncated enzymes had similar strand passage activity to full length enzymes, but the presence of the opposite C-terminal domain had a large effect, with the topoIIalpha-CTD increasing activity, and the topoIIbeta-CTD decreasing activity.In vivo complementation data show that the topoIIalpha C-terminal domain is needed for growth, but the topoIIbeta isoform is able to support low levels of growth without a C-terminal domain. This may indicate that topoIIbeta has an additional localisation signal. In vitro data suggest that, while the lack of any C-terminal domain has little effect on activity, the presence of either the topoIIalpha or beta C-terminal domain can affect strand passage activity. Data indicates that the topoIIbeta-CTD may be a negative regulator. This is the first report of in vitro data with chimeric human topoIIs.

  14. Roles of Type 1A Topoisomerases in Genome Maintenance in Escherichia coli

    Science.gov (United States)

    Usongo, Valentine; Drolet, Marc

    2014-01-01

    In eukaryotes, type 1A topoisomerases (topos) act with RecQ-like helicases to maintain the stability of the genome. Despite having been the first type 1A enzymes to be discovered, much less is known about the involvement of the E. coli topo I (topA) and III (topB) enzymes in genome maintenance. These enzymes are thought to have distinct cellular functions: topo I regulates supercoiling and R-loop formation, and topo III is involved in chromosome segregation. To better characterize their roles in genome maintenance, we have used genetic approaches including suppressor screens, combined with microscopy for the examination of cell morphology and nucleoid shape. We show that topA mutants can suffer from growth-inhibitory and supercoiling-dependent chromosome segregation defects. These problems are corrected by deleting recA or recQ but not by deleting recJ or recO, indicating that the RecF pathway is not involved. Rather, our data suggest that RecQ acts with a type 1A topo on RecA-generated recombination intermediates because: 1-topo III overproduction corrects the defects and 2-recQ deletion and topo IIII overproduction are epistatic to recA deletion. The segregation defects are also linked to over-replication, as they are significantly alleviated by an oriC::aph suppressor mutation which is oriC-competent in topA null but not in isogenic topA+ cells. When both topo I and topo III are missing, excess supercoiling triggers growth inhibition that correlates with the formation of extremely long filaments fully packed with unsegregated and diffuse DNA. These phenotypes are likely related to replication from R-loops as they are corrected by overproducing RNase HI or by genetic suppressors of double topA rnhA mutants affecting constitutive stable DNA replication, dnaT::aph and rne::aph, which initiates from R-loops. Thus, bacterial type 1A topos maintain the stability of the genome (i) by preventing over-replication originating from oriC (topo I alone) and R-loops and (ii

  15. Resistance to sulfur poisoning of Ni-based alloy with coinage (IB) metals

    International Nuclear Information System (INIS)

    Xu, Xiaopei; Zhang, Yanxing; Yang, Zongxian

    2015-01-01

    Highlights: • The effects of IB metal dopants on the S poisoning features of Ni are analyzed. • IB metal dopants can modify the surface electronic structure of Ni. • IB metal dopants can increase the S tolerance of Ni at an optimized concentration. • Au is a preferred dopant to increase the resistance to sulfur poisoning of Ni. - Abstract: The poisoning effects of S atom on the (1 0 0), (1 1 0) and (1 1 1) metal surfaces of pure Ni and Ni-based alloy with IB (coinage) metals (Cu, Ag, Au) are systematically studied. The effects of IB metal dopants on the S poisoning features are analyzed combining the density functional theory (DFT) results with thermodynamics data using the ab initio atomistic thermodynamic method. It is found that introducing IB doping metals into Ni surface can shift the d-band center downward from the Fermi level and weaken the adsorption of S on the (1 0 0) and (1 1 0) surfaces, and the S tolerance ability increases in the order of Ni, Cu/Ni, Ag/Ni and Au/Ni. Nevertheless, on the (1 1 1) surface, the S tolerance ability increases in the order of Ag/Ni (or Cu/Ni), Ni, and Au/Ni. When we increase the coverage of the IB metal dopants, we found that not only Au, but Cu and Ag can increase its S tolerance. We therefore propose that alloying can increase its S tolerance and alloying with Au would be a better way to increase the resistance to sulfur poisoning of the Ni anode as compared with the pure Ni and the Ag- or, Cu-doped Ni materials.

  16. Rendimientos del colágeno, poliornitinas (tipos: IB, IIB y IC) y colágeno mas poliornitina IB, como substratos para el cultivo de ganglios ciliares disociados de embrión de pollo

    OpenAIRE

    Bustos Ruiz, M.; Alcaín Tejada, F.J.; Padilla-Alvarez, F.

    1981-01-01

    Dissociated ciliary ganglia of 8 days embryos were cultured in heart conditioned medium, employing differents substrata types: collagen, po¬lyornithines (types: IB,IIB and IC) and collagen plus polyornithine IB. The results from neuron survival (with and without prolongations) and non neuronal cells it obtained graphically. The polyornithines mollecular weights are discussed respect inductor factors binding for conditioned medium. The type IB is better than others types (IIB y IC), but collag...

  17. The scintigraphic determination of small intestinal transit time in patients with irritable bowel syndrome

    International Nuclear Information System (INIS)

    Marano, A.R.; Caride, V.J.; Shah, R.V.; Prokop, E.K.; Troncale, F.J.; McCallum, R.W.

    1984-01-01

    Diffuse disturbance in gastrointestinal motility may be present in patients with irritable bowel syndrome (IBS). To further investigate small intestinal motility in IBS patients small intestinal transit time (SITT) was determined and related to the symptom status. 11 female patients with IBS (mean age 29 years) were divided into those whose predominate symptom was diarrhea (N=6), and those with only constipation (N=5). All subjects ingested an isosmotic solution of lactulose (10 gm in 150cc of water) labeled with 99m-Tc-DTPA (Sn). The patient was studied supine under a 25 inch gamma camera with data collected at 1 frame per minute for 180 minutes or until activity appeared in the ascending colon. Regions of interest were selected over the cecum and ascending colon. The time of first appearance of radioactivity in the region of the cecum was taken as the small intestinal transit time. SITT in the 5 normal females was 98.7 +- 13 min (mean +- SEM). SITT in the IBS patients with diarrhea, 67.3 +- 7 min was significantly faster (p< 0.08). SITT in the constipated IBS patients, 126 +- 12 min, was slower than normals and significantly different from diarrhea patients (p< 0.001). These studies show that IBS patients with diarrhea have significantly faster SITT than normals while constipated IBS patients have significantly slower SITT than the diarrhea subgroup. Further, this study emphasizes the need to study the various symptomatic subgroups of IBs patients independently and indicates a possible role for abnormal SITT in the pathogenesis of IBS

  18. The scintigraphic determination of small intestinal transit time in patients with irritable bowel syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Marano, A.R.; Caride, V.J.; Shah, R.V.; Prokop, E.K.; Troncale, F.J.; McCallum, R.W.

    1984-01-01

    Diffuse disturbance in gastrointestinal motility may be present in patients with irritable bowel syndrome (IBS). To further investigate small intestinal motility in IBS patients small intestinal transit time (SITT) was determined and related to the symptom status. 11 female patients with IBS (mean age 29 years) were divided into those whose predominate symptom was diarrhea (N=6), and those with only constipation (N=5). All subjects ingested an isosmotic solution of lactulose (10 gm in 150cc of water) labeled with 99m-Tc-DTPA (Sn). The patient was studied supine under a 25 inch gamma camera with data collected at 1 frame per minute for 180 minutes or until activity appeared in the ascending colon. Regions of interest were selected over the cecum and ascending colon. The time of first appearance of radioactivity in the region of the cecum was taken as the small intestinal transit time. SITT in the 5 normal females was 98.7 +- 13 min (mean +- SEM). SITT in the IBS patients with diarrhea, 67.3 +- 7 min was significantly faster (p< 0.08). SITT in the constipated IBS patients, 126 +- 12 min, was slower than normals and significantly different from diarrhea patients (p< 0.001). These studies show that IBS patients with diarrhea have significantly faster SITT than normals while constipated IBS patients have significantly slower SITT than the diarrhea subgroup. Further, this study emphasizes the need to study the various symptomatic subgroups of IBs patients independently and indicates a possible role for abnormal SITT in the pathogenesis of IBS.

  19. Disturbances in small bowel motility.

    LENUS (Irish Health Repository)

    Quigley, E M

    2012-02-03

    Recently, the small intestine has become the focus of investigation as a potential site of dysmotility in the irritable bowel syndrome (IBS). A number of motor abnormalities have been defined in some studies, and include \\'clustered\\' contractions, exaggerated post-prandial motor response and disturbances in intestinal transit. The significance of these findings remains unclear. The interpretation of available studies is complicated by differences in subject selection, the direct influence of certain symptoms, such as diarrhoea and constipation, and the interference of compounding factors, such as stress and psychopathology. Dysmotility could also reflect autonomic dysfunction, disturbed CNS control and the response to heightened visceral sensation or central perception. While motor abnormalities may not explain all symptoms in IBS, sensorimotor interactions may be important in symptom pathogenesis and deserve further study.

  20. Enhanced accumulation of carotenoids in sweetpotato plants overexpressing IbOr-Ins gene in purple-fleshed sweetpotato cultivar.

    Science.gov (United States)

    Park, Sung-Chul; Kim, Sun Ha; Park, Seyeon; Lee, Hyeong-Un; Lee, Joon Seol; Park, Woo Sung; Ahn, Mi-Jeong; Kim, Yun-Hee; Jeong, Jae Cheol; Lee, Haeng-Soon; Kwak, Sang-Soo

    2015-01-01

    Sweetpotato [Ipomoea batatas (L.) Lam] is an important root crop that produces low molecular weight antioxidants such as carotenoids and anthocyanin. The sweetpotato orange (IbOr) protein is involved in the accumulation of carotenoids. To increase the levels of carotenoids in the storage roots of sweetpotato, we generated transgenic sweetpotato plants overexpressing IbOr-Ins under the control of the cauliflower mosaic virus (CaMV) 35S promoter in an anthocyanin-rich purple-fleshed cultivar (referred to as IbOr plants). IbOr plants exhibited increased carotenoid levels (up to 7-fold) in their storage roots compared to wild type (WT) plants, as revealed by HPLC analysis. The carotenoid contents of IbOr plants were positively correlated with IbOr transcript levels. The levels of zeaxanthin were ∼ 12 times elevated in IbOr plants, whereas β-carotene increased ∼ 1.75 times higher than those of WT. Quantitative RT-PCR analysis revealed that most carotenoid biosynthetic pathway genes were up-regulated in the IbOr plants, including PDS, ZDS, LCY-β, CHY-β, ZEP and Pftf, whereas LCY-ɛ was down-regulated. Interestingly, CCD1, CCD4 and NCED, which are related to the degradation of carotenoids, were also up-regulated in the IbOr plants. Anthocyanin contents and transcription levels of associated biosynthetic genes seemed to be altered in the IbOr plants. The yields of storage roots and aerial parts of IbOr plants and WT plants were not significantly different under field cultivation. Taken together, these results indicate that overexpression of IbOr-Ins can increase the carotenoid contents of sweetpotato storage roots. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. A new method using insert-based systems (IBS) to improve cell behavior study on flexible and rigid biomaterials

    OpenAIRE

    Grenade, Charlotte; Moniotte, Nicolas; Rompen, Eric; Vanheusden, Alain; Mainjot, Amélie; De Pauw-Gillet, Marie-Claire

    2016-01-01

    In vitro studies about biomaterials biological properties are essential screening tests. Yet cell cultures encounter difficulties related to cell retention on material surface or to the observation of both faces of permeable materials. The objective of the present study was to develop a reliable in vitro method to study cell behavior on rigid and flexible/permeable biomaterials elaborating two specific insert-based systems (IBS-R and IBS-F respectively). IBS-R was designed as a specific cylin...

  2. Mucosal pathobiology and molecular signature of epithelial barrier dysfunction in the small intestine in irritable bowel syndrome.

    Science.gov (United States)

    González-Castro, Ana M; Martínez, Cristina; Salvo-Romero, Eloísa; Fortea, Marina; Pardo-Camacho, Cristina; Pérez-Berezo, Teresa; Alonso-Cotoner, Carmen; Santos, Javier; Vicario, María

    2017-01-01

    Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders in developed countries. Its etiology remains unknown; however, a common finding, regardless of IBS subtype, is the presence of altered intestinal barrier. In fact, signaling and location of cell-to-cell adhesion proteins, in connection with increased immune activity, seem abnormal in the intestinal epithelium of IBS patients. Despite that most research is performed on distal segments of the intestine, altered permeability has been reported in both, the small and the large bowel of all IBS subtypes. The small intestine carries out digestion and nutrient absorption and is also the site where the majority of immune responses to luminal antigens takes place. In fact, the upper intestine is more exposed to environmental antigens than the colon and is also a site of symptom generation. Recent studies have revealed small intestinal structural alterations of the epithelial barrier and mucosal immune activation in association with intestinal dysfunction, suggesting the commitment of the intestine as a whole in the pathogenesis of IBS. This review summarizes the most recent findings on mucosal barrier alterations and its relationship to symptoms arising from the small intestine in IBS, including epithelial structural abnormalities, mucosal immune activation, and microbial dysbiosis, further supporting the hypothesis of an organic origin of IBS. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  3. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial.

    Science.gov (United States)

    McIntosh, Keith; Reed, David E; Schneider, Theresa; Dang, Frances; Keshteli, Ammar H; De Palma, Giada; Madsen, Karen; Bercik, Premysl; Vanner, Stephen

    2017-07-01

    To gain mechanistic insights, we compared effects of low fermentable oligosaccharides, disaccharides and monosaccharides and polyols (FODMAP) and high FODMAP diets on symptoms, the metabolome and the microbiome of patients with IBS. We performed a controlled, single blind study of patients with IBS (Rome III criteria) randomised to a low (n=20) or high (n=20) FODMAP diet for 3 weeks. Symptoms were assessed using the IBS symptom severity scoring (IBS-SSS). The metabolome was evaluated using the lactulose breath test (LBT) and metabolic profiling in urine using mass spectrometry. Stool microbiota composition was analysed by 16S rRNA gene profiling. Thirty-seven patients (19 low FODMAP; 18 high FODMAP) completed the 3-week diet. The IBS-SSS was reduced in the low FODMAP diet group (pmetabolome. In subsets of patients, FODMAPs modulate histamine levels and the microbiota, both of which could alter symptoms. NCT01829932. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  4. Critical ICT-Inhibiting Factors on IBS Production Management Processes in the Malaysia Construction Industry

    Science.gov (United States)

    Ern, Peniel Ang Soon; Kasim, Narimah; Hamid, Zuhairi Abd; Chen, Goh Kai

    2017-10-01

    Industrialized Building System (IBS) is one of the approaches that had been introduced as an alternative to conventional building method where it becomes the new strategy of enhancing the sustainable construction in current industries while spearheading a huge advancement of benefits with green constructions into the existing industries. The IBS approach is actively promoted through several strategies and incentives as an alternative to conventional building methods. Extensive uptakes of modern Information Communication Technology (ICT) applications are able to support the different IBS processes for effective production. However, it is argued that ICT uptake at the organisational level is still in its infancy. This raises the importance to identify critical inhibitors which are inhibing the effective uptake of ICT in the IBS production management process. Critical inhibitors to ICT uptake were identified through questionnaire survey with the IBS industry stakeholders. The mean index and critical t-values are generated with the use of the quantitative tool, Statistical Package for Social Sciences (SPSS). The top ten priority ranked inhibitors reflect the Cost, People and Process elements to ICT uptake. High costs in acquiring the technologies and resistance to change were some main concerns from the findings.

  5. BUSINESS STRATEGY OF LARGE CONTRACTORS IN ADOPTING INDUSTRIALISED BUILDING SYSTEM (IBS: THE MALAYSIAN CASE

    Directory of Open Access Journals (Sweden)

    FRANKY AMBON

    2012-12-01

    Full Text Available Industrialised Building System (IBS is the term coined by the government and industry in Malaysia to represent the construction industry and the application of prefabrication method in building construction. The purpose of this exploratory research paper is to highlight business strategy being pursued by large Malaysian contractors in adopting IBS. The paper uses case study as research method. The analysis is based primarily on cross-case analysis and pattern matching technique. The paper observes contractors which involved in IBS are part of larger holding companies in a corporate set-up include design and manufacturing subsidiaries. The companies positioned themselves as one-stop total solution provider for IBS and offer a wider range of services from design, production, and installation to clients. To become competitive and able to create total solution, contractors need to establish cluster and consortium of integrated project team by creating a partnership when and where it is needed. A vendor development programme modelled along the lines of the development of automotive industry should also be established. Future empirical studies should extensively examine these areas, especially the development of business model for contractors. The availability of this model could help to accelerate the uptake of IBS among contractors.

  6. The Significance of Coordination for Industrialised Building System (IBS Precast Concrete in Construction Industry

    Directory of Open Access Journals (Sweden)

    Fitri Othman Mohd Khairul

    2017-01-01

    Full Text Available IBS precast concrete is construction system which is meant to improve the conventional construction process. However IBS precast concrete projects are suffering from serious problems such as cost overrun, delays and less quality of the end product. The absence of coordination is perceived as the reason for this issue. The purpose of this paper is to review the significance of coordination for IBS precast concrete in the construction industry. It if found that the fragmentation which occurs in the construction industry requires continuity of coordination due to the construction activities are intertwined in nature. Coordination is designated to assist stakeholders in completing and complementing each other with the paramount focus of achieving the objective. Proper coordination is required in delivering the desired construction product at the ideal time, cost and quality. As for the findings, the significance of coordination for IBS precast concrete can be seen through the precast concrete construction phases which consist of planning; design; manufacturing; transportation and installation/construction. These phases are meant to complement construction process with the purpose to reduce issues of fragmentation and enhance IBS precast concrete project delivery.

  7. BK polyomavirus genotypes Ia and Ib1 exhibit different biological properties in renal transplant recipients.

    Science.gov (United States)

    Varella, Rafael B; Zalona, Ana Carolina J; Diaz, Nuria C; Zalis, Mariano G; Santoro-Lopes, Guilherme

    2018-01-02

    BK polyomavirus (BKV) is an opportunist agent associated with nephropathy (BKVAN) in 1-10% of kidney transplant recipients. BKV is classified into genotypes or subgroups according to minor nucleotidic variations with unknown biological implications. Studies assessing the possible association between genotypes and the risk of BKVAN in kidney transplant patients have presented conflicting results. In these studies, genotype Ia, which is highly prevalent in Brazil, was less frequently found and, thus, comparative data on the biological properties of this genotype are lacking. In this study, BKV Ia and Ib1 genotypes were compared according to their viral load, genetic evolution (VP1 and NCCR) - in a cohort of renal transplant recipients. The patients infected with Ia (13/23; 56.5%) genotype exhibited higher viral loads in urine [>1.4 log over Ib1 (10/23; 43.5%); p=0.025]. In addition, genotype Ia was associated with diverse mutations at VP1 loops and sites under positive selection outside loops, which were totally absent in Ib1. Although the number of viremic patients was similar, the three patients who had BK nephropathy (BKVAN) were infected with Ia genotype. NCCR architecture (ww or rr) were not distinctive between Ia and Ib1 genotypes. Ia genotype, which is rare in other published BKV cohorts, presented some diverse biological properties in transplanted recipients in comparison to Ib1. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Overcoming ICT Barriers in IBS Management Process in Malaysia Construction Industry

    Directory of Open Access Journals (Sweden)

    Soon Ern Peniel Ang

    2017-01-01

    Full Text Available As the result of government’s initiative and future outlook in uprising the awareness towards the implementation of sustainable elements in construction industries, the Industrialized Building System (IBS is one of the approaches that had been introduced as an alternative to conventional building method and produce the new strategy of reducing the waste of materials in construction. The IBS approach is actively promoted through several strategies and incentives as an alternative to conventional building methods. Extensive uptakes of modern Information Communication Technology (ICT applications are able to support the different IBS processes for effective production. However, it is argued that ICT uptake at the organizational level needs to be regularly improved. Thus, this paper fulfills the need to identify the critical barriers to ICT employment and highlighting the ICT drivers in enhancing the IBS management process. Critical barriers and drivers to ICT uptake were identified through questionnaire survey with industry stakeholders and were analyzed using mean index and critical t-value with the use of SPSS software. The critical drivers are top management support and commitment and improving the availability of the technologies. The critical drivers which were identified are significant in ensuring the enhancement of ICT implementation. Hence, any system in place should avoid the highest ranked barriers or seek to alleviate their impact by focusing on the identified drivers in order to enhance implementation of ICT in IBS process management.

  9. Supply Chain Management on IBS Implementation in Klang Valley Construction Industry: Challenges and Issues

    Science.gov (United States)

    Azrizal Fauzi, Mohd; Hasim, Sulaiman; Awang, Anizah; Ridzuan, Ahmad Ruslan Mohd; Nur Yunus, Juzailah

    2017-12-01

    Industrialized Building System (IBS) is a system where the components of the building are manufactured in a factory and it will be transported to the site to form the structures. The supply chain management (SCM) is a system where the delivery flows of the IBS products from manufacturers to the site. The aim of this research is to identify the major challenges and to analyze the issues on IBS implementation in SCM in Klang Valley from the manufacturers perspective. The methodology used in this paper is based on primary data through questionnaire and interview. Questionnaires were sent to the Manufacturers. It can be concluded that this paper attempts to present more on the challenges and issues that those companies of manufacturers faced during their success journey in finding integration in their supply chain. The main contributions of this paper are integrating all the supply chain integration challenges and issues on IBS. Therefore, these contributions will be helpful for the organization of manufacturers and IBS players that establish the integration in their SCM.

  10. Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis

    International Nuclear Information System (INIS)

    Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.; Murphy, W.H.

    1978-01-01

    The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log 10 PD 50 values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplanted Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain

  11. Imágenes del rapto de la doncella en rituales festivos ibéricos

    Directory of Open Access Journals (Sweden)

    Brisset, Demetrio E.

    2003-12-01

    Full Text Available During the patron saint's feasts in several small towns of the Iberian Peninsula, it is the devil who persuades the "moors" to kidnap the Virgin Mary. This ritual abduction of the model woman in Iberian culture can be regarded as part of a symbolic complex expressed throughout the centuries in various significant ways, the persistency of which indicating its deeprooted presence in hearts and minds and its influence on collective values and beliefs. Here I propose a comparative ethnohistorical approach, using the analytical tools of visual anthropology, to the symbolism of the different images of the abducted woman appearing in such patron saint's feasts, whether sacred or profane.

    En las fiestas patronales de varios pueblos ibéricos, Luzbel convence a los «moros» para que se apoderen de la Virgen María. Este rapto ritual de la bella imagen de la mujer modélica en nuestra cultura se puede incluir dentro de un complejo simbólico expresado a lo largo de los siglos con muy vanadas formas significantes; persistencia que indica su profunda implantación psíquica e influencia en las creencias y valores colectivos. Aquí se propone una aproximación comparativa etnohistórica, con el instrumental analítico de la antropología visual, para abordar el simbolismo de las diversas imágenes de la mujer raptada que aparecen en dichas representaciones festivas, tanto religiosas como profanas.

  12. Klinefelter's Syndrome with Seizure, Pseudohypoparathyroidism Type Ib and Multiple Endocrine Dysfunctions

    Directory of Open Access Journals (Sweden)

    Chwen-Yi Yang

    2005-12-01

    Full Text Available Klinefelter's syndrome is rarely associated with hypocalcemia, especially pseudohypoparathyroidism (PHP type Ib. We describe a case of Klinefelter's syndrome associated with seizure, PHP type Ib and multiple endocrine dysfunctions. A 19-year-old Taiwanese male was admitted due to seizures with loss of consciousness. He had been diagnosed with Klinefelter's syndrome with seizure disorder and hypocalcemia 3 months previously. Physical examination revealed eunuchoidism but no osteodystrophy, while laboratory data revealed severe hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone. Chromosomal study showed 47, XXY. Osteoporosis was found on chest and abdominal radiography. Dense calcification in the cerebrum and cerebellum was shown on brain computed tomography and magnetic resonance imaging. Elevation of the patient's serum calcium level was noted after vitamin D and calcium carbonate supplements were given. Klinefelter's syndrome is rarely associated with PHP type Ib; our patient's hypocalcemia improved after long-term aggressive treatment.

  13. A Support Vector Machine Classification Model for Benzo[c]phenathridine Analogues with Topoisomerase-I Inhibitory Activity

    Directory of Open Access Journals (Sweden)

    Thanh-Dao Tran

    2012-04-01

    Full Text Available Benzo[c]phenanthridine (BCP derivatives were identified as topoisomerase I (TOP-I targeting agents with pronounced antitumor activity. In this study, a support vector machine model was performed on a series of 73 analogues to classify BCP derivatives according to TOP-I inhibitory activity. The best SVM model with total accuracy of 93% for training set was achieved using a set of 7 descriptors identified from a large set via a random forest algorithm. Overall accuracy of up to 87% and a Matthews coefficient correlation (MCC of 0.71 were obtained after this SVM classifier was validated internally by a test set of 15 compounds. For two external test sets, 89% and 80% BCP compounds, respectively, were correctly predicted. The results indicated that our SVM model could be used as the filter for designing new BCP compounds with higher TOP-I inhibitory activity.

  14. Inhibition of topoisomerase IIα activity in CHO K1 cells by 2-[(aminopropyl)amino]ethanethiol (WR-1065)

    International Nuclear Information System (INIS)

    Grdina, D.J.

    1993-06-01

    The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied radioprotective agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector and antimutagenic agent when it is administered 30 min prior to radiation exposure to Chinese hamster ovary Kl cells at a concentration of 4 mM. Under these exposure conditions, topoisomerase (topo) I and II activities and associated protein contents were measured in the K1 cell line using the DNA relaxation assay, the P4 unknotting assay, and immunoblotting, respectively. WR-1065 was ineffective in modifying topo I activity, but it did reduce topo IIa activity by an average of 50 percent. The magnitude of topo IIa protein content, however, was not affected by these exposure conditions. Cell cycle effects were monitored by the method of flow cytometry. Exposure of cells to 4 mM WR-1065 for a period of up to 6 h resulted in a buildup of cells in the G2 compartment. However, in contrast to topo II inhibitors used in chemotherapy, WR-1065 is an effective radioprotector agent capable of protecting against both radiation-induced cell lethality and mutagenesis. One of several mechanisms of radiation protection attributed to aminothiol compounds such as WR-1065 has been their ability to affect endogenous enzymatic reactions involved in DNA synthesis, repair, and cell cycle progression. These results are consistent with such a proposed mechanism and demonstrate in particular a modifying effect by 2-[(aminopropyl)amino]ethanethiol on type II topoisomerase, which is involved in DNA synthesis

  15. Inhibition of topoisomerase II{alpha} activity in CHO K1 cells by 2-[(aminopropyl)amino]ethanethiol (WR-1065)

    Energy Technology Data Exchange (ETDEWEB)

    Grdina, D.J. [Argonne National Lab., IL (United States)]|[Chicago Univ., IL (United States). Dept. of Radiation and Cellular Oncology; Constantinou, A. [Illinois Univ., Chicago, IL (United States). Specialized Cancer Center; Shigematsu, N.; Murley, J.S. [Argonne National Lab., IL (United States)

    1993-06-01

    The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied radioprotective agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector and antimutagenic agent when it is administered 30 min prior to radiation exposure to Chinese hamster ovary Kl cells at a concentration of 4 mM. Under these exposure conditions, topoisomerase (topo) I and II activities and associated protein contents were measured in the K1 cell line using the DNA relaxation assay, the P4 unknotting assay, and immunoblotting, respectively. WR-1065 was ineffective in modifying topo I activity, but it did reduce topo IIa activity by an average of 50 percent. The magnitude of topo IIa protein content, however, was not affected by these exposure conditions. Cell cycle effects were monitored by the method of flow cytometry. Exposure of cells to 4 mM WR-1065 for a period of up to 6 h resulted in a buildup of cells in the G2 compartment. However, in contrast to topo II inhibitors used in chemotherapy, WR-1065 is an effective radioprotector agent capable of protecting against both radiation-induced cell lethality and mutagenesis. One of several mechanisms of radiation protection attributed to aminothiol compounds such as WR-1065 has been their ability to affect endogenous enzymatic reactions involved in DNA synthesis, repair, and cell cycle progression. These results are consistent with such a proposed mechanism and demonstrate in particular a modifying effect by 2-[(aminopropyl)amino]ethanethiol on type II topoisomerase, which is involved in DNA synthesis.

  16. The sweet potato IbMYB1 gene as a potential visible marker for sweet potato intragenic vector system.

    Science.gov (United States)

    Kim, Cha Young; Ahn, Young Ock; Kim, Sun Ha; Kim, Yun-Hee; Lee, Haeng-Soon; Catanach, Andrew S; Jacobs, Jeanne M E; Conner, Anthony J; Kwak, Sang-Soo

    2010-07-01

    MYB transcription factors play important roles in transcriptional regulation of many secondary metabolites including anthocyanins. We cloned the R2R3-MYB type IbMYB1 complementary DNAs from the purple-fleshed sweet potato (Ipomoea batatas L. cv Sinzami) and investigated the expression patterns of IbMYB1 gene with IbMYB1a and IbMYB1b splice variants in leaf and root tissues of various sweet potato cultivars by reverse transcription-polymerase chain reaction. The transcripts of IbMYB1 were predominantly expressed in the purple-fleshed storage roots and they were also detectable in the leaf tissues accumulating anthocyanin pigments. In addition, transcript levels of IbMYB1 gene were up-regulated by treatment with methyl jasmonate or salicylic acid in leaf and root tissues of cv. White Star. To set up the intragenic vector system in sweet potato, we first evaluated the utilization of the IbMYB1 gene as a visible selectable marker. The IbMYB1a was transiently expressed in tobacco leaves under the control of a constitutive cauliflower mosaic virus 35S promoter, a root-specific and sucrose-inducible sporamin promoter, and an oxidative stress-inducible sweet potato anionic peroxidase2 promoter. We also showed that overexpression of IbMYB1a induced massive anthocyanin pigmentation in tobacco leaves and up-regulated the transcript levels of the structural genes in anthocyanin biosynthetic pathway. Furthermore, high-performance liquid chromatography analysis revealed that the expression of IbMYB1a led to production of cyanidin as a major core molecule of anthocyanidins in tobacco leaves. These results suggest that the IbMYB1 gene can be applicable to a visible marker for sweet potato transformation with intragenic vectors, as well as the production of anthocyanin as important nutritive value in other plant species.

  17. ′Belonging without Belonging′: Colm Tóibín′s Dialogue with the Past

    DEFF Research Database (Denmark)

    Bøss, Michael

    2005-01-01

    It is argued that Tóibín is not the typical 'revisionist' intellectual that some have made him into, but a humanist and a sort of in-between, making a virtue of his own ambivalences towards notions of tradition, community and nationhood. The essay makes an analysis of these ambivalences with refe......It is argued that Tóibín is not the typical 'revisionist' intellectual that some have made him into, but a humanist and a sort of in-between, making a virtue of his own ambivalences towards notions of tradition, community and nationhood. The essay makes an analysis of these ambivalences...

  18. Purification, crystallization and preliminary X-ray analysis of Enterococcus faecium aminoglycoside-2′′-phosphotransferase-Ib [APH(2′′)-Ib

    International Nuclear Information System (INIS)

    Walanj, Rupa; Young, Paul; Baker, Heather M.; Baker, Edward N.; Metcalf, Peter; Chow, Joseph W.; Lerner, Stephen; Vakulenko, Sergei; Smith, Clyde A.

    2005-01-01

    APH(2′′)-Ib is an enzyme responsible for high-level gentamicin resistance in E. faecium isolates. Native crystals of this enzyme have been prepared and preliminary X-ray diffraction experiments have been undertaken. Bacterial resistance to the aminoglycoside antibiotics is primarily the result of deactivation of the drugs. Three families of enzymes are responsible for this activity, with one such family being the aminoglycoside phosphotransferases (APHs). The gene encoding one of these enzymes, APH(2′′)-Ib, has been cloned and the protein (comprising 299 amino-acid residues) expressed in Escherichia coli, purified and crystallized in the presence of 16%(w/v) PEG 3350 and gentamicin. The crystals belong to the monoclinic space group P2 1 , with approximate unit-cell parameters a = 79.7, b = 58.8, c = 81.4 Å, β = 98.4°, and preliminary X-ray diffraction analysis is consistent with the presence of two molecules in the asymmetric unit. Synchrotron diffraction data to approximately 2.65 Å resolution were collected from a native APH(2′′)-Ib crystal at beamline BL9-2 at SSRL (Stanford, CA, USA). Selenium-substituted crystals have also been produced and structure determination is proceeding

  19. Purification, crystallization and preliminary X-ray analysis of Enterococcus faecium aminoglycoside-2′′-phosphotransferase-Ib [APH(2′′)-Ib

    Energy Technology Data Exchange (ETDEWEB)

    Walanj, Rupa; Young, Paul; Baker, Heather M.; Baker, Edward N.; Metcalf, Peter [Laboratory of Structural Biology, School of Biological Sciences, University of Auckland, Auckland (New Zealand); Chow, Joseph W.; Lerner, Stephen [Division of Infectious Diseases, Wayne State University School of Medicine and VA Medical Center, Detroit, Michigan 48201 (United States); Vakulenko, Sergei [Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556 (United States); Smith, Clyde A., E-mail: csmith@slac.stanford.edu [Stanford Synchrotron Radiation Laboratory, Stanford University, Menlo Park, CA 94025 (United States); Laboratory of Structural Biology, School of Biological Sciences, University of Auckland, Auckland (New Zealand)

    2005-04-01

    APH(2′′)-Ib is an enzyme responsible for high-level gentamicin resistance in E. faecium isolates. Native crystals of this enzyme have been prepared and preliminary X-ray diffraction experiments have been undertaken. Bacterial resistance to the aminoglycoside antibiotics is primarily the result of deactivation of the drugs. Three families of enzymes are responsible for this activity, with one such family being the aminoglycoside phosphotransferases (APHs). The gene encoding one of these enzymes, APH(2′′)-Ib, has been cloned and the protein (comprising 299 amino-acid residues) expressed in Escherichia coli, purified and crystallized in the presence of 16%(w/v) PEG 3350 and gentamicin. The crystals belong to the monoclinic space group P2{sub 1}, with approximate unit-cell parameters a = 79.7, b = 58.8, c = 81.4 Å, β = 98.4°, and preliminary X-ray diffraction analysis is consistent with the presence of two molecules in the asymmetric unit. Synchrotron diffraction data to approximately 2.65 Å resolution were collected from a native APH(2′′)-Ib crystal at beamline BL9-2 at SSRL (Stanford, CA, USA). Selenium-substituted crystals have also been produced and structure determination is proceeding.

  20. EVALUATION OF LOW URINARY TRACT SYMPTOMS AND ERECTILE FUNCTION IN MEN WITH IRRITABLE BOWEL SYNDROME(IBS

    Directory of Open Access Journals (Sweden)

    Dogan Atilgan

    2014-06-01

    Conclusion: IBS, is a major health problem with serious psychosocial side effects and significantly reduces patients quality of life. LUTS and ED may be seen frequently in patients with IBS. Therefore, during menagement of these patients multydiciplinary assesment should be kept in mind. [J Contemp Med 2014; 4(2.000: 64-68

  1. Molecular Characterization and Growth Association of Two Apolipoprotein A-Ib Genes in Common Carp (Cyprinus carpio).

    Science.gov (United States)

    Wang, Xinhua; Yu, Xiaomu; Tong, Jingou

    2016-09-16

    Apolipoprotein A-I (ApoA-I) is functionally involved in the transportation and metabolism of lipids in vertebrates. In this study, two isoforms of apoA-Ib in common carp (Cyprinus carpio L.) were characterized. Sequence comparison and phylogenetic analysis showed that C. carpio ApoA-Ib is relatively conserved within cyprinid fishes. During embryonic development, C. carpio apoA-Ib was first expressed at the stage of multi-cells, and the highest mRNA level was observed at the stage of optic vesicle. A ubiquitous expression pattern was detected in various tissues with extreme predominance in the liver. Significantly different expression levels were observed between light and heavy body weight groups and also in the compensatory growth test. Seventeen and eight single-nucleotide polymorphisms (SNPs) were identified in matured mRNA of the C. carpio apoA-Ib.1 and apoA-Ib.2, respectively. Two of these SNPs (apoA-Ib.2-g.183A>T and apoA-Ib.2-g.1753C>T) were significantly associated with body weight and body length in two populations of common carp. These results indicate that apoA-Ib may play an important role in the modulation of growth and development in common carp.

  2. Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

    Science.gov (United States)

    Xu, Xiao-juan; Liu, Liang; Yao, Shu-kun

    2016-01-01

    Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.

  3. A patient with common glycogen storage disease type Ib mutations without neutropenia or neutrophil dysfunction

    NARCIS (Netherlands)

    Martens, DHJ; Kuijpers, TW; Maianski, NA; Rake, JP; Smit, GPA; Visser, G

    We describe a 16-year old boy with glycogen storage disease type Ib, homozygous for the common 1211-1212delCT mutation, who never experienced neutropenia, and did not suffer from frequent infections or inflammatory bowel disease. In addition, neutrophil function tests showed no abnormalities.

  4. Welcome address / Mats Estonius, Toomas Hendrik Ilves, Eduardo Ibàñes, Uffe A. Baslev

    Index Scriptorium Estoniae

    2010-01-01

    Läänemere strateegia konverentsi avasõnad laususid Tallinna Ülikooli teadusprorektor Mats Estonius, Eesti Vabariigi president Toomas Hendrik Ilves ((vt. ka foto lk. 21), Hispaania Kuningriigi suursaadik Eestis Eduardo Ibáñes ja Taani Kuningriigi suursaadik Eestis Uffe A. Baslev

  5. Contributions of type II and Ib/c supernovae to Galactic chemical evolution

    International Nuclear Information System (INIS)

    Sahijpal Sandeep

    2014-01-01

    Type II and Ib/c supernovae (SNe II and Ib/c) have made major stellar nucleosynthetic contributions to the inventories of stable nuclides during chemical evolution of the Galaxy. A case study is performed here with the help of recently developed numerical simulations of Galactic chemical evolution in the solar neighborhood to understand the contributions of SNe II and Ib/c by comparing the stellar nucleosynthetic yields obtained by two leading groups in this field. These stellar nucleosynthetic yields differ in terms of their treatment of stellar evolution and nucleosynthesis. The formulation describing Galactic chemical evolution is developed with the recently revised solar metallicity of ∼0.014. Furthermore, the recent nucleosynthetic yields of stellar models based on the revised solar metallicity are also used. The analysis suggests that it could be difficult to explain, in a self-consistent manner, the various features associated with the elemental evolutionary trends over Galactic timescales by any single adopted stellar nucleosynthetic model that incorporates SNe II and Ib/c

  6. Towards Integrated Team Practice: A Case of Malaysian Industrialised Building System (IBS Construction Projects

    Directory of Open Access Journals (Sweden)

    Mohd Nawi Mohd Nasrun

    2014-01-01

    Full Text Available Problems associated with fragmentation in the traditional construction process, such as isolation of professionals, lack of co-ordination between design and construction, and the sequential manner of its processes, has impacted on construction performance leading to a lack of integration, wastage, low productivity and efficiency. Integrated team practice is perceived as paramount. Unfortunately, there has a limitation of study focus on the dimension of fully integrated team especially for Malaysian Industrialised Building System (IBS projects. Accordingly, this research paper explores and identifies the dimension of fully integrated team from the traditional approach and conduct a validation process for implementing it in Malaysian IBS projects. The research presented uses interviews case study to obtain qualitative data. It was found that the dimension of fully integrated team from the traditional construction process could apply to the Malaysian IBS projects. Suggestions on how an integrated team practice in IBS design and construction process in order to minimise the fragmentation gaps will be concluded.

  7. Trino IB ameliorates the oxidative stress of cryptorchidism in the rat ...

    African Journals Online (AJOL)

    The study examined the effect of Trino IB, a mixture of oleuropein and -lipoic acid, on the plasma concentration of g-glutamyl transpeptidase (GGT), malondialdehyde (MDA), sperm count and apoptotic degeneration of testicular germ cells in experimentally induced cryptorchidism in adult male rats. Oral administration of ...

  8. The communication in industrialised building system (IBS) construction project: Virtual environment

    Science.gov (United States)

    Pozin, Mohd Affendi Ahmad; Nawi, Mohd Nasrun Mohd

    2017-10-01

    Large portion of numbers team organization in the IBS construction sector is known are being fragmented. That is contributed from a segregation of construction activity thus create team working in virtually. Virtual team are the nature when teams are working in distributed area, across culture and time. Therefore, teams can be respond to the task without relocating to the site project and settle down a problem through information and communication technology (ICT). The emergence of virtual team are carry out by advancements in communication technologies as a medium to improve project team communication in project delivery process on IBS construction. Based on literature review from previous study and data collected from interviewing, this paper aim to identified communication challenges among project team members according to current project development practices in IBS construction project. Hence, in attempt to develop effective communication through the advantages of virtual team approach for IBS construction project. In order to ensure the data is gathered comprehensively and accurately, the data was collected from project managers by using semi structured interview method. It was found that virtual team approach could be enable competitive challenges on complexity in the construction project management process.

  9. Comparison of breath testing with fructose and high fructose corn syrups in health and IBS.

    Science.gov (United States)

    Skoog, S M; Bharucha, A E; Zinsmeister, A R

    2008-05-01

    Although incomplete fructose absorption has been implicated to cause gastrointestinal symptoms, foods containing high fructose corn syrup (HFCS) contain glucose. Glucose increases fructose absorption in healthy subjects. Our hypothesis was that fructose intolerance is less prevalent after HFCS consumption compared to fructose alone in healthy subjects and irritable bowel syndrome (IBS). Breath hydrogen levels and gastrointestinal symptoms were assessed after 40 g of fructose (12% solution) prepared either in water or as HFCS, administered in double-blind randomized order on 2 days in 20 healthy subjects and 30 patients with IBS. Gastrointestinal symptoms were recorded on 100-mm Visual Analogue Scales. Breath hydrogen excretion was more frequently abnormal (P fructose (68%) than HFCS (26%) in controls and patients. Fructose intolerance (i.e. abnormal breath test and symptoms) was more prevalent after fructose than HFCS in healthy subjects (25% vs. 0%, P = 0.002) and patients (40% vs. 7%, P = 0.062). Scores for several symptoms (e.g. bloating r = 0.35) were correlated (P fructose but not HFCS; in the fructose group, this association did not differ between healthy subjects and patients. Symptoms were not significantly different after fructose compared to HFCS. Fructose intolerance is more prevalent with fructose alone than with HFCS in health and in IBS. The prevalence of fructose intolerance is not significantly different between health and IBS. Current methods for identifying fructose intolerance should be modified to more closely reproduce fructose ingestion in daily life.

  10. Using "Competing Visions of Human Rights" in an International IB World School

    Science.gov (United States)

    Tolley, William J.

    2013-01-01

    William Tolley, a teaching fellow with the Choices Program, is the Learning and Innovation Coach and head of history at the International School of Curitiba, Brazil (IB). He writes in this article that he has found that the "Competing Visions of Human Rights" teaching unit, developed by Brown University's Choices Program, provides a…

  11. Web and Internet-based Capabilities (IbC) Policies - U.S. Department of

    Science.gov (United States)

    &IIC DCIO IE DCIO R&A DCIO CS In the News Library Contact us Web and Internet-based Capabilities (IbC) Policies Army Navy Air Force Marine Corps General DoD Internet Services and Internet-Based ) Information Collection under the Paperwork Reduction Act (PRA) (OMB Memo) Internet Domain Name and Internet

  12. Platelet apoptosis by cld-induced glycoportein Ibα clustering

    DEFF Research Database (Denmark)

    van der Wal, Dianne E; Du, V X; Lo, KS

    2010-01-01

    Summary Background:  Cold-storage of platelets followed by rewarming induces changes in Glycoprotein (GP) Ibα-distribution indicative of receptor clustering and initiates thromboxane A2-formation. GPIbα is associated with 14-3-3 proteins, which contribute to GPIbα-signaling and in nucleated cells...

  13. Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib

    NARCIS (Netherlands)

    Correia, Catherine E.; Bhattacharya, Kaustuv; Lee, Philip J.; Shuster, Jonathan J.; Theriaque, Douglas W.; Shankar, Meena N.; Smit, G. Peter A.; Weinstein, David A.

    2008-01-01

    Background: Type I glycogen storage disease (GSD) is caused by a deficiency of glucose-6-phosphatase resulting in severe fasting hypoglycemia. Objective: We compared the efficacy of a new modified starch with the currently used cornstarch therapy in patients with type Ia and Ib GSD. Design: This was

  14. Intellectually Gifted Females and Their Perspectives of Lived Experience in the AP and IB Programs

    Science.gov (United States)

    Vanderbrook, Carrie M.

    2006-01-01

    The Advanced Placement (AP) and International Baccalaureate (IB) programs serve as popular choices for many intellectually gifted high school students. This article describes an aspect of a larger study that examined 5 intellectually gifted females' perceptions of their educational experience while enrolled in one of the programs. Using the…

  15. ′Belonging without Belonging′: Colm Tóibín′s Dialogue with the Past

    DEFF Research Database (Denmark)

    Bøss, Michael

    2005-01-01

    It is argued that Tóibín is not the typical 'revisionist' intellectual that some have made him into, but a humanist and a sort of in-between, making a virtue of his own ambivalences towards notions of tradition, community and nationhood. The essay makes an analysis of these ambivalences with refe...

  16. Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss

    DEFF Research Database (Denmark)

    Dahl, Mette; Hviid, Thomas Vauvert F

    2013-01-01

    AND CONCLUSIONS The HLA class Ib molecules seem to induce suppression of the maternal immune system, but are not necessarily fundamental factors for pregnancy success. However, evidence points towards low expression of these proteins, especially HLA-G, being associated with reduced fertility. To clarify...

  17. A convenient diagnostic function test of peripheral blood neutrophils in glycogen storage disease type Ib

    NARCIS (Netherlands)

    Verhoeven, A.J.; Visser, G; Van Zwieten, R; Gruszczynska, B; Poll-The, DWEET; Smit, GPA

    Neutrophils from patients suffering from glycogen storage disease type To (GSD-Ib) show several defects, one of which is a decreased rate of glucose utilization. In this study, we established experimental conditions to show the stimulation of the neutrophil respiratory burst by extracellular

  18. Comparison of medical costs generated by IBS patients in primary and secondary care in the Netherlands

    NARCIS (Netherlands)

    Flik, Carla E.; Laan, Wijnand; Smout, Andre J. P. M.; Weusten, Bas L. A. M.; de Wit, Niek J.

    2015-01-01

    Background: Irritable Bowel Syndrome (IBS) is a functional somatic syndrome characterized by patterns of persistent bodily complaints for which a thorough diagnostic workup does not reveal adequate explanatory structural pathology. Detailed insight into disease-specific health-care costs is critical

  19. Nitrogen aggregation in Ib type synthetic diamonds at low pressure and high-temperature annealing

    International Nuclear Information System (INIS)

    Kazyuchits, N.M.; Rusetskij, M.S.; Latushko, Ya.I.; Kazyuchits, V.N.; Zajtsev, A.M.

    2015-01-01

    A new technique for annealing of diamonds at low pressure and high temperature (LPHT) is considered. The absorption spectra of synthetic Ib diamonds are given before and after annealing. This is evident from a comparison of the spectra that nitrogen aggregation process takes place at the LPHT annealing diamond. (authors)

  20. Measuring IBS patient reported outcomes with an abdominal pain numeric rating scale: results from the proof cohort

    Science.gov (United States)

    SPIEGEL, B.; BOLUS, R.; HARRIS, L. A.; LUCAK, S.; NALIBOFF, B.; ESRAILIAN, E.; CHEY, W. D.; LEMBO, A.; KARSAN, H.; TILLISCH, K.; TALLEY, J.; MAYER, E.; CHANG, L.

    2009-01-01

    Background Controversy exists about how to effectively measure patient reported outcomes in IBS clinical trials. Pain numeric rating scales (NRS) are widely used in the non-IBS pain literature. The FDA has proposed using the NRS in IBS. Aim To test the psychometrics of an abdominal pain NRS in IBS. Methods We analyzed data from a longitudinal cohort of Rome III IBS subjects. At entry, subjects completed a 10-point NRS, bowel symptoms, IBS severity measurements (IBSSS, FBDSI), health related quality of life indices (IBS-QOL, EQ5D), and the worker productivity activity index (WPAI). We repeated assessments at 3 months along with a response scale to calculate the minimal clinically important difference (MCID). Results There were 277 subjects (82% women; age=42±15) at baseline and 90 at 3 months. The NRS correlated cross-sectionally with IBSSS (r=0.60; p<0.0011), FBDSI (r=0.49; p<0.0001), IBS-QOL (r=0.43; p<0.0001), EQ5D (r=0.48; p<0.0001), presenteeism (r=0.39; p<0.0001), absenteeism (r=0.17; p=0.04), and distension (r=0.46; p<0.0001), but not stool frequency or form. The MCID was 2.2 points, correlating with a 29.5% reduction over time. Conclusions An abdominal pain NRS exhibits excellent validity and can be readily interpreted with an MCID in patients with IBS. These data support the use of the NRS in IBS clinical trials. PMID:19751360

  1. Role of Topoisomerases in Pediatric High Grade Osteosarcomas: TOP2A Gene Is One of the Unique Molecular Biomarkers of Chemoresponse

    Directory of Open Access Journals (Sweden)

    Natacha Entz-Werle

    2013-06-01

    Full Text Available Currently, the treatment of pediatric high-grade osteosarcomas systematically includes one topoisomerase IIα inhibitor. This chemotherapy is usually adapted to the response to the neo-adjuvant therapy after surgery. The current and unique marker of chemoresponsiveness is the percentage of viable residual cells in the surgical resection. This late patient management marker has to be evaluated earlier in the therapeutic history of the patients on initial biopsy. Therefore, new biomarkers, especially those involved in the topoisomerase IIα inhibitor response might be good candidates. Therefore, our study was designed to target TOP1, TOP2A and TOP2B genes in 105 fresh-frozen diagnostic biopsies by allelotyping and real-time quantitative PCR. Our analyses in those pediatric osteosarcomas, homogeneously treated, highlighted the frequent involvement of topo-isomerase genes. The main and most important observation was the statistical link between the presence of TOP2A amplification and the good response to neo-adjuvant chemotherapy. Compared to adult cancers, the 17q21 amplicon, including TOP2A and ERBB2 genes, seems to be differentially implicated in the osteosarcoma chemoresponsiveness. Surprisingly, there is no ERBB2 gene co-amplification and the patients harboring TOP2A amplification tend to show a worse survival, so TOP2A analyses remain a preliminary, but a good molecular approach for the evaluation at diagnosis of pediatric osteosarcoma chemoresponsiveness.

  2. Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition.

    Science.gov (United States)

    Bell, C A; Dykstra, C C; Naiman, N A; Cory, M; Fairley, T A; Tidwell, R R

    1993-01-01

    Nine dicationically substituted bis-benzimidazoles were examined for their in vitro activities against Giardia lamblia WB (ATCC 30957). The potential mechanisms of action of these compounds were evaluated by investigating the relationship among in vitro antigiardial activity and the affinity of the molecules for DNA and their ability to inhibit the activity of giardial topoisomerase II. Each compound demonstrated antigiardial activity, as measured by assessing the incorporation of [methyl-3H]thymidine by giardial trophozoites exposed to the test agents. Three compounds exhibited excellent in vitro antigiardial activities, with 50% inhibitory concentrations which compared very favorably with those of two currently used drugs, quinacrine HCl and metronidazole. Putative mechanisms of action for these compounds were suggested by the strong correlation observed among in vitro antigiardial activity and the affinity of the molecules for natural and synthetic DNA and their ability to inhibit the relaxation activity of giardial topoisomerase II. A strong correlation between the DNA binding affinity of these compounds and their inhibition of giardial topoisomerase II activity was also observed. Images PMID:8109934

  3. Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage

    Directory of Open Access Journals (Sweden)

    Harish C. Pal

    2016-12-01

    Full Text Available Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non-melanoma skin cancer cells (NMSCC and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2.5, 5.0 and 7.5 µM for 24 h resulted in marked decrease in topoisomerase activity, which was associated with substantial DNA damage as detected by the comet assay. Cryptolepine induced DNA damage resulted in: (i an increase in the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2 and γH2AX; (ii activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii downregulation of cyclin-dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b leading to cell cycle arrest at S-phase; and (iv mitochondrial membrane potential was disrupted and cytochrome c released. These changes in NMSCC by cryptolepine resulted in significant reduction in cell viability, colony formation and increase in apoptotic cell death.

  4. Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS.

    Science.gov (United States)

    Di Nardo, G; Barbara, G; Cucchiara, S; Cremon, C; Shulman, R J; Isoldi, S; Zecchi, L; Drago, L; Oliva, S; Saulle, R; Barbaro, M R; Stronati, L

    2014-02-01

    Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern. Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured. 21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p Abdominal pain intensity score correlated with ileal MC count (r(s) = 0.47, p = 0.030) and right colon MC-NF count (r(s) = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern. Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain. © 2013 John Wiley & Sons Ltd.

  5. Quality of life in patients with Irritable Bowel Syndrome (IBS), assessed using the IBS-Quality of Life (IBS-QOL) measure after 4 and 8 weeks of treatment with mebeverine hydrochloride or pinaverium bromide: results of an international prospective observational cohort study in Poland, Egypt, Mexico and China.

    Science.gov (United States)

    Hou, Xiaohua; Chen, Shengliang; Zhang, Yali; Sha, Weihong; Yu, Xiaofeng; Elsawah, Hesham; Afifi, Afifi Fahmy; El-Khayat, Hisham Raafat; Nouh, Alaa; Hassan, Mohamed Fathalla; Fatah, Ayman Abdel; Rucker Joerg, Isabel; Sánchez Núñez, Juan Manuel; Osthoff Rueda, Rodolfo; Jurkowska, Grazyna; Walczak, Michal; Malecka-Panas, Ewa; Linke, Krzysztof; Hartleb, Marek; Janssen-van Solingen, Gwendolyn

    2014-11-01

    Irritable Bowel Syndrome (IBS) has a substantial impact on health-related quality of life (HR-QoL) but high-quality data pre- and post-treatment using the IBS-Quality of Life (IBS-QOL) measure are limited. The objective of this study was to evaluate the changes from baseline of the IBS-QOL scores, symptom scores and health economic data in IBS patients, after 4 and 8 weeks of treatment with mebeverine hydrochloride or pinaverium bromide. This was a prospective observational cohort study in patients with IBS, diagnosed using the Rome III criteria in four countries (Poland, Egypt, Mexico and China). A total of 607 patients were enrolled. At baseline, the IBS-QOL total scores were 52.0 in Poland, 48.9 in Egypt, 51.9 in Mexico, 76.4 in China and 56.4 overall. Increases in IBS-QOL total score were statistically significant at Weeks 4 and 8 overall and in each country (overall: 11.8 at Week 4, 24.3 at Week 8; p < 0.001). Improvements were shown in all IBS-QOL subscales and scores. Symptoms and health economic outcomes were improved. Furthermore, the favourable safety profile of these treatments was confirmed in this study. This study demonstrated that IBS patients have a substantially reduced HR-QoL and that treatment with mebeverine hydrochloride or pinaverium bromide improved HR-QoL.

  6. Chlamydia trachomatis antigens in enteroendocrine cells and macrophages of the small bowel in patients with severe irritable bowel syndrome

    Directory of Open Access Journals (Sweden)

    Sandström Gunnar

    2010-02-01

    Full Text Available Abstract Background Inflammation and immune activation have repeatedly been suggested as pathogentic factors in irritable bowel syndrome (IBS. The driving force for immune activation in IBS remains unknown. The aim of our study was to find out if the obligate intracellular pathogen Chlamydia could be involved in the pathogenesis of IBS. Methods We studied 65 patients (61 females with IBS and 42 (29 females healthy controls in which IBS had been excluded. Full thickness biopsies from the jejunum and mucosa biopsies from the duodenum and the jejunum were stained with a monoclonal antibody to Chlamydia lipopolysaccharide (LPS and species-specific monoclonal antibodies to C. trachomatis and C. pneumoniae. We used polyclonal antibodies to chromogranin A, CD68, CD11c, and CD117 to identify enteroendocrine cells, macrophages, dendritic, and mast cells, respectively. Results Chlamydia LPS was present in 89% of patients with IBS, but in only 14% of healthy controls (p C. trachomatis major outer membrane protein (MOMP. Staining for C. pneumoniae was negative in both patients and controls. Chlamydia LPS was detected in enteroendocrine cells of the mucosa in 90% of positive biopsies and in subepithelial macrophages in 69% of biopsies. Biopsies taken at different time points in 19 patients revealed persistence of Chlamydia LPS up to 11 years. The odds ratio for the association of Chlamydia LPS with presence of IBS (43.1; 95% CI: 13.2-140.7 is much higher than any previously described pathogenetic marker in IBS. Conclusions We found C. trachomatis antigens in enteroendocrine cells and macrophages in the small bowel mucosa of patients with IBS. Further studies are required to clarify if the presence of such antigens has a role in the pathogenesis of IBS.

  7. Translation and validation of a Japanese version of the irritable bowel syndrome-quality of life measure (IBS-QOL-J

    Directory of Open Access Journals (Sweden)

    Hongo Michio

    2007-03-01

    Full Text Available Abstract Aims To compare quality of life (QOL for patients with irritable bowel syndrome (IBS between the U.S. and Japan, it is indispensable to develop common instruments. The IBS-QOL, which is widely used in Western countries, was translated into Japanese as there has been a lack of Japanese disease-specific QOL measures for IBS. Methods The original 34 items of the IBS-QOL were translated from English into Japanese through two independent forward translations, resolution, back translation, and resolution of differences. Forty nine patients who had GI symptoms but did not have any organic diseases (including 30 IBS patients diagnosed by Rome II criteria were recruited from Tohoku University Hospital in Sendai, Japan and completed a Japanese version of the IBS-QOL (IBS-QOL-J concomitant with a Japanese version of the IBS severity index (IBSSI-J twice within 7–14 days. Results The IBS-QOL-J demonstrated high internal consistency (Cronbach's alpha; 0.96 and high reproducibility (intraclass correlation coefficient; 0.92, p Conclusion The IBS-QOL-J is a reliable instrument to assess the disease-specific QOL for IBS. Considering cross-cultural comparison, this measure is likely to be a valuable tool to investigate the QOL in Japanese patients with IBS.

  8. Dual Inhibition of Topoisomerase II and Tyrosine Kinases by the Novel Bis-Fluoroquinolone Chalcone-Like Derivative HMNE3 in Human Pancreatic Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Yong-Chao Ma

    Full Text Available Both tyrosine kinase and topoisomerase II (TopII are important anticancer targets, and their respective inhibitors are widely used in cancer therapy. However, some combinations of anticancer drugs could exhibit mutually antagonistic actions and drug resistance, which further limit their therapeutic efficacy. Here, we report that HMNE3, a novel bis-fluoroquinolone chalcone-like derivative that targets both tyrosine kinase and TopII, induces tumor cell proliferation and growth inhibition. The viabilities of 6 different cancer cell lines treated with a range of HMNE3 doses were detected using the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Cellular apoptosis was determined using Hoechst 33258 fluorescence staining and the terminal deoxynucleotidyl transferase (TdT dUTP nick-end labeling (TUNEL assay. The expression of activated Caspase-3 was examined by immunocytochemistry. The tyrosine kinase activity was measured with a human receptor tyrosine kinase (RTK detection kit using a horseradish peroxidase (HRP-conjugated phosphotyrosine (pY20 antibody as the substrate. The topoisomerase II activity was measured using agarose gel electrophoresis with the DNA plasmid pBR322 as the substrate. The expression levels of the P53, Bax, Bcl-2, Caspase-3, -8, -9, p-cSrc, c-Src and topoisomerase II proteins were detected by western blot analysis. The proliferation of five of the six cancer cell lines was significantly inhibited by HMNE3 at 0.312 to 10 μmol/L in a time- and dose-dependent manner. Treatment of the Capan-1 and Panc-1 cells with 1.6 to 3.2 μM HMNE3 for 48 h significantly increased the percentage of apoptotic cells (P<0.05, and this effect was accompanied by a decrease in tyrosine kinase activity. HMNE3 potentially inhibited tyrosine kinase activity in vitro with an IC50 value of 0.64±0.34 μmol/L in Capan-1 cells and 3.1±0.86 μmol/L in Panc-1 cells. The activity of c-Src was significantly inhibited by HMNE3 in a dose

  9. A new method using insert-based systems (IBS) to improve cell behavior study on flexible and rigid biomaterials.

    Science.gov (United States)

    Grenade, Charlotte; Moniotte, Nicolas; Rompen, Eric; Vanheusden, Alain; Mainjot, Amélie; De Pauw-Gillet, Marie-Claire

    2016-12-01

    In vitro studies about biomaterials biological properties are essential screening tests. Yet cell cultures encounter difficulties related to cell retention on material surface or to the observation of both faces of permeable materials. The objective of the present study was to develop a reliable in vitro method to study cell behavior on rigid and flexible/permeable biomaterials elaborating two specific insert-based systems (IBS-R and IBS-F respectively). IBS-R was designed as a specific cylindrical polytetrafluoroethylene (PTFE) system to evaluate attachment, proliferation and morphology of human gingival fibroblasts (HGFs) on grade V titanium and lithium disilicate glass-ceramic discs characteristics of dental prostheses. The number of cells, their covering on discs and their morphology were determined from MTS assays and microscopic fluorescent images after 24, 48 and 72 h. IBS-F was developed as a two components system to study HGFs behavior on guided bone regeneration polyester membranes. The viability and the membrane barrier effect were evaluated by metabolic MTS assays and by scanning electron microscopy. IBS-R and IBS-F were shown to promote (1) easy and rapid handling; (2) cell retention on biomaterial surface; (3) accurate evaluation of the cellular proliferation, spreading and viability; (4) use of non-toxic material. Moreover IBS-F allowed the study of the cell migration through degradable membranes, with an access to both faces of the biomaterial and to the bottom of culture wells for medium changing.

  10. Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products

    Directory of Open Access Journals (Sweden)

    Lan-Ting Xin

    2017-07-01

    Full Text Available Currently, DNA topoisomerase I (Topo I inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA at the concentrations of 5–100 µM. Notably, the flavonoids showed higher Topo I inhibitory activities than other compounds. These newly discovered Topo I inhibitors exhibited structurally diverse and could be considered as a good starting point for the development of new antitumor lead compounds.

  11. The role of the Zn(II binding domain in the mechanism of E. coli DNA topoisomerase I

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    Tse-Dinh Yuk-Ching

    2002-05-01

    Full Text Available Abstract Background Escherichia coli DNA topoisomerase I binds three Zn(II with three tetracysteine motifs which, together with the 14 kDa C-terminal region, form a 30 kDa DNA binding domain (ZD domain. The 67 kDa N-terminal domain (Top67 has the active site tyrosine for DNA cleavage but cannot relax negatively supercoiled DNA. We analyzed the role of the ZD domain in the enzyme mechanism. Results Addition of purified ZD domain to Top67 partially restored the relaxation activity, demonstrating that covalent linkage between the two domains is not necessary for removal of negative supercoils from DNA. The two domains had similar affinities to ssDNA. However, only Top67 could bind dsDNA with high affinity. DNA cleavage assays showed that the Top67 had the same sequence and structure selectivity for DNA cleavage as the intact enzyme. DNA rejoining also did not require the presence of the ZD domain. Conclusions We propose that during relaxation of negatively supercoiled DNA, Top67 by itself can position the active site tyrosine near the junction of double-stranded and single-stranded DNA for cleavage. However, the interaction of the ZD domain with the passing single-strand of DNA, coupled with enzyme conformational change, is needed for removal of negative supercoils.

  12. AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.

    Science.gov (United States)

    Kobayashi, Maki; Aida, Masatoshi; Nagaoka, Hitoshi; Begum, Nasim A; Kitawaki, Yoko; Nakata, Mikiyo; Stanlie, Andre; Doi, Tomomitsu; Kato, Lucia; Okazaki, Il-mi; Shinkura, Reiko; Muramatsu, Masamichi; Kinoshita, Kazuo; Honjo, Tasuku

    2009-12-29

    To initiate class switch recombination (CSR) activation-induced cytidine deaminase (AID) induces staggered nick cleavage in the S region, which lies 5' to each Ig constant region gene and is rich in palindromic sequences. Topoisomerase 1 (Top1) controls the supercoiling of DNA by nicking, rotating, and religating one strand of DNA. Curiously, Top1 reduction or AID overexpression causes the genomic instability. Here, we report that the inactivation of Top1 by its specific inhibitor camptothecin drastically blocked both the S region cleavage and CSR, indicating that Top1 is responsible for the S region cleavage in CSR. Surprisingly, AID expression suppressed Top1 mRNA translation and reduced its protein level. In addition, the decrease in the Top1 protein by RNA-mediated knockdown augmented the AID-dependent S region cleavage, as well as CSR. Furthermore, Top1 reduction altered DNA structure of the Smu region. Taken together, AID-induced Top1 reduction alters S region DNA structure probably to non-B form, on which Top1 can introduce nicks but cannot religate, resulting in S region cleavage.

  13. Invasive cervical carcinoma (stage IB-IIB): assessment with MR imaging

    International Nuclear Information System (INIS)

    Sironi, S.; Del Maschio, A.; Belloni, C.; Taccagni, L.

    1990-01-01

    In patients with cervical carcinoma the selection of the optimal therapy depends on the precise preoperative assessment of the extent of disease. Currently, decisions regarding the management of these patients are made on the basis of clinical (FIGO) staging that has 50% mean error rate. To investigate the value of MR imaging in staging patients with invasive cervical cancer, we performed 25 MR examinations on 23 patients with histologic diagnosis of cervical cancer. All patients were clinically considered as having stage IB or IIB disease and underwent radical hysterectomy, providing specimens for pathologic correlation. The overall accuracy of MR imaging in staging cervical carcinoma (stage IB-IIB) was 78.1%. MR imaging seems to be the most reliable preoperative modality for staging invasive cervical cancer

  14. Revisión de epigrafía Ibérica turolense

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    Ignacio SIMÓN CORNAGO

    2012-07-01

    Full Text Available El objetivo de este artículo es revisar varias inscripciones ibéricas procedentes de tres yacimientos de la provincia de Teruel: un grafito grabado sobre un adobe de San Antonio de Calaceite, recuperado en las excavaciones de Juan Cabré y que se conserva en el Museo Arqueológico de Barcelona; una posible inscripción bilingüe de Azaila, incisa sobre un pequeño canto rodado, actualmente perdido y que presenta una notable similitud con otro descubierto en La Moleta dels Frares (Castellón; y, finalmente, dos estelas de La Iglesuela del Cid, reutilizadas como material de construcción en la ermita de Nuestra Señora del Cid, donde también se conservan una tercera inscripción ibérica y un conjunto de epígrafes latinos.

  15. FIST/6IB1, BWR/6 System Responses to Intermediate Break in Recirculation Suction Line LINE

    International Nuclear Information System (INIS)

    1993-01-01

    1 - Description of test facility: BWR/6-218 standard plant. A full size bundle with electrically heated rods is used to simulate the reactor core. A scaling ratio of 1/624 is applied in the design of the system components. Key features of the FIST facility include: (1) Full height test vessel and internals; (2) correctly scaled fluid volume distribution; (3) simulation of ECCS, S/RV, and ADS; (4) level trip capability; (5) heated feedwater supply system, which provides the capability for steady state operation. 2 - Description of test: Test 6IB1 investigates system responses to an intermediate break in the recirculation suction line. BWR system licensing evaluations for various size recirculation break LOCA's indicates that a break size of about 0.2 sq.ft., without LPCS operation, is the highest PCT case for the intermediate break LOCA. Test 6IB1 simulates this event

  16. Record of Lower Gondwana megafloral assemblage from Lower Kamthi Formation of Ib River Coalfield, Orissa, India

    Energy Technology Data Exchange (ETDEWEB)

    Goswami, S. [Birbal Sahni Institute of Paleobotany, Lucknow (India)

    2006-03-15

    Recent investigations carried out in the Ib River Coalfield, Mahanadi Master Basin, Orissa, identified some fossiliferous beds in the Lower Gondwana deposits. Two exposures of the Lower Kamthi Formation yielded diverse and abundant plant remains, which include Neomariopteris, Vertebraria, and a scale leaf along with 14 Glossopteris species otherwise mapped as Barren Measures and Upper Kamthi formations. Glossopteris indica dominates the flora (22.78%) followed by G. communis (17.72%) and G. browniana (13.92%). Based on megafloral assemblages, different beds exposed at Gopalpur and Laxamanpur Pahar are assigned here to the Lower Kamthi Formation (Late Permian). The floristic composition suggests that a warm and humid climate prevailed during the Late Permian. The status of the Kamthi Formation in the Ib River Coalfield has been redefined in the present study.

  17. Effectiveness of postoperative radiation therapy in stage IB cervical cancer with residual disease

    International Nuclear Information System (INIS)

    Herman, J.; Perez-Tamayo, C.; Komaki, R.U.; Terada, K.; Roberts, J.A.; Morley, G.W.; Greenberg, M.; Mattingly, R.; Hopkins, M.

    1987-01-01

    Twenty-one patients with stage IB cervical cancer were treated with radical hysterectomy, pelvic lymph node dissection, and pelvic radiation therapy to approximately 5,090 rad. Patients were divided into two groups: group I, nine patients with involved parametria or positive margins at surgery; group II, 12 patients with metastatic pelvic lymph nodes. Patients in group I had an actuarial survival of 40% at 5 years and 20% at 10 years; patients in group II had an actuarial survival of 67% at 5 and 10 years (.01 < P < .05). The overall actuarial survival was 55% at 5 years and 43% at 10 years. Thus, patients with stage IB disease and involved parametrium or surgical margins do poorly. Alternative forms of therapy should be considered when this disease picture is clinically suspected preoperatively

  18. Saccharomyces boulardii CNCM I-745 supplementation reduces gastrointestinal dysfunction in an animal model of IBS

    OpenAIRE

    Brun, Paola; Scarpa, Melania; Marchiori, Chiara; Sarasin, Gloria; Caputi, Valentina; Porzionato, Andrea; Giron, Maria Cecilia; Palù, Giorgio; Castagliuolo, Ignazio

    2017-01-01

    Background We evaluated the effect of Saccharomyces boulardii CNCM I-745 on intestinal neuromuscular anomalies in an IBS-type mouse model of gastrointestinal motor dysfunctions elicited by Herpes Simplex Virus type 1 (HSV-1) exposure. Methods Mice were inoculated intranasally with HSV-1 (102 PFU) or vehicle at time 0 and 4 weeks later by the intragastric (IG) route (108 PFU). Six weeks after IG inoculum, mice were randomly allocated to receive oral gavage with either S. boulardii (107 CFU/day...

  19. Motivational Factors on Adopting Modular Coordination Concept in Industrialized Building System (IBS

    Directory of Open Access Journals (Sweden)

    Yunus Riduan

    2016-01-01

    Full Text Available Modular coordination (MC is recognized as a tool towards rationalization and industrialization. The implementation of MC concept in the design stage may improve the constructability and construction time. However, the implementation of MC in Industrialized Building System (IBS implementation is still low compare to other developed countries such as the United Kingdom, Sweden and Japan. This paper examined the interrelationship between motivational factors of stakeholders in adopting MC concept using Interpretative Structural Modeling (ISM. Questionnaire survey was engaged in this study to identify significant motivational factors. Then, semi-structure interviews were used to collect qualitative data. ISM was adopted to build relationship between factors and develop an initial model to promote the adoption of MC in IBS construction. Seven (7 significant motivational factors were identified in this research namely 1 ‘stakeholder’s commitment’, 2 ‘reduce site disruption’, 3 ‘increase productivity’, 4 ‘high skilled workers’, 5 ‘site sustainability (environment, economy and social benefits’ 6 ‘standardization’ and 7 ‘enabling ‘open building’ concept’. The result using Matrice d’Impacts Croises Multiplication Applique an Clasment (MICMAC shows that there are three factors can be categorized as Independent / Driving Factors namely ‘stakeholder’s commitment’, ‘standardization’ and ‘enabling “open building” concept’. These factors should be explored in details to enhance the adoption of IBS in Malaysia. The findings provide a very good platform for a further research in formulating an efficient solution to promote MC concept adoption among the stakeholders. This scenario will improve the deliverables of IBS construction and eliminate negative perception in its implementation.

  20. Comparison of breath testing with fructose and high fructose corn syrups in health and IBS

    OpenAIRE

    Skoog, S. M.; Bharucha, A. E.; Zinsmeister, A. R.

    2008-01-01

    Although incomplete fructose absorption has been implicated to cause gastrointestinal symptoms, foods containing high fructose corn syrup (HFCS) contain glucose. Glucose increases fructose absorption in healthy subjects. Our hypothesis was that fructose intolerance is less prevalent after HFCS consumption compared to fructose alone in healthy subjects and irritable bowel syndrome (IBS). Breath hydrogen levels and gastrointestinal symptoms were assessed after 40 g of fructose (12% solution) pr...

  1. Colm Tóibín and Post-Nationalist Ireland: Redefining Family Through Alterity

    Directory of Open Access Journals (Sweden)

    José Carregal-Romero

    2012-03-01

    Full Text Available In nationalist Ireland, definitions of family have traditionally followed a hetero-normative and sexist pattern whereby husbands and wives fulfilled deeply unequal roles. Moreover, the notion of family has been too often idealized as a site of peace and unconditional love, its members being united by unbreakable bonds of mutual affection. In Colm Tóibín’s fiction, “traditional” families tend to be dysfunctional and the relations between their members become strained because of emotional distance, regrets and distrust. However, Tóibín’s protagonists do find their sense of home and domesticity outside the traditional parameters of family. In this regard, this paper intends to analyze the manner in which Tóibín de-stabilizes canonical definitions through his revisionist agenda and his inscription of alternative forms of family. In order to shed light on these points, I shall refer to his novels The South (1990, The Heather Blazing (1992, The Blackwater Lightship (1999 and his short stories “A Long Winter” (Mothers and Sons, 2006, “Two Women” and “The Street” (The Empty Family, 2010.

  2. [Synthesis of exo-β-glucosaminidase BY FUNGUS Penicillium sp. IB-37-2].

    Science.gov (United States)

    Aktuganov, G E; Galimzyanova, N F; Teregulova, G A; Melentjev, A I

    2016-01-01

    A new strain Penicillium sp. IB-37-2, which actively hydrolyzes chitosan (SD ∼80–85%) but possesses low activity against colloidal chitin, was isolated. The fungus was observed to have a high level chitosanase biosynthesis (1.5–3.0 U/mL) during submerged cultivation at 28°C, with a pH of 3.5–7.0 and 220 rpm in nutrient media containing chitosan or chitin from shells of crabs. Purification of the chitosanase enzyme complex from Penicillium sp. IB-37-2 by ultrafiltration and hydrophobic chromatography, followed by denaturing electrophoresis, revealed two predominant proteins with molecular weights of 89 and 41 kDa. The purified enzyme complex demonstrated maximal activity (maximal rate of hydrolysis of dissolved chitosan) and stability at 50–55°C and a pH of 3.5–4.0. The enzyme preparation also hydrolyzed laminarin, β-(1,3)-(1,4)-glycan, and colloidal chitin. Exohydrolysis of chitosan by the preparation isolated from Penicillium sp. IB-37-2 resulted in the formation of single product, D-glucosamine.

  3. Using the skin protective lotion IB1 as a substitute for chemical protective gloves.

    Science.gov (United States)

    Ophir, Nimrod; Milk, Nadav; Mayer, Talia; Ravfogel, Shaul; Yavnai, Nirit; Eisenkraft, Arik; Kadar, Tamar; Kassirer, Michael; Rosman, Yossi

    2016-10-01

    We aimed to evaluate the performance of medical personnel in using the IB1 topical protective lotion on their hands and wrists together with standard disposable medical gloves, compared to standard-issued medical chemical protective gloves. This randomized cross-over study included 144 medical personnel. Primary endpoints were time-to-completion of autoinjection; success rate, number of attempts, and time-to-achieve successful endotracheal intubation; time-to-achieve satisfactory tube fixation; time-to-draw and inject the content of an ampoule; and the total time-to-perform all medical procedures. Secondary endpoints included the subjective assessment of convenience to perform these four procedures with each protective measure. Mean time was significantly shorter using IB1 compared to chemical protective gloves for tube fixation, ampoule drawing, and the total time-to-perform all procedures (58.6±22.7 seconds vs. 71.7±29.7; 31.5±21.8 vs. 38.2±19.4; 137.4±56.1 vs. 162.5±63.6, respectively; Pgloves (Pgloves significantly shorten the time-to-perform medical procedures requiring fine motor dexterities and is subjectively more convenient than chemical protective gloves. IB1 should be considered as an appropriate alternative for medical teams in a chemical event. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Short Stories, Novels and Spain. An Interview With Colm Tóibín

    Directory of Open Access Journals (Sweden)

    José-Francisco Fernández Sánchez

    2009-03-01

    Full Text Available Colm Tóibín (Enniscorthy, 1955 is the author of five novels, The South (1990, The Heather Blazing (1992, The Story of the Night (1996, The Blackwater Lightship(1999 and The Master (2004. This last novel won the IMPAC Dublin Literary Award, the Los Angeles Times Novel of the Year, the Prix du Meilleur Livre Etranger for the best foreign novel published in 2005 in France, and it was shortlisted for the Man Booker Prize. Colm Tóibín has a long career in journalism and was the editor of the magazine Magill from 1982 to 1985. He is also the author of several non-fiction books, including Homage to Barcelona (1990 and The Sign of the Cross: Travels in Catholic Europe (1994. He edited The Penguin Book of Irish Fiction (1999 and has recently published his first book of short stories,Mothers and Sons (2006. Colm Tóibín attended the 10th International Conference on the Short Story in English, held at University College Cork on 19-21 June 2008, where this interview took place.

  5. Descending pain modulation in irritable bowel syndrome (IBS): a systematic review and meta-analysis.

    Science.gov (United States)

    Chakiath, Rosemary J; Siddall, Philip J; Kellow, John E; Hush, Julia M; Jones, Mike P; Marcuzzi, Anna; Wrigley, Paul J

    2015-12-10

    Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. While abdominal pain is a dominant symptom of IBS, many sufferers also report widespread hypersensitivity and present with other chronic pain conditions. The presence of widespread hypersensitivity and extra-intestinal pain conditions suggests central nervous dysfunction. While central nervous system dysfunction may involve the spinal cord (central sensitisation) and brain, this review will focus on one brain mechanism, descending pain modulation. We will conduct a comprehensive search for the articles indexed in the databases Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and Cochrane Central Register of Controlled Trial (CENTRAL) from their inception to August 2015, that report on any aspect of descending pain modulation in irritable bowel syndrome. Two independent reviewers will screen studies for eligibility, assess risk of bias and extract relevant data. Results will be tabulated and, if possible, a meta-analysis will be carried out. The systematic review outlined in this protocol aims to summarise current knowledge regarding descending pain modulation in IBS. PROSPERO CRD42015024284.

  6. The brachytherapy vaginal cuff boost in patients with cervix cancer IB1-IB2 that have been treated with surgery plus pelvic radiotherapy in ION SOLCA, Guayaquil Ecuador from November 1 to October 2002

    International Nuclear Information System (INIS)

    Gamboa, Eugenia; Falquez, Roberto

    2003-01-01

    To determine if the additional vaginal cuff irradiation is necessary or not in patients with cervix cancer, stages IB 1- IB 2, that has been treated previously with radical hysterectomies and pelvic radiotherapy, to get better local control and global survival versus presence of complications. We studied 54 patients from Radiation Oncology Department of ION SOLCA Guayaquil Ecuador, with cervix cancer stages IB1 - IB2, that have been treated with surgery plus pelvic radiotherapy plus or not brachytherapy. They have been divides into two arms, group one included surgery plus Rx T (radiotherapy) plus BxT (Brachytherapy), and group two included those patients with surgery plus external RxT alone. We studied, aged, histologic type, surgery type, doses and techniques of teletherapy and brachytherapy and we analyzed the presence of complications. Conclusions: The brachytherapy vaginal cuff boost in patients with cervix cancer IB1-IB2 that have been treated with surgery plus pelvic radiotherapy is not useful to get better local control and global survival in some patients carefully chosen without desfavorable factors, because this therapy represent and increase in the complication. (The author)

  7. Avasõnad / Mats Estonius, Toomas Hendrik Ilves, Eduardo Ibáñes, Uffe A. Baslev

    Index Scriptorium Estoniae

    2010-01-01

    Konverentsi avasõnad laususid Tallinna Ülikooli prorektor Mats Estonius, Eesti Vabariigi president Toomas Hendrik Ilves, Hispaania Kuningriigi suursaadik Eestis Eduardo Ibáñes, Taani Kuningriigi suursaadik Eestis Uffe A. Baslev

  8. A review on the current issues and barriers of Industrialised Building System (IBS) adoption in Malaysia’s construction industry

    Science.gov (United States)

    Amin, M. A. Mohd; Abas, N. H.; Shahidan, S.; Rahmat, M. H.; Suhaini, N. A.; Nagapan, S.; Rahim, R. Abdul

    2017-11-01

    Malaysia considers the construction industry as one of the main contributors to its Gross Domestic Product (GDP). However, there are some unresolved issues arising from the ongoing and widespread adoption of the conventional method of construction such as the resultant fragmentation of the industry itself; delays in production and delivery time of unnecessary wastages and lack of sustainability practice. Malaysian Government has been continuously encouraging the industry to use, partly or if not wholly, the Industrialized Building System (IBS), which is considered to be an important part of sustainable construction initiative. IBS was introduced to Malaysia as the solution to issues related to dependencies of foreign workers, raising demand for affordable accommodations and improving image, quality and productivity of construction industry. However, the IBS adoption in Malaysia remains low. This paper presents the review of the current issues and barriers of IBS adoption in Malaysian construction industry.

  9. Expression of the sweetpotato R2R3-type IbMYB1a gene induces anthocyanin accumulation in Arabidopsis.

    Science.gov (United States)

    Chu, Hyosub; Jeong, Jae Cheol; Kim, Wook-Jin; Chung, Dong Min; Jeon, Hyo Kon; Ahn, Young Ock; Kim, Sun Ha; Lee, Haeng-Soon; Kwak, Sang-Soo; Kim, Cha Young

    2013-06-01

    R2R3-type MYB transcription factors (TFs) play important roles in transcriptional regulation of anthocyanins. The R2R3-type IbMYB1 is known to be a key regulator of anthocyanin biosynthesis in the storage roots of sweetpotato. We previously showed that transient expression of IbMYB1a led to anthocyanin pigmentation in tobacco leaves. In this article, we generated transgenic Arabidopsis plants expressing the IbMYB1a gene under the control of CaMV 35S promoter, and the sweetpotato SPO and SWPA2 promoters. Overexpression of IbMYBa in transgenic Arabidopsis produced strong anthocyanin pigmentation in seedlings and generated a deep purple color in leaves, stems and seeds. Reverse transcription-polymerase chain reaction analysis showed that IbMYB1a expression induced upregulation of several structural genes in the anthocyanin biosynthetic pathway, including 4CL, CHI, F3'H, DFR, AGT, AAT and GST. Furthermore, overexpression of IbMYB1a led to enhanced expression of the AtTT8 (bHLH) and PAP1/AtMYB75 genes. high-performance liquid chromatography analysis revealed that IbMYB1a expression led to the production of cyanidin as a major core molecule of anthocyanidins in Arabidopsis, as occurs in the purple leaves of sweetpotato (cv. Sinzami). This result shows that the IbMYB1a TF is sufficient to induce anthocyanin accumulation in seedlings, leaves, stems and seeds of Arabidopsis plants. Copyright © Physiologia Plantarum 2012.

  10. [Using a multicomponent functional food in IBS patients with constipation a comparative controlled study].

    Science.gov (United States)

    Pilipenko, V I; Teplyuk, D A; Shakhovskaya, A K; Isakov, V A; Vorobyova, V M; Vorobyova, I S; Sarkisyan, V A; Kochetkova, A A; Mikheeva, G A; Yudina, A V

    2016-01-01

    Irritable bowel syndrome (IBS) is highly prevalent functional gastrointestinal disorder associated with decrease in quality of life and a high social cost. Diet is one of several therapeutic options in IBS treatment; therefore the development and clinical evaluation of innovative functional food for IBS patients are actual. Instant drink containing 4 g inulin, 4 mg menthol and 2 mg of pyridoxine (in daily dose) has been evaluated. 49 patients 18-68 (41.5±16.5) years old fulfilling the Rome III criteria for IBS-C were randomly assigned into two groups: one received standard diet plus two drinks per day for 2 weeks and control group received standard diet. Response to therapy was recorded daily using Likert scale of abdominal pain, bloating and feeling of incomplete bowel emptying, frequency of bowel movement, Bristol stool scale, and quality of life was assessed by IBSQoL questionnaire before and after the treatment. The consumption of the drink with inulin and menthol contributed to a significant positive effect on the stool parameters (from 0.91±0.73 to 1.12±0.45 bowel movements per day in stool frequency, p=0.05, from 2.68±1.63 to 3.43±1.27 index Bristol scale, p=0.05), reduced the severity of abdominal pain (from 1.78±0.58 to 1.47?0.61 Likert scale points, p=0.05), bloating (from 2.22±0.83 to 1.53±0.71 points ofLikertscale,p= 0.01) and a sense of incomplete bowelemptying (from 2.22 ± 0.88 to 1.61± 0.81 points of Likert scale, p=0.001), as well as increased the quality of life (from 75.3± 12.0 to 83.3±6.7%, p=0.05), but a significant part of patients (10 of 25) complained the appearance of heartburn after the start of the treatment. In conclusion, the consumption of the functional drink containing inulin, menthol and pyridoxine is associated with improve in stool parameters, abdominal pain, Bristol scale index and increase in quality of life in patients with IBS-C, but produce noticeable heartburn. Changes in functional drink composition are needed to

  11. SYMPOSIUM REPORT: An Evidence-Based Approach to IBS and CIC: Applying New Advances to Daily Practice

    Science.gov (United States)

    Chey, William D.

    2017-01-01

    Many nonpharmacologic and pharmacologic therapies are available to manage irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC). The American College of Gastroenterology (ACG) regularly publishes reviews on IBS and CIC therapies. The most recent of these reviews was published by the ACG Task Force on the Management of Functional Bowel Disorders in 2014. The key objective of this review was to evaluate the efficacy of therapies for IBS or CIC compared with placebo or no treatment in randomized controlled trials. Evidence-based approaches to managing diarrhea-predominant IBS include dietary measures, such as a diet low in gluten and fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs); loperamide; antispasmodics; peppermint oil; probiotics; tricyclic antidepressants; alosetron; eluxadoline, and rifaximin. Evidence-based approaches to managing constipation-predominant IBS and CIC include fiber, stimulant laxatives, polyethylene glycol, selective serotonin reuptake inhibitors, lubiprostone, and guanylate cyclase agonists. With the growing evidence base for IBS and CIC therapies, it has become increasingly important for clinicians to assess the quality of evidence and understand how to apply it to the care of individual patients. PMID:28729815

  12. Increased Expression of Toll-Like Receptors 4, 5, and 9 in Small Bowel Mucosa from Patients with Irritable Bowel Syndrome

    Directory of Open Access Journals (Sweden)

    Aldona Dlugosz

    2017-01-01

    Full Text Available The aim of our study was to compare patients with irritable bowel syndrome (IBS and healthy controls regarding the expression of toll-like receptors 2, 4, 5, and 9 (TLR2, TLR4, TLR5, and TLR9, the primary mucosal receptors of bacterial components, in small and large bowel mucosa. Methods. We analysed biopsies from jejunum and sigmoid colon of 22 patients (17 females with IBS aged 18–66 (median: 39 years and 14 healthy volunteers (12 females aged 22–61 (median: 42 years. Eight patients had constipation-predominant IBS (C-IBS, 7 had diarrhoea-predominant IBS (D-IBS, and 7 had IBS without predominance of constipation or diarrhoea. We analysed mRNA levels for TLRs using quantitative PCR and distribution of TLRs in mucosa using immunohistochemistry. Results. We found increased mRNA expression of TLR4 (mean fold change 1.85±0.31 versus 1.0±0.20; p<0.05, TLR5 (1.96±0.36 versus 1.0±0.20; p<0.05 and TLR9 (2.00±0.24 versus 1.0±0.25; p<0.01 but not of TLR2 in the small bowel mucosa from patients with IBS compared to the controls. There was no significant difference in mRNA levels for TLRs in colon mucosa between patients and controls. Conclusion. Upregulation of TLR4, TLR5, and TLR9 suggests the involvement of bacteria or dysregulation of the immune response to commensal flora in small bowel mucosa in IBS patients.

  13. Characterization of DNA topoisomerase-1 in Spodoptera exigua for toxicity evaluation of camptothecin and hydoxy-camptothecin.

    Directory of Open Access Journals (Sweden)

    Lan Zhang

    Full Text Available Camptothecin (CPT, a plant alkaloid originally isolated from the native Chinese tree, Camptotheca acuminate, exerts the toxic effect by targeting eukaryotic DNA topoisomerase 1 (DNA Topo1. Besides as potent anti-cancer agents, CPT and its derivatives are now being explored as potential pesticides for insect control. In this study, we assessed their toxicity to an insect homolog, the Topo1 protein from beet armyworms (Spodoptera exigua Hübner, a worldwide pest of many important crops. The S. exigua Topo1 gene contains an ORF of 2790 base pairs that is predicted to encode a polypeptide of 930 amino acids. The deduced polypeptide exhibits polymorphism at residue sites V420, L530, A653 and T729 (numbered according to human Topo1 among insect species, which are predicted to confer sensitivity to CPT. The DNA relaxation activity of this protein was subsequently examined using a truncated form that contained the residues 337-930 and was expressed in bacteria BL21 cells. The purified protein retained the ability to relax double-stranded DNA and was susceptible to CPT and its derivative hydroxy-camptothecin (HCPT in a dose-dependent manner. The same inhibitory effect was also found on the native Topo1 extracted from IOZCAS-Spex-II cells, a cell line established from beet armyworms. Additionally, CPT and HCPT treatment reduced the steady accumulation of Topo1 protein despite the increased mRNA expression in response to the treatment. Our studies provide information of the S. exigua Topo1 gene and its amino acid polymorphism in insects and uncover some clues about potential mechanisms of CPT toxicity against insect pests. These results also are useful for development of more effective Topo1-targeted CPT insecticides in the future.

  14. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    Energy Technology Data Exchange (ETDEWEB)

    Hua, Wei [Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Yang, An-Gang [State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 710032 Xi' an (China); Zhang, Rui, E-mail: ruizhang@fmmu.edu.cn [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Fan, Jing, E-mail: jingfan@fmmu.edu.cn [Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Bian, Ka, E-mail: kakamax85@hotmail.com [State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 710032 Xi' an (China); Department of Otolaryngology, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)

    2015-08-07

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells.

  15. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    International Nuclear Information System (INIS)

    Hua, Wei; Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing; Yang, An-Gang; Zhang, Rui; Fan, Jing; Bian, Ka

    2015-01-01

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells

  16. Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site

    Directory of Open Access Journals (Sweden)

    Sebastian Franco-Ulloa

    2018-02-01

    Full Text Available DNA gyrases are enzymes that control the topology of DNA in bacteria cells. This is a vital function for bacteria. For this reason, DNA gyrases are targeted by widely used antibiotics such as quinolones. Recently, structural and biochemical investigations identified a new class of DNA gyrase inhibitors called NBTIs (i.e., novel bacterial topoisomerase inhibitors. NBTIs are particularly promising because they are active against multi-drug resistant bacteria, an alarming clinical issue. Structural data recently demonstrated that these NBTIs bind tightly to a newly identified pocket at the dimer interface of the DNA–protein complex. In the present study, we used molecular dynamics (MD simulations and docking calculations to shed new light on the binding of NBTIs to this site. Interestingly, our MD simulations demonstrate the intrinsic flexibility of this binding site, which allows the pocket to adapt its conformation and form optimal interactions with the ligand. In particular, we examined two ligands, AM8085 and AM8191, which induced a repositioning of a key aspartate (Asp83B, whose side chain can rotate within the binding site. The conformational rearrangement of Asp83B allows the formation of a newly identified H-bond interaction with an NH on the bound NBTI, which seems important for the binding of NBTIs having such functionality. We validated these findings through docking calculations using an extended set of cognate oxabicyclooctane-linked NBTIs derivatives (~150, in total, screened against multiple target conformations. The newly identified H-bond interaction significantly improves the docking enrichment. These insights could be helpful for future virtual screening campaigns against DNA gyrase.

  17. ERK1/2 signaling plays an important role in topoisomerase II poison-induced G2/M checkpoint activation.

    Science.gov (United States)

    Kolb, Ryan H; Greer, Patrick M; Cao, Phu T; Cowan, Kenneth H; Yan, Ying

    2012-01-01

    Topo II poisons, which target topoisomerase II (topo II) to generate enzyme mediated DNA damage, have been commonly used for anti-cancer treatment. While clinical evidence demonstrate a capability of topo II poisons in inducing apoptosis in cancer cells, accumulating evidence also show that topo II poison treatment frequently results in cell cycle arrest in cancer cells, which was associated with subsequent resistance to these treatments. Results in this report indicate that treatment of MCF-7 and T47D breast cancer cells with topo II poisons resulted in an increased phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and an subsequent induction of G2/M cell cycle arrest. Furthermore, inhibition of ERK1/2 activation using specific inhibitors markedly attenuated the topo II poison-induced G2/M arrest and diminished the topo II poison-induced activation of ATR and Chk1 kinases. Moreover, decreased expression of ATR by specific shRNA diminished topo II poison-induced G2/M arrest but had no effect on topo II poison-induced ERK1/2 activation. In contrast, inhibition of ERK1/2 signaling had little, if any, effect on topo II poison-induced ATM activation. In addition, ATM inhibition by either incubation of cells with ATM specific inhibitor or transfection of cells with ATM specific siRNA did not block topo II poison-induced G2/M arrest. Ultimately, inhibition of ERK1/2 signaling greatly enhanced topo II poison-induced apoptosis. These results implicate a critical role for ERK1/2 signaling in the activation of G2/M checkpoint response following topo II poison treatment, which protects cells from topo II poison-induced apoptosis.

  18. A Randomized Controlled Trial Comparing the Low FODMAP Diet vs. Modified NICE Guidelines in US Adults with IBS-D.

    Science.gov (United States)

    Eswaran, Shanti L; Chey, William D; Han-Markey, Theresa; Ball, Sarah; Jackson, Kenya

    2016-12-01

    There has been an increasing interest in the role of fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) in irritable bowel syndrome (IBS). We report results from the first randomized controlled trial of the low FODMAP diet in US adults with IBS and diarrhea (IBS-D). The objectives were to compare the efficacy of the low FODMAP diet vs. a diet based upon modified National Institute for Health and Care Excellence guidelines (mNICE) on overall and individual symptoms in IBS-D patients. This was a single-center, randomized-controlled trial of adult patients with IBS-D (Rome III) which compared 2 diet interventions. After a 2-week screening period, eligible patients were randomized to a low FODMAP or mNICE diet for 4 weeks. The primary end point was the proportion of patients reporting adequate relief of IBS-D symptoms ≥50% of intervention weeks 3-4. Secondary outcomes included a composite end point which required response in both abdominal pain (≥30% reduction in mean daily pain score compared with baseline) and stool consistency (decrease in mean daily Bristol Stool Form of ≥1 compared with baseline), abdominal pain and stool consistency responders, and other key individual IBS symptoms assessed using daily questionnaires. After screening, 92 subjects (65 women, median age 42.6 years) were randomized. Eighty-four patients completed the study (45 low FODMAP, 39 mNICE). Baseline demographics, symptom severity, and nutrient intake were similar between groups. Fifty-two percent of the low FODMAP vs. 41% of the mNICE group reported adequate relief of their IBS-D symptoms (P=0.31). Though there was no significant difference in the proportion of composite end point responders (P=0.13), the low FODMAP diet resulted in a higher proportion of abdominal pain responders compared with the mNICE group (51% vs. 23%, P=0.008). Compared with baseline scores, the low FODMAP diet led to greater reductions in average daily scores of abdominal pain, bloating

  19. Escherichia coli class Ib ribonucleotide reductase contains a dimanganese(III)-tyrosyl radical cofactor in vivo†

    Science.gov (United States)

    Cotruvo, Joseph A.; Stubbe, JoAnne

    2011-01-01

    Escherichia coli class Ib ribonucleotide reductase (RNR) converts nucleoside 5′-diphosphates to deoxynucleoside 5′-diphosphates in iron-limited and oxidative stress conditions. We have recently demonstrated in vitro that this RNR is active with both diferric-tyrosyl radical (FeIII2-Y•) and dimanganese(III)-Y• (MnIII2-Y•) cofactors in the β2 subunit, NrdF [Cotruvo J.A., Jr. and Stubbe J., Biochemistry (2010) 49, 1297–1309]. Here we demonstrate, by purification of this protein from its endogenous levels in an E. coli strain deficient in its five known iron uptake pathways and grown under iron-limited conditions, that the MnIII2-Y• cofactor is assembled in vivo. This is the first definitive determination of the active cofactor of a class Ib RNR purified from its native organism without overexpression. From 88 g of cell paste, 150 μg of NrdF was isolated with ~95% purity, with 0.2 Y•/β2, 0.9 Mn/β2, and a specific activity of 720 nmol/min/mg. In these conditions, the class Ib RNR is the primary active RNR in the cell. Our results strongly suggest that E. coli NrdF is an obligate manganese protein in vivo and that the MnIII2-Y• cofactor assembly pathway we have identified in vitro involving the flavodoxin-like protein NrdI, present inside the cell at catalytic levels, is operative in vivo. PMID:21250660

  20. Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Abhay Kumar [Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis MO USA; Pantouris, Georgios [Department of Pharmacology, Yale University School of Medicine, New Haven CT USA; Borosch, Sebastian [Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen Germany; Rojanasthien, Siripong [Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis MO USA; Cho, Thomas Yoonsang [Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis MO USA

    2016-09-13

    Macrophage migration inhibitory factor (MIF) is a master regulator of proinflammatory cytokines and plays pathological roles when not properly regulated in rheumatoid arthritis, lupus, atherosclerosis, asthma and cancer. Unlike canonical cytokines, MIF has vestigial keto-enol tautomerase activity. Most of the current MIF inhibitors were screened for the inhibition of this enzymatic activity. However, only some of the enzymatic inhibitors inhibit receptor-mediated biological functions of MIF, such as cell recruitment, through an unknown molecular mechanism. The goal of this study was to understand the molecular basis underlying the pharmacological inhibition of biological functions of MIF. Here, we demonstrate how the structural changes caused upon inhibitor binding translate into the alteration of MIF-induced downstream signalling. Macrophage migration inhibitory factor activates phosphoinositide 3-kinases (PI3Ks) that play a pivotal role in immune cell recruitment in health and disease. There are several different PI3K isoforms, but little is known about how they respond to MIF. We demonstrate that MIF up-regulates the expression of Class IB PI3Ks in leucocytes. We also demonstrate that MIF tautomerase active site inhibitors down-regulate the expression of Class IB PI3Ks as well as leucocyte recruitment in vitro and in vivo. Finally, based on our MIF:inhibitor complex crystal structures, we hypothesize that the reduction in Class IB PI3K expression occurs because of the displacement of Pro1 towards the second loop of MIF upon inhibitor binding, which results in increased flexibility of the loop 2 and sub-optimal MIF binding to its receptors. These results will provide molecular insights for fine-tuning the biological functions of MIF.

  1. IX Simposio Ibérico sobre Nutrición Mineral de las Plantas

    OpenAIRE

    Abadía Bayona, Javier

    2003-01-01

    Del 10 al 13 de Septiembre de 2002 se celebró el IX Simposio Ibérico sobre Nutrición Mineral de las Plantas en el Campus de Aula Dei de Zaragoza. El Simposio se realizó bajo los auspicios de la Sociedad Española de Fisiología Vegetal, el Consejo Superior de Investigaciones Científicas (CSIC), el Instituto Agronómico Mediterráneo de Zaragoza-Centro Internacional de Altos Estudios Agronómicos Mediterráneos (CIHEAM-IAMZ), la Asociación Internacional para la Optimización de...

  2. Puñales de antenas en territorio ibérico

    Directory of Open Access Journals (Sweden)

    Emeterio CUADRADO

    2009-10-01

    Full Text Available Así como en la zona peninsular ocupada por los iberos históricos encontramos la falcata como su espada peculiar, en las Mesetas y otros lugares del país, habitados por los invasores Célticos, hallamos en la segunda Edad del Hierro, la de antenas. La introducción de espadas de la Tene, que debe comenzar en el s. IV a. J. C, se hace más intensa en el mundo ibérico que en el céltico.

  3. Art, Politics and Memory: a Conversation with Colm Tóibín

    Directory of Open Access Journals (Sweden)

    Claudia Luppino

    2013-03-01

    Full Text Available The participation to a literary festival in Florence gave the interviewer the occasion to meet one of the most prolific and best loved Irish writers of our days. In what immediately took the shape and flavour of an informal and multifarious conversation – more than a strictly academic interview – Colm Tóibín, thus, shed an insightful light on his aesthetic beliefs and practice, but also on his political views, interest in current affairs and the impact of autobiography on his fiction. His relationship with John McGahern, one of the greatest twentieth-century Irish novelists, was also thoroughly addressed.

  4. Novel water soluble morpholine substituted Zn(II) phthalocyanine: Synthesis, characterization, DNA/BSA binding, DNA photocleavage and topoisomerase I inhibition.

    Science.gov (United States)

    Barut, Burak; Demirbaş, Ümit; Özel, Arzu; Kantekin, Halit

    2017-12-01

    In this study, novel peripherally tetra 3-morpholinophenol substituted zinc(II) phthalocyanine (4) and its water soluble form quaternized zinc(II) phthalocyanine (ZnQ) were synthesized for the first time. These novel compounds were characterized by a combination of different spectroscopic techniques such as FT-IR, 1 H NMR, 13 C NMR, UV-vis and mass. The DNA binding of ZnQ was investigated using UV-vis absorption titration, competitive ethidium bromide, thermal denaturation and viscosity experiments that the ZnQ bound to CT-DNA via intercalation mode. ZnQ indicated photocleavage activity on supercoiled pBR322 plasmid DNA via formation of singlet oxygen under irradiation at 700nm. Besides, the topoisomerase I inhibitory effect experiments showed that ZnQ inhibited topoisomerase I enzyme in a concentration-dependent manner. The bovine serum albumin (BSA) binding experiments indicated that ZnQ bound to proteins through a static quenching mechanism. All of these results claim that ZnQ has potential agent for photodynamic therapy owing to its nucleic acid interactions and photobiological or photochemical properties. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Reports of "satisfactory relief" by IBS patients receiving usual medical care are confounded by baseline symptom severity and do not accurately reflect symptom improvement.

    Science.gov (United States)

    Whitehead, William E; Palsson, Olafur S; Levy, Rona L; Feld, Andrew D; VonKorff, Michael; Turner, Marsha

    2006-05-01

    Treatment trials for irritable bowel syndrome (IBS) usually define a responder as a patient who reports satisfactory relief or adequate relief of symptoms at the end of the trial. However, these measures have not been adequately validated. (1) Compare a binary satisfactory relief measure to alternative ways of defining a treatment responder. (2) Determine whether baseline IBS symptom severity or psychological distress influence the sensitivity of these outcome measures. A total of 350 patients (81% females, average age 50 yr) who had a medical diagnosis of IBS and satisfied Rome II criteria, were recruited from Group Health Cooperative of Puget Sound. At baseline the Irritable Bowel Severity Scale (IBSS) was used to assess symptom severity and to classify patients as mild, moderate, or severe. Psychological distress and IBS-specific quality of life (IBS-QOL) were also assessed. After 6 months treatment with standard medical care, IBSS and IBS-QOL were reassessed, and patients were asked whether they had experienced satisfactory relief and whether they were somewhat or markedly better. Initial severity of IBS significantly affected the proportion who reported satisfactory relief (mild, 72%; moderate, 53%; severe, 44%) and the proportion who were somewhat or markedly better (mild, 62%; moderate, 44%; severe, 38%), but did not affect the proportion with a 50% reduction in symptoms (mild, 26%; moderate, 25%; severe, 23%). Although mild patients were the most likely to report satisfactory relief, they showed no average decrease in symptom severity or improvement in IBS-QOL. Conversely, severe patients, who were the least likely to report satisfactory relief, had the largest reductions in IBS symptom severity and the largest improvements in IBS-QOL. Psychological distress had no significant effect on the responder rate after adjusting for IBS symptom severity. These data from a descriptive study suggest that satisfactory relief is confounded with initial IBS symptom

  6. Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

    Energy Technology Data Exchange (ETDEWEB)

    Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.; Murphy, W.H.

    1978-12-01

    The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplanted Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.

  7. Investigation of the feasibility of elective irradiation to neck level Ib using intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma: a retrospective analysis

    International Nuclear Information System (INIS)

    Zhang, Fan; Cheng, Yi-Kan; Li, Wen-Fei; Guo, Rui; Chen, Lei; Sun, Ying; Mao, Yan-Ping; Zhou, Guan-Qun; Liu, Xu; Liu, Li-Zhi; Lin, Ai-Hua; Tang, Ling-Long; Ma, Jun

    2015-01-01

    To assess the feasibility of elective neck irradiation to level Ib in nasopharyngeal carcinoma (NPC) using intensity-modulated radiation therapy (IMRT). We retrospectively analyzed 1438 patients with newly-diagnosed, non-metastatic and biopsy-proven NPC treated with IMRT. Greatest dimension of level IIa LNs (DLN-IIa) ≥ 20 mm and/or level IIa LNs with extracapsular spread (ES), oropharynx involvement and positive bilateral cervical lymph nodes (CLNs) were independently significantly associated with metastasis to level Ib LN at diagnosis. No recurrence at level Ib was observed in the 904 patients without these characteristics (median follow-up, 38.7 months; range, 1.3–57.8 months), these patients were classified as low risk. Level Ib irradiation was not an independent risk factor for locoregional failure-free survival, distant failure-free survival, failure-free survival or overall survival in low risk patients. The frequency of grade ≥ 2 subjective xerostomia at 12 months after radiotherapy was not significantly different between low risk patients who received level Ib-sparing, unilateral level Ib-covering or bilateral level Ib-covering IMRT. Level Ib-sparing IMRT should be safe and feasible for patients without a DLN-IIa ≥ 20 mm and/or level IIa LNs with ES, positive bilateral CLNs or oropharynx involvement at diagnosis. Further investigations based on specific criteria for dose constraints for the submandibular glands are warranted to confirm the benefit of elective level Ib irradiation

  8. Validity, reliability, and factor analysis of Persian version of quality of life questionnaire for irritable bowel syndrome (IBS-QOL-34

    Directory of Open Access Journals (Sweden)

    Nasrine Masaeli

    2013-01-01

    Full Text Available Background: Quality of life (QOL improvement is the main objective of treating patients with irritable bowel syndrome (IBS. This study aimed to assess the validity, reliability, and factor analysis of IBS-QOL-34 questionnaire as a common transcultural instrument for Iranian IBS patients. Materials and Methods: Two hundred and forty patients with IBS (based on gastroenterologists′ diagnosis according to ROM III criteria were referred to Digestive Health Clinic in Psychosomatic Research Center have been selected in this study. Aside with IBS-QOL-34, MOS 36-item short-form health survey (SF-36 and IBS severity index (IBSSI questionnaires were completed by the cases for determination of correlation coefficients; the data were analyzed using descriptive statistics, factor analysis, Cronbach′s alpha, Pearson correlation coefficient by Statistical Package for Social Sciences (SPSS software, version 18. Results: Total reliability of the questionnaire was reported by using Cronbach′s alpha as 0.95, ranging from 0.65 to 0.90. Correlation coefficients of concurrent implementation of IBS-QOL with SF-36 and IBSSI resulted in −0.61 and 0.64, respectively. Exploratory factor analysis using varimax rotation identified eight principle components, which will determine QOL at 67% variance. Conclusion: According to the results, IBS-QOL-34 questionnaire has good psychometric properties in the research community and can be safely used as a valid tool to assess QOL of patients with IBS for healthcare and therapeutic purposes.

  9. P-glycoprotein expression and DNA topoisomerase I and II activity in benign tumors of the ovary and in malignant tumors of the ovary, before and after platinum/cyclophosphamide chemotherapy

    NARCIS (Netherlands)

    van der Zee, A G; Hollema, H; de Jong, S; Boonstra, H; Gouw, A; Willemse, P H; Zijlstra, J G; de Vries, E G; de Jong, Steven

    1991-01-01

    P-glycoprotein (P-gp) expression and DNA topoisomerase (Topo) II are important variables in multidrug resistant tumor cell lines. The aim of this study was to evaluate P-gp expression and Topo I and II activity in benign and malignant epithelial ovarian tumors. P-gp expression was analyzed

  10. Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer

    DEFF Research Database (Denmark)

    Erber, Ramona; Gluz, Oleg; Brünner, Nils

    2015-01-01

    . In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4...

  11. Development of a Rhizoctonia solani AG1-IB Specific Gene Model Enables Comparative Genome Analyses between Phytopathogenic R. solani AG1-IA, AG1-IB, AG3 and AG8 Isolates.

    Directory of Open Access Journals (Sweden)

    Daniel Wibberg

    Full Text Available Rhizoctonia solani, a soil-born plant pathogenic basidiomycetous fungus, affects various economically important agricultural and horticultural crops. The draft genome sequence for the R. solani AG1-IB isolate 7/3/14 as well as a corresponding transcriptome dataset (Expressed Sequence Tags--ESTs were established previously. Development of a specific R. solani AG1-IB gene model based on GMAP transcript mapping within the eukaryotic gene prediction platform AUGUSTUS allowed detection of new genes and provided insights into the gene structure of this fungus. In total, 12,616 genes were recognized in the genome of the AG1-IB isolate. Analysis of predicted genes by means of different bioinformatics tools revealed new genes whose products potentially are involved in degradation of plant cell wall components, melanin formation and synthesis of secondary metabolites. Comparative genome analyses between members of different R. solani anastomosis groups, namely AG1-IA, AG3 and AG8 and the newly annotated R. solani AG1-IB genome were performed within the comparative genomics platform EDGAR. It appeared that only 21 to 28% of all genes encoded in the draft genomes of the different strains were identified as core genes. Based on Average Nucleotide Identity (ANI and Average Amino-acid Identity (AAI analyses, considerable sequence differences between isolates representing different anastomosis groups were identified. However, R. solani isolates form a distinct cluster in relation to other fungi of the phylum Basidiomycota. The isolate representing AG1-IB encodes significant more genes featuring predictable functions in secondary metabolite production compared to other completely sequenced R. solani strains. The newly established R. solani AG1-IB 7/3/14 gene layout now provides a reliable basis for post-genomics studies.

  12. IbM PENYUSUNAN PENILAIAN AUTENTIK BAGI GURU SEKOLAH DI PONPES DARUL FIKRI BAWEN

    Directory of Open Access Journals (Sweden)

    Joko Siswanto

    2015-09-01

    Full Text Available Abstract Low motivation of teachers in implementing authentic assessment becomes the basis for IbM team to carry out extension activities. Authentic assessment has actually been around a long time, but this issue arose when the curriculum was launched in 2013. During this time, most of the teachers at school in the field only make an assessment test course, not many people touched assessment tests that are written. Through activities of IbM Authentic Assessment Preparation Training for Teachers of Pesantren Darul Fikri Bawen, participants are expected to conduct a written assessment, performance assessment, product assessment projects, portfolio assessment, and manage the mark using computer-based process. Prior to socialization, teachers must first take pretest and post test. Pre test shows an average score of 89.65 while the average of post-test scores shows 97.6. During the activities, the participants felt helped and gave a positive response to organized similar activities. Keywords: Preparation, Assessment Authentic, Darul Fikri Boarding School Teacher

  13. Sparing bilateral neck level IB in oropharyngeal carcinoma and xerostomia outcomes.

    Science.gov (United States)

    Tam, Moses; Riaz, Nadeem; Kannarunimit, Danita; Peña, Angela P; Schupak, Karen D; Gelblum, Daphna Y; Wolden, Suzanne L; Rao, Shyam; Lee, Nancy Y

    2015-08-01

    To assess whether sparing neck-level IB in target delineation of node-positive (N+) oropharyngeal carcinoma (OPC) can improve xerostomia outcomes without compromising locoregional control (LRC). A total of 125 N+ OPC patients with a median age of 57 years underwent chemoradiation between May 2010 and December 2011. A total of 74% of patients had T1-T2 disease, 26% T3-T4, 16% N1, 8% N2A, 48% N2B, 28% N2C; 53% base of tongue, 41% tonsil, and 6% other. Patients were divided into those who had target delineation sparing of bilateral level IB (the spared cohort) versus no sparing (the treated cohort). Sparing of contralateral high-level II nodes was also performed more consistently in the spared cohort. A prospective xerostomia questionnaire (patient reported) was given at each patient follow-up visit to this cohort of patients to assess late xerostomia. Clinical assessment (observer rated) at each patient follow-up visit was also recorded. The 2-year LRC for the spared and treated cohorts was 97.5% and 93.8%, respectively (median follow-up, 23.2 mo). No locoregional failures occurred outside of treatment fields. The spared cohort experienced significant benefits in patient-reported xerostomia summary scores (P=0.021) and observer-rated xerostomia scores (P=0.006). In addition, there were significant reductions in mean doses to the ipsilateral submandibular gland (63.9 vs. 70.5 Gy; Pxerostomia outcomes.

  14. Vicente Blasco Ibáñez (1867-1928: viaje por Oriente y Egipto

    Directory of Open Access Journals (Sweden)

    Lara Peinado, Federico

    2005-04-01

    Full Text Available Con este artículo se pretende rememorar los viajes efectuados a Turquía (1907 y años después al país del Nilo (1924 por el famoso novelista Vicente Blasco Ibáñez (1867-1928. Sus impresiones, la historia de los países visitados, la descripción de sus ciudades y paisajes tomaron cuerpo en las obras tituladas Oriente y La vuelta al mundo de un novelista. Blasco Ibáñez supo resumir la historia de Constantinopla así como la de Egipto -especialmente su antigüedad- con sencillas palabras, sin tecnicismos, haciendo llegar al lector el impacto que le causaron monumentos y ambientes de la ciudad turca en un caso, y las pirámides, tumbas y el paisaje nilotico en otro, además de introducirlo en el alma de sus gentes.…

  15. Estructuras de fondo rehundido altomedievales en la Península Ibérica

    Directory of Open Access Journals (Sweden)

    TEJERIZO GARCÍA, C.

    2014-01-01

    Full Text Available La presencia de estructuras de fondo rehundido en contextos arqueológicos altomedievales está ampliamente documentada en toda Europa y cuenta con una dilatada historiografía. En la Península Ibérica, asociado a la expansión urbanística, se ha podido detectar un conjunto muy significativo de estas estructuras. Sin embargo, la falta de sistematización y análisis ha llevado a algunos problemas en su detección y documentación, así como a excesos conceptuales y de interpretación. En este trabajo se realiza una recopilación analítica de las evidencias de estructuras de fondo rehundido de época altomedieval presentes en la Península Ibérica mostrando su alta complejidad y diversidad. Basado en un análisis de la evidencia disponible, y frente a las tesis etnicistas que las vinculan a la llegada de grupos alóctonos, se propone una interpretación relacionada con el desarrollo de un modo de producción campesino tras la desarticulación de la economía imperial romana.

  16. Sintaxis espacial en el oppidum ibérico. Reflexiones sobre los modelos espaciales y sociales

    Directory of Open Access Journals (Sweden)

    Grau Mira, Ignasi

    2015-12-01

    Full Text Available In this paper we propose an approach to the analysis based on the space syntax applied to the domestic space of the societies of Iron Age in the central region of Mediterranean Iberia. In the first section, the importance of setting the houses to understand the Iberian society is introduced. Secondly, an analysis of some examples of Mediterranean central area is developed, in which we identify two clearly defined spatial models. Finally these models are related to the aggregation of households to make up the Iberian communities.En el presente trabajo realizamos un aproximación mediante el análisis basado en la sintaxis espacial aplicado al espacio doméstico de las sociedades de la edad del Hierro de la franja central de la Iberia Mediterránea, entre los siglos VI y III a. C. En una primera sección se introduce la importancia de la configuración de las casas para comprender la sociedad ibérica. A continuación seleccionamos algunos ejemplos de la mitad meridional del País Valenciano para realizar nuestro análisis. Se identifican de dos modelos espaciales claramente definidos. Por último se relacionan estos esquemas constructivos con los procesos de agregación de unidades familiares para constituir las comunidades ibéricas.

  17. Therapeutic Results of Surgery and Radiation Therapy in Younger Patients with Stage IB Cervical Cancer

    International Nuclear Information System (INIS)

    Huh, Gil Cha; Yang, Kwang Mo; Suh, Hyun Suk; Kim, Yong Bong; Lee, Eung Soo; Park, Sung Kwan

    1995-01-01

    Purpose : To evaluate the prognostic importance of age in patients with Stage IB cervical cancer, we examined the relationship between age and survival in patients. Methods and materials : Retrospective analysis was performed on 107 patients were treated with surgery followed by postoperative radiotherapy or radiation alone between October 1983 and August 1993 and 28 patients with Stage IB cervical cancer treated with surgery alone between January 1989 and August 1993 at Inje University Seoul Paik Hospital. Patients ranged in age from 26 to 74 (median 48) and were followed for a median period of 39 months. Patients were divided into two groups; Group A comprising 32 patients with≤age 40 and Group B comprising 75 patients with>age 40. Both Group A and Group B patients were comparable with respect to all covariables studied. Results : The overall 5-year survival and the disease free 5-year survival for the 107 patients studied were 85.2% and 82.1% respectively. The overall survival for group A and Group B was 92% and 83%, respectively(p>0.05). The disease free 5-year survival for Group A and Group B was 82.3% and 82.6%, respectively(p>0.05). There was no difference in both local and distant failure in Group A and Group B. Conclusion : On the basis of the this analysis it is concluded that age alone is a poor indicator of prognosis and should not be used as an indication for adjuvant treatment

  18. Rapid detection of AAC(6')-Ib-cr production using a MALDI-TOF MS strategy.

    Science.gov (United States)

    Pardo, C-A; Tan, R N; Hennequin, C; Beyrouthy, R; Bonnet, R; Robin, F

    2016-12-01

    Plasmid-mediated quinolone resistance mechanisms have become increasingly prevalent among Enterobacteriaceae strains since the 1990s. Among these mechanisms, AAC(6')-Ib-cr is the most difficult to detect. Different detection methods have been developed, but they require expensive procedures such as Sanger sequencing, pyrosequencing, polymerase chain reaction (PCR) restriction, or the time-consuming phenotypic method of Wachino. In this study, we describe a simple matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) method which can be easily implemented in clinical laboratories that use the MALDI-TOF technique for bacterial identification. We tested 113 strains of Enterobacteriaceae, of which 64 harbored the aac(6')-Ib-cr gene. We compared two MALDI-TOF strategies, which differed by their norfloxacin concentration (0.03 vs. 0.5 g/L), and the method of Wachino with the PCR and sequencing strategy used as the reference. The MALDI-TOF strategy, performed with 0.03 g/L norfloxacin, and the method of Wachino yielded the same high performances (Se = 98 %, Sp = 100 %), but the turnaround time of the MALDI-TOF strategy was faster (<5 h), simpler, and inexpensive (<1 Euro). Our study shows that the MALDI-TOF strategy has the potential to become a major method for the detection of many different enzymatic resistance mechanisms.

  19. Classification of ulnar triangular fibrocartilage complex tears. A treatment algorithm for Palmer type IB tears.

    Science.gov (United States)

    Atzei, A; Luchetti, R; Garagnani, L

    2017-05-01

    The classical definition of 'Palmer Type IB' triangular fibrocartilage complex tear, includes a spectrum of clinical conditions. This review highlights the clinical and arthroscopic criteria that enable us to categorize five classes on a treatment-oriented classification system of triangular fibrocartilage complex peripheral tears. Class 1 lesions represent isolated tears of the distal triangular fibrocartilage complex without distal radio-ulnar joint instability and are amenable to arthroscopic suture. Class 2 tears include rupture of both the distal triangular fibrocartilage complex and proximal attachments of the triangular fibrocartilage complex to the fovea. Class 3 tears constitute isolated ruptures of the proximal attachment of the triangular fibrocartilage complex to the fovea; they are not visible at radio-carpal arthroscopy. Both Class 2 and Class 3 tears are diagnosed with a positive hook test and are typically associated with distal radio-ulnar joint instability. If required, treatment is through reattachment of the distal radio-ulnar ligament insertions to the fovea. Class 4 lesions are irreparable tears due to the size of the defect or to poor tissue quality and, if required, treatment is through distal radio-ulnar ligament reconstruction with tendon graft. Class 5 tears are associated with distal radio-ulnar joint arthritis and can only be treated with salvage procedures. This subdivision of type IB triangular fibrocartilage complex tear provides more insights in the pathomechanics and treatment strategies. II.

  20. IB2d: a Python and MATLAB implementation of the immersed boundary method.

    Science.gov (United States)

    Battista, Nicholas A; Strickland, W Christopher; Miller, Laura A

    2017-03-29

    The development of fluid-structure interaction (FSI) software involves trade-offs between ease of use, generality, performance, and cost. Typically there are large learning curves when using low-level software to model the interaction of an elastic structure immersed in a uniform density fluid. Many existing codes are not publicly available, and the commercial software that exists usually requires expensive licenses and may not be as robust or allow the necessary flexibility that in house codes can provide. We present an open source immersed boundary software package, IB2d, with full implementations in both MATLAB and Python, that is capable of running a vast range of biomechanics models and is accessible to scientists who have experience in high-level programming environments. IB2d contains multiple options for constructing material properties of the fiber structure, as well as the advection-diffusion of a chemical gradient, muscle mechanics models, and artificial forcing to drive boundaries with a preferred motion.

  1. Nurse-Administered, Gut-Directed Hypnotherapy in IBS: Efficacy and Factors Predicting a Positive Response.

    Science.gov (United States)

    Lövdahl, Jenny; Ringström, Gisela; Agerforz, Pia; Törnblom, Hans; Simrén, Magnus

    2015-07-01

    Hypnotherapy is an effective treatment in irritable bowel syndrome (IBS). It is often delivered by a psychotherapist and is costly and time consuming. Nurse-administered hypnotherapy could increase availability and reduce costs. In this study the authors evaluate the effectiveness of nurse-administered, gut-directed hypnotherapy and identify factors predicting treatment outcome. Eighty-five patients were included in the study. Participants received hypnotherapy by a nurse once/week for 12 weeks. Patients reported marked improvement in gastrointestinal (GI) and extra-colonic symptoms after treatment, as well as a reduction in GI-specific anxiety, general anxiety, and depression. Fifty-eight percent were responders after the 12 weeks treatment period, and of these 82% had a favorable clinical response already at week 6. Women were more likely than men to respond favorably to the treatment. Nurse-administered hypnotherapy is an effective treatment for IBS. Being female and reporting a favorable response to treatment by week 6 predicted a positive treatment response at the end of the 12 weeks treatment period.

  2. iB1350 no.1. A generation III.7 reactor after the Fukushima Daiichi accident

    International Nuclear Information System (INIS)

    Sato, Takashi; Matsumoto, Keiji; Hosomi, Kenji; Kojima, Yoshihiro; Taguchi, Keisuke

    2017-01-01

    iB1350 stands for an innovative, intelligent and inexpensive BWR 1350. It is the first generation III.7 reactor after the Fukushima Daiichi accident. It has incorporated lessons learned from the Fukushima Daiichi accident and WENRA safety objectives. It has innovative safety to cope with devastating natural disasters including a giant earthquake, a large tsunami and a monster hurricane. The iB1350 can survive passively such devastation and a very prolonged SBO without any support from the outside of a site up to 7 days even preventing core melt. It, however, is based on the well-established proven ABWR design. The NSSS is exactly the same as that of the current ABWR. As for safety design, it has a double cylinder RCCV (Mark W containment) and in-depth hybrid safety systems (IDHS). The Mark W containment has double FP confinement barriers and the in-containment filtered venting system (IFVS) that enable passively no emergency evacuation outside the immediate vicinity of the plant for a SA. It has a large volume to hold hydrogen, an innovative core catcher (iCC), a passive flooding system and an innovative passive containment cooling system (iPCCS) establishing passively practical elimination of containment failure even in a long term. The IDHS consists of 4 division active safety systems for a DBA, 2 division active safety systems for a SA and built-in passive safety systems (BiPSS) consisting of an isolation condenser (IC) and the iPCCS for a SA. While the conventional PCCS can never cool the S/P, the iPCCS can automatically cool the S/P directly even in a DBA LOCA. That makes it possible for the iB1350 to optimize the active safety systems for a DBA. Sato came up with several optimized configurations of the IDHS that are expected to achieve further cost reduction and enhance its reliability resulting from passive feature of the iPCCS. The IC/iPCCS pool has enough capacity for 7 day grace period. The IC/iPCCS heat exchangers, the core and the spent fuel pool are

  3. El Calloviense de los Ibérides (dominio Ibérico, España. Síntesis bioestratigráfica

    Directory of Open Access Journals (Sweden)

    Meléndez, G.

    1987-04-01

    Full Text Available More than 60 Callovian geological profiles in the Iberides (between Burgos and Alicante have been studied. The Ricla (Zaragoza Callovian section as reference biostratigraphic outline has been established, documenting almost all Callovian Mesogean Zones and Subzones and many biohorizons. The others profiles in relation with the elected as reference are briefly described, standing out the scarce thickness and Upper Callovian and frequently Middle Callovian absence.Se han estudiado más de 60 perfiles geológicos de edad Calloviense en los Ibérides (entre Burgos y Alicante. El Calloviense de Ricla (Zaragoza se toma como esquema bioestratigráfico de referencia, documentándose casi todas las zonas y subzonas y muchos de los biohorizontes del Calloviense de la Mesogea. Los demás perfiles se describen sumariamente en relación al elegido como referencia, destacando su escasa potencia y la falta de Calloviense superior y frecuentemente de Calloviense medio.

  4. Reduced responses of submucous neurons from irritable bowel syndrome patients to a cocktail containing histamine, serotonin, TNFα and tryptase (IBS-cocktail

    Directory of Open Access Journals (Sweden)

    Daniela eOstertag

    2015-12-01

    Full Text Available Background & Aims:Malfunctions of enteric neurons are believed to play an important role in the pathophysiology of irritable bowel syndrome (IBS. Our aim was to investigate whether neuronal activity in biopsies from IBS patients is altered in comparison to healthy controls (HC.Methods:Activity of human submucous neurons in response to electrical nerve stimulation and local application of nicotine or a mixture of histamine, serotonin, tryptase and TNF-α (IBS-cocktail was recorded in biopsies from 17 HC and 35 IBS patients with the calcium-sensitive-dye Fluo-4 AM. The concentrations of the mediators resembeled those found in biopsy supernatants or blood. Neuronal activity in guinea-pig submucous neurons was studied with the voltage-sensitive-dye di-8-ANEPPS. Results:Activity in submucous ganglia in response to nicotine or electrical nerve stimulation was not different between HC and IBS patients (P=0.097 or P=0.448. However, the neuronal response after application of the IBS-cocktail was significantly decreased (P=0.039 independent of whether diarrhea (n=12, constipation (n=5 or bloating (n=5 was the predominant symptom. In agreement with this we found that responses of submucous ganglia conditioned by overnight incubation with IBS mucosal biopsy supernatant to spritz application of this supernatant was significantly reduced (P=0.019 when compared to incubation with HC supernatant.Conclusion:We demonstrated for the first time reduced neuronal responses in mucosal IBS biopsies to an IBS mediator cocktail. While excitability to classical stimuli of enteric neurons was comparable to HC, the activation by the IBS-cocktail was decreased. This was very likely due to desensitization to mediators constantly released by mucosal and immune cells in the gut wall of IBS patients.

  5. The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS and Wheat-Sensitive Irritable Bowel Syndrome (IBS: An Update

    Directory of Open Access Journals (Sweden)

    Carlo Catassi

    2017-11-01

    Full Text Available Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS. New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.

  6. Assessment of topoisomerase II-alpha gene status by dual color chromogenic in situ hybridization in a set of Iraqi patients with invasive breast carcinoma

    Directory of Open Access Journals (Sweden)

    Rasha Abd Alraouf Neama

    2017-01-01

    Full Text Available Background: The human epidermal growth factor receptor 2(HER2 proto-oncogene is overexpressed or amplified in approximately 15%–25% of invasive breast cancers. Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A gene encoding an enzyme that is a major target of anthracyclines. Hence, the determination of genetic alteration (amplification or deletion of both genes is considered as an important predictive factor that determines the response of breast cancer patients to treatment. The aims of this study are to determinate TOP2A status gene amplification in a set of Iraqi patients with breast cancer that have had an equivocal (2+ and positive HER2/neu by immunohistochemistry (IHC and to compare the results with estrogen receptor (ER and progesterone receptor (PR and HER2/neu status. Patients and Methods: A cross-sectional prospective study done on 53 patients with invasive breast carcinoma. Twenty-six out of total 53 cases were positive HER2/neu (3+, the remaining 27 equivocal HER2-IHC (2+ cases reanalyzed using dual-color chromogenic in situ hybridization (ZytoVision probe kit for further identification of HER2/neu gene amplification. Using chromogenic in situ hybridization (CISH, TOP2A gene status determination was done for all cases. Results: There is a direct significant correlation between TOP2A gene amplification and HER2/neu positivity, P < 0.05 in that 15 (39.4% out of 38 positive HER2/neu cases were associated with topoisomerase gene amplification. Regarding relation of topoisomerase gene to hormone receptor status (ER and PR, there was a significant negative relationship between the gene and ER receptor status. The higher level of gene amplification was noticed in ER and PR negative cases in about 13 (43.3% and 14 (48.2% for ER and PR, respectively. Conclusion: TOP2A gene status has a significantly positive correlation with HER2/neu status while it has a significantly negative

  7. Risk model in stage IB1-IIB cervical cancer with positive node after radical hysterectomy

    Directory of Open Access Journals (Sweden)

    Chen Z

    2016-05-01

    Full Text Available Zhilan Chen,1,2,* Kecheng Huang,1,* Zhiyong Lu,1,3 Song Deng,1,4 Jiaqiang Xiong,1 Jia Huang,1 Xiong Li,5 Fangxu Tang,1 Zhihao Wang,6 Haiying Sun,1 Lin Wang,1 Shasha Zhou,1 Xiaoli Wang,1 Yao Jia,1 Ting Hu,1 Juan Gui,7 Dongyi Wan,1 Ding Ma,1 Shuang Li,1 Shixuan Wang11Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, 2Department of Obstetrics and Gynecology, Wuhan General Hospital of Guangzhou Military Command, Wuhan, 3Hubei Key Laboratory of Embryonic Stem Cell Research, Tai-He Hospital, Hubei University of Medicine, Shiyan, Hubei, 4Department of Obstetrics and Gynecology, University Hospital of Hubei University for Nationalities, Enshi, Hubei, 5Department of Obstetrics and Gynecology, Wuhan Central Hospital, Wuhan, 6Department of Pathology and Pathophysiology, Key Laboratory of Ministry of Education of China for Neurological Disorders, Huazhong University of Science and Techonology, Wuhan, 7Department of Obstetrics and Gynecology, Renmin Hospital, Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workAbstract: The purpose of this study was to identify risk factors in patients with surgically treated node-positive IB1-IIB cervical cancer and to establish a risk model for disease-free survival (DFS and overall survival (OS. A total of 170 patients who underwent radical hysterectomy and bilateral pelvic lymphadenectomy as primary treatment for node-positive International Federation of Gynaecology and Obstetrics (FIGO stage IB1-IIB cervical cancer from January 2002 to December 2008 were retrospectively analyzed. Five published risk models were evaluated in this population. The variables, including common iliac lymph node metastasis and parametrial invasion, were independent predictors of outcome in a multivariate analysis using a Cox regression model. Three distinct prognostic groups (low, intermediate, and high risk

  8. Las copas tipo Cástulo en la Península Ibérica

    Directory of Open Access Journals (Sweden)

    Sánchez, Carmen

    1992-12-01

    Full Text Available The Castulo cup is one of the most common black glaze Attic forms in the Iberian Peninsula from the Atlantic coast to Ampurias. Their date in the Iberian Peninsula is some years later than that proposed for Athens. They did not appear till some years after the second half of the 5th c. B.C. Their production probably continued until the first quarter of the 4th century B.C. They are almost fixed in their form for about a century, but some differences in the outside decoration and the underside of the foot can be pointed out. Two main types are proposed for the second half of the 5th century and the first quarter of the 4th century B.C. The differences in date compared with those found at Athens can be explained as an adaptation of the workshops to the demands of Iberian customers. Athen's artisans continued making Castulo cups for export at a time when in Athens they did not use them any more, because the stemless cup had been replaced by the popular kantharoi and cup-kantharoi.

    La copa Cástulo es una de las formas áticas de barniz negro más abundante en los yacimientos peninsulares desde la costa atlántica hasta Ampurias. Su cronología es en la Península Ibérica algo posterior a la propuesta para Atenas. No aparecen hasta algo después de mediados del siglo V y probablemente se continúan fabricando hasta el primer cuarto del IV a. C. No experimentan durante casi un siglo de producción ninguna variación formal, sin embargo sí se pueden ver diferencias en el tratamiento de la decoración exterior y del fondo externo. Se proponen aquí fundamentalmente dos tipos de la segunda mitad del siglo V y primer cuarto del IV a. C. La diferencia cronológica con las halladas en Atenas se explica como una adaptación de los talleres áticos a la demanda de los clientes ibéricos. Los artesanos atenienses continúan fabricando copas Cástulo para la exportación cuando en Atenas se han dejado ya de utilizar las copas de pie bajo al ser

  9. The impact of abuse and mood on bowel symptoms and health-related quality of life in irritable bowel syndrome (IBS).

    Science.gov (United States)

    Kanuri, N; Cassell, B; Bruce, S E; White, K S; Gott, B M; Gyawali, C P; Sayuk, G S

    2016-10-01

    Irritable bowel syndrome (IBS) is a common abdominal pain disorder without an organic explanation. Abuse histories (physical, sexual, emotional) are prevalent in IBS. While abuse relates to mood disorders (depression and anxiety) also common in IBS, the influence of abuse on gastrointestinal (GI) symptoms and health-related quality of life (HRQOL) and its independence from psychological symptom comorbidity has not been studied. Consecutive GI outpatients completed the ROME III Research Diagnostic Questionnaire and questionnaires on trauma (Life-Stress Questionnaire), mood (Beck Depression/Anxiety Inventories), somatic symptoms (PHQ-12), and HRQOL (SF-36). Current GI symptom severity and bother were assessed using 10-cm Visual Analog Scales. 272 ROME-defined IBS (47.6 ± 0.9 years, 81% female) and 246 non-FGID (51.6 ± 1.0 years, 65% female) subjects participated. IBS patients reported greater rates of physical, sexual, and emotional abuse (p IBS with abuse. Abuse effects were additive, with greater IBS symptom severity and poorer HRQOL noted in cases with multiple forms of abuse. Mediation analyses suggested that abuse effects on GI symptoms and HRQOL were partially mediated by mood. Abuse experiences common among IBS sufferers are associated with reports of greater GI symptoms and poorer HRQOL, particularly in those with multiple forms of abuse; this relationship may be partially mediated by concomitant mood disturbances. © 2016 John Wiley & Sons Ltd.

  10. Clinical and Microbiological Effect of a Multispecies Probiotic Supplementation in Celiac Patients With Persistent IBS-type Symptoms: A Randomized, Double-Blind, Placebo-controlled, Multicenter Trial.

    Science.gov (United States)

    Francavilla, Ruggiero; Piccolo, Maria; Francavilla, Antonio; Polimeno, Lorenzo; Semeraro, Francesco; Cristofori, Fernanda; Castellaneta, Stefania; Barone, Michele; Indrio, Flavia; Gobbetti, Marco; De Angelis, Maria

    2018-04-23

    The goals of this study were to evaluate the efficacy and safety of a probiotic mixture in patients with celiac disease (CD) with irritable bowel syndrome (IBS)-type symptoms despite a strict gluten-free diet (GFD). About 30% of patients with CD adherent to a GFD suffer from IBS-type symptoms; a possible cause resides in the imbalances of the intestinal microbiota in CD. Probiotics may represent a potential treatment. CD patients with IBS-type symptoms entered a prospective, double-blind, randomized placebo-controlled study. A 6-week treatment period was preceded by a 2-week run-in and followed by a 6-week follow-up phase. Clinical data were monitored throughout the study by validated questionnaires: IBS Severity Scoring System (IBS-SSS); Gastrointestinal Symptom Rating Scale (GSRS); Bristol Stool Form Scale (BSFS); and IBS Quality of Life Questionnaire (IBS-QOL). The fecal microbiota were assayed using plate counts and 16S rRNA gene-based analysis. In total, 109 patients were randomized to probiotics (n=54) or placebo (n=55). IBS-SSS and GSRS decreased significantly in probiotics, as compared with placebo [(-15.9%±14.8% vs. 8.2%±25.9%; Psymptoms, in CD patients on strict GFD, and is associated with a modification of gut microbiota, characterized by an increase of bifidobacteria.

  11. Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant IBS.

    LENUS (Irish Health Repository)

    Wilcz-Villega, E

    2013-11-29

    Increased intestinal permeability and altered expression of tight junction (TJ) proteins may be implicated in the pathogenesis of irritable bowel syndrome (IBS). This study aimed to investigate the expression of adherens junction (AJ) protein E-cadherin and TJ proteins zonula occludens (ZO)-1 and claudin (CLD)-1 and associations with IBS symptoms.

  12. Astronomy in Denver: The polarization evolution of the luminous Type Ib SN 2012au

    Science.gov (United States)

    Hoffman, Jennifer L.; DeKlotz, Sophia; Cooper, Kevin; Slay, Hannah; Williams, George Grant; Supernova Spectropolarimetry Project (SNSPOL)

    2018-06-01

    We present an analysis of the spectropolarimetric behavior of the Type Ib SN 2012au over the first 315 days of its evolution. Our data were obtained by the Supernova Spectropolarimetry Project using the CCD Imaging/Spectropolarimeter (SPOL) at the 61" Kuiper, the 90" Bok, and the 6.5-m MMT telescopes. SN 2012au was a very energetic, luminous, and slowly evolving event that may represent an intermediate case between normal core-collapse supernovae and the enigmatic superluminous supernovae. Strong, time-variable line polarization signatures, particularly in the He Il λ5876 line, support previous hypotheses of an asymmetric explosion and allow us to trace detailed structures within the supernova ejecta as they change over time. We compare the polarimetric evolution of the continuum and emission lines in SN 2012au and compare its behavior with that of other bright and polarimetrically variable supernovae.

  13. IB-LBM study on cell sorting by pinched flow fractionation.

    Science.gov (United States)

    Ma, Jingtao; Xu, Yuanqing; Tian, Fangbao; Tang, Xiaoying

    2014-01-01

    Separation of two categories of cells in pinched flow fractionation(PFF) device is simulated by employing IB-LBM. The separation performances at low Reynolds number (about 1) under different pinched segment widths, flow ratios, cell features, and distances between neighboring cells are studied and the results are compared with those predicted by the empirical formula. The simulation indicates that the diluent flow rate should approximate to or more than the flow rate of particle solution in order to get a relatively ideal separation performance. The discrepancy of outflow position between numerical simulation and the empirical prediction enlarges, when the cells become more flexible. Too short distance between two neighboring cells could lead to cell banding which would result in incomplete separation, and the relative position of two neighboring cells influences the banding of cells. The present study will probably provide some new applications of PFF, and make some suggestions on the design of PFF devices.

  14. IB: A Monte Carlo simulation tool for neutron scattering instrument design under PVM and MPI

    International Nuclear Information System (INIS)

    Zhao Jinkui

    2011-01-01

    Design of modern neutron scattering instruments relies heavily on Monte Carlo simulation tools for optimization. IB is one such tool written in C++ and implemented under Parallel Virtual Machine and the Message Passing Interface. The program was initially written for the design and optimization of the EQ-SANS instrument at the Spallation Neutron Source. One of its features is the ability to group simple instrument components into more complex ones at the user input level, e.g. grouping neutron mirrors into neutron guides and curved benders. The simulation engine manages the grouped components such that neutrons entering a group are properly operated upon by all components, multiple times if needed, before exiting the group. Thus, only a few basic optical modules are needed at the programming level. For simulations that require higher computer speeds, the program can be compiled and run in parallel modes using either the PVM or the MPI architectures.

  15. MODEL PENGUKURAN KINERJA INTELLECTUAL CAPITAL DENGAN IB-VAIC DI PERBANKAN SYARIAH

    Directory of Open Access Journals (Sweden)

    Ihyaul Ulum

    2013-06-01

    Full Text Available The aim of this study is to develop a measurement of intellectual capital performance of Indonesian syariah banking by modifying the Pulic’s model that popular with the name of VAIC (value added intellectual coefficient. This study was done by documentation and focus group discussion with some financial accounting experts and public accountants. The result show that the main formula to measure IC performance of syariah banking is not too different with Pulic model, it was: iB-VAIC™ = iB-VACA + IB-VAHU + iB-STVA. The different one is the accounts to develop VA. VA in Pulic model was constructed by total revenue, while in iB-VAIC, VA was constructed from syariah activities.

  16. Dinosaurios de la Península Ibérica

    Directory of Open Access Journals (Sweden)

    Sanz, J. L.

    2006-12-01

    Full Text Available Body fossils of the Iberian Peninsula dinosaurs are very relevant for the knowledge of several aspects of the evolutionary history of the group, and, in addition, for the interpretation of the distribution of many of its components, due to the geographic situation of the Iberian Peninsula. Almost all of the groups of dinosaurs are represented in the Iberian Peninsula record: ornithopods, thyreophorans, theropods and sauropods. These groups are present, mainly, in the transit Jurassic-Cretaceous (Kimmeridigian- Berriasian, the upper part of the Lower Cretaceous (Barremian-Aptian and in the end of the Upper Cretaceous (Campanian-Masstrichtian. Ornithischian dinosaurs are represented by thyreophorans such as the stegosaurians Dacentrurus and Stegosaurus, the ankylosaurs Dracopelta, Polacanthus and Struthiosaurus, and ornithopods like hypsilophodontids, basal iguanodontians (Rhabdodon, dryosaurids, camptosaurids (Draconyx and Camptosaurus, iguanodontids (Iguanodon and hadrosaurids (Pararhabdodon. Some Incertae sedis and taxa in process of description are present too. Sauropods are represented by taxa related to Neosauropoda (Lourinhasaurus, Dinheirosaurus, Galveosaurus and Losillasaurus and titanosauriforms (Aragosaurus, Lusotitan and Lirainosaurus. In addition, new forms are still in description, like the sauropods of Riodeva (Teruel, Peñarroya de Tastavins (Teruel and Morella (Castellón. Theropods are represented by the ceratosaurian Ceratosaurus, the spinosauroid Torvosaurus, the carnosaurs Lourinhanosaurus and Allosaurus, the tyrannosaurid Aviatyrannis, the ornithomimosaur Pelecanimimus, and the avian-theropods Iberomesornis, Concornis, Eoalulavis and Noguerornis. Nevertheless, theropods diversity is more abundant as it shows the great variability of teeth morphotypes identified.registro de restos directos de dinosaurios en la Península Ibérica ha mostrado, en los últimos años, que puede ser muy relevante para el conocimiento de distintos

  17. Runoff formation in a small mountainous catchment

    Czech Academy of Sciences Publication Activity Database

    Tesař, Miroslav; Šír, Miloslav; Lichner, Ľ.

    2003-01-01

    Roč. 4, č. 2 (2003), s. 265-270 ISSN 1335-6291 R&D Projects: GA AV ČR IAA3060001; GA AV ČR IBS2060104; GA MŽP SE/610/3/00 Grant - others:Slovak Scientific Grant Agency(SK) 2/7065/20; 5th EC Framework Programme(XE) IST-2000-28084 Institutional research plan: CEZ:AV0Z2060917 Keywords : hydrology * rainfall-runoff relationship * small mountainous catchment Subject RIV: DA - Hydrology ; Limnology

  18. A common central engine for long gamma-ray bursts and Type Ib/c supernovae

    Science.gov (United States)

    Sobacchi, E.; Granot, J.; Bromberg, O.; Sormani, M. C.

    2017-11-01

    Long-duration, spectrally soft gamma-ray bursts (GRBs) are associated with Type Ic core collapse (CC) supernovae (SNe), and thus arise from the death of massive stars. In the collapsar model, the jet launched by the central engine must bore its way out of the progenitor star before it can produce a GRB. Most of these jets do not break out, and are instead 'choked' inside the star, as the central engine activity time, te, is not long enough. Modelling the long-soft GRB duration distribution assuming a power-law distribution for their central engine activity times, ∝ t_e^{-α } for te > tb, we find a steep distribution (α ∼ 4) and a typical GRB jet breakout time of tb ∼ 60s in the star's frame. The latter suggests the presence of a low-density, extended envelope surrounding the progenitor star, similar to that previously inferred for low-luminosity GRBs. Extrapolating the range of validity of this power law below what is directly observable, to te < tb, by only a factor of ∼4-5 produces enough events to account for all Type Ib/c SNe. Such extrapolation is necessary to avoid fine-tuning the distribution of central engine activity times with the breakout time, which are presumably unrelated. We speculate that central engines launching relativistic jets may operate in all Type Ib/c SNe. In this case, the existence of a common central engine would imply that (i) the jet may significantly contribute to the energy of the SN; (ii) various observational signatures, like the asphericity of the explosion, could be directly related to jet's interaction with the star.

  19. The Dimanganese(II) Site of Bacillus subtilis Class Ib Ribonucleotide Reductase

    Energy Technology Data Exchange (ETDEWEB)

    Boal, Amie K.; Cotruvo, Jr., Joseph A.; Stubbe, JoAnne; Rosenzweig, Amy C. (MIT); (NWU)

    2014-10-02

    Class Ib ribonucleotide reductases (RNRs) use a dimanganese-tyrosyl radical cofactor, Mn{sub 2}{sup III}-Y{sm_bullet}, in their homodimeric NrdF ({beta}2) subunit to initiate reduction of ribonucleotides to deoxyribonucleotides. The structure of the Mn{sub 2}{sup II} form of NrdF is an important component in understanding O{sub 2}-mediated formation of the active metallocofactor, a subject of much interest because a unique flavodoxin, NrdI, is required for cofactor assembly. Biochemical studies and sequence alignments suggest that NrdF and NrdI proteins diverge into three phylogenetically distinct groups. The only crystal structure to date of a NrdF with a fully ordered and occupied dimanganese site is that of Escherichia coli Mn{sub 2}{sup II}-NrdF, prototypical of the enzymes from actinobacteria and proteobacteria. Here we report the 1.9 {angstrom} resolution crystal structure of Bacillus subtilis Mn{sub 2}{sup II}-NrdF, representative of the enzymes from a second group, from Bacillus and Staphylococcus. The structures of the metal clusters in the {beta}2 dimer are distinct from those observed in E. coli Mn{sub 2}{sup II}-NrdF. These differences illustrate the key role that solvent molecules and protein residues in the second coordination sphere of the Mn{sub 2}{sup II} cluster play in determining conformations of carboxylate residues at the metal sites and demonstrate that diverse coordination geometries are capable of serving as starting points for Mn{sub 2}{sup III}-Y{sm_bullet} cofactor assembly in class Ib RNRs.

  20. Quantifying women's stated benefit-risk trade-off preferences for IBS treatment outcomes.

    Science.gov (United States)

    Johnson, F Reed; Hauber, A Brett; Ozdemir, Semra; Lynd, Larry

    2010-01-01

    The Food and Drug Administration, currently, is exploring quantitative benefit-risk methods to support regulatory decision-making. A scientifically valid method for assessing patients' benefit-risk trade-off preferences is needed to compare risks and benefits in a common metric. The study aims to quantify the maximum acceptable risk (MAR) of treatment-related adverse events (AEs) that women with diarrhea-predominant irritable bowel syndrome (IBS) are willing to accept in exchange for symptom relief. A stated-choice survey was used to elicit trade-off preferences among constructed treatment profiles, each defined by symptom severity and treatment-related AEs. Symptom attributes included frequency of abdominal pain and discomfort, frequency of diarrhea, and frequency of urgency. AE attributes included frequency of mild-to-moderate constipation and the risk of four possible serious AEs. A Web-enabled survey was administered to 589 female US residents at least 18 years of age with a self-reported diagnosis of diarrhea-predominant IBS. Preference weights and MAR were estimated using mixed-logit methods. SUBJECTS were willing to accept higher risks of serious AEs in return for treatments offering better symptom control. For an improvement from the lowest to the highest of four benefit levels, subjects were willing to tolerate a 2.65% increase in impacted-bowel risk, but only a 1.34% increase in perforated-bowel risk. Variation in MARs across AE types is consistent with the relative seriousness of the AEs. Stated-preference methods offer a scientifically valid approach to quantifying benefit-risk trade-off preferences that can be used to inform regulatory decision-making.

  1. Jinetes en Grecia y sus ecos en la cultura ibérica

    Directory of Open Access Journals (Sweden)

    Domínguez Monedero, Adolfo J.

    2005-12-01

    Full Text Available The uses of the horse in Greece are reviewed from the Mycenaean until Late Classical times in order to trace its development as a military weapon. Besides, the social projection of the use of the horse in Greece is also addressed, as well as the development of equestrian contests which served also as a means of stressing the social status of the leading groups within the Greek poleis. In a final chapter the possible reflections of the uses of the horse in Greece in the Iberian world are also considered, although the possible relationships are confined mainly to iconographical loans from Greek prototypes to some Iberian artistic manifestations.

    Se pasa revista a los usos del caballo en Grecia desde época micénica hasta el final del Clasicismo a fin de observar su desarrollo como arma militar. Además, se estudia también la proyección social del uso del caballo en Grecia así como el desarrollo de competiciones ecuestres que sirvieron también como medio de exhibir el estatus social de los grupos dirigentes de las poleis griegas. En el capítulo final se consideran también los posibles ecos de los usos del caballo en Grecia en el mundo ibérico, aunque estas posibles relaciones se limitan sobre todo a préstamos iconográficos de modelos griegos a algunas manifestaciones artísticas ibéricas.

  2. La habitación sagrada de la ciudad ibérica de La Serreta

    Directory of Open Access Journals (Sweden)

    Grau, Ignacio

    2008-12-01

    Full Text Available In this paper a department with probable sacred functions in the Iberian settlement of La Serreta (Alcoi-Cocentaina- Penàguila, Alicante is analyzed. In this room an exceptional material record was found that includes some of the better examples of the so-called narrative figured pottery style, the image of a nurse goddess in terracotta, imported vessels and specialized metal instruments. This outstanding ensemble allows us to define this space as a singular deposit and a representative room with possible religious functions, which formed the back bone of the complex social and political relationships of the Iberian oppidum at the end of the 3rd cent. B.C.En el siguiente artículo se analiza un departamento con probables funciones sagradas en el asentamiento ibérico de La Serreta (Alcoi-Cocentaina-Penàguila, Alicante. En esta habitación se recuperó un excepcional conjunto material que incluye algunos de los mejores ejemplos de cerámica con decoración figurada de estilo narrativo, una plaqueta de terracota que representa una divinidad nutricia, vajilla de importación e instrumental especializado de orfebre. Las características de este destacado conjunto nos llevan a definir el espacio como un depósito singular y una habitación representativa con posibles funciones religiosas que contribuiría a articular las complejas relaciones sociales y políticas del oppidum ibérico a finales del s. III a.C.

  3. Microscopic colitis and small intestinal bacterial overgrowth--diagnosis behind the irritable bowel syndrome?

    Science.gov (United States)

    Stoicescu, Adriana; Andrei, M; Becheanu, G; Stoicescu, M; Nicolaie, T; Diculescu, M

    2012-01-01

    Some patients previously diagnosed with irritable bowel syndrome (IBS) may develop microscopic colitis or small intestinal bacterial overgrowth (SIBO). To estimate the prevalence of microscopic colitis and SIBO in patients with IBS, to evaluate the symptoms and the efficacy of treatment. We examined patients with IBS admitted in our clinic during a three-year period. We identified patients with microscopic colitis by performing total colonoscopy with multiple biopsies from normal intestinal mucosa and those with SIBO by performing a H2-breath test with glucose. We compared the symptoms and the effectiveness of the treatment. Out of the 132 patients initially diagnosed with IBS 3% (n=4) had microscopic colitis and 43.9% (n=58) had SIBO. Diarrhea was the main symptom in patients with microscopic colitis and SIBO (p=0.041), while abdominal pain, abdominal bloating and flatulence were prominent in IBS patients (p=0.042; p=0.039; p=0.048). Specific treatment with rifaximin in SIBO patients negativated H2-breath test in 70.9% cases. Patients suspected to have irritable bowel syndrome should be evaluated for microscopic colitis and SIBO. The proper diagnosis and the specific treatment may cure some difficult cases of the so called "irritable bowel syndrome".

  4. Small intestine bacterial overgrowth and irritable bowel syndrome-related symptoms: experience with Rifaximin.

    Science.gov (United States)

    Peralta, Sergio; Cottone, Claudia; Doveri, Tiziana; Almasio, Piero Luigi; Craxi, Antonio

    2009-06-07

    To estimate the prevalence of small intestinal bacterial overgrowth (SIBO) in our geographical area (Western Sicily, Italy) by means of an observational study, and to gather information on the use of locally active, non-absorbable antibiotics for treatment of SIBO. Our survey included 115 patients fulfilling the Rome II criteria for diagnosis of irritable bowel syndrome (IBS); a total of 97 patients accepted to perform a breath test with lactulose (BTLact), and those who had a positive test, received Rifaximin (Normix, Alfa Wassermann) 1200 mg/d for 7 d; 3 wk after the end of treatment, the BTLact was repeated. Based on the BTLact results, SIBO was present in about 56% of IBS patients, and it was responsible for some IBS-related symptoms, such as abdominal bloating and discomfort, and diarrhoea. 1-wk treatment with Rifaximin turned the BTLact to negative in about 50% of patients and significantly reduced the symptoms, especially in those patients with an alternated constipation/diarrhoea-variant IBS. SIBO should be always suspected in patients with IBS, and a differential diagnosis is done by means of a "breath test". Rifaximin may represent a valid approach to the treatment of SIBO.

  5. Aportaciones a la flora vascular del norte de la Península Ibérica

    Directory of Open Access Journals (Sweden)

    Fidalgo, E., Llorente, A., Cadiñanos, J.A., Tarruella, J.

    2012-01-01

    Full Text Available Se citan varios taxones nuevos o interesantes de la flora vascular del norte de la Península Ibérica, concretamente de las provincias vascas de Álava, Vizcaya y Guipúzcoa y de las comunidades de Cantabria, Asturias, Castilla-León y Navarra.

  6. STRATEGI PEMASARAN TERHADAP PENJUALAN PRODUK TABUNGAN IB HASANAH DI PT. BANK NEGARA INDONESIA SYARIAH KANTOR CABANG JAKARTA BARAT

    Directory of Open Access Journals (Sweden)

    Raden Ajeng Entaresmen

    2017-02-01

    Full Text Available BNI Syariah branch office in West Jakarta has one of funding products that Savings iB Hasanah useful for pure investment vehicles Shariah compliance, where customers can make deposits and withdrawals of cash very easily. In marketing this product, BNI Syariah use 2 pattern to implement a marketing strategy that intensification patterns for customers who already have a product BNI Syariah and extension patterns for prospective customers at other banks that have not used that product at BNI Syariah. Besides, in general BNI Syariah has some marketing strategies that include 9P is Process, People, Product, Price, Place, Promotion, Partners, Presentation, and Passion. Employees who are experts in marketing their products to barriers such as the lack of make Savings iB Hasanah customers, how to services and lack of staff was quick to respond, competition between conventional banks and Islamic banks BNI Syariah office supplies in some areas. Keywords : Marketing strategy, Savings iB Hasanah, Product marketing barriers savings iB Hasanah

  7. IB-MECA, an Adenosine A(3) Receptor Agonist, Does Not Influence Survival of Lethally gamma-Irradiated Mice

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Dušek, L.; Hoferová, Zuzana; Komůrková, Denisa

    2012-01-01

    Roč. 61, č. 6 (2012), s. 649-654 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/08/0158; GA ČR(CZ) GAP303/11/0128 Institutional support: RVO:68081707 Keywords : Mouse * IB-MECA * Adenosine A(3) receptor agonist Subject RIV: BO - Biophysics Impact factor: 1.531, year: 2012

  8. HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients

    DEFF Research Database (Denmark)

    Melsted, Wenna Nascimento; Johansen, Lasse Lindholm; Lock-Andersen, Jørgen

    2017-01-01

    HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM...

  9. OC5 Project Phase Ib: Validation of Hydrodynamic Loading on a Fixed, Flexible Cylinder for Offshore Wind Applications

    DEFF Research Database (Denmark)

    Robertson, Amy N.; Wendt, Fabian; Jonkman, Jason M.

    2016-01-01

    at the Danish Hydraulic Institute (DHI) with support from the Technical University of Denmark (DTU). The first phase of OC5 examined two simple cylinder structures (Phase Ia and Ib) to focus on validation of hydrodynamic models used in the various tools before moving on to more complex offshore wind systems...

  10. Mida kujutab endast IB õppekava? / Toomas Kruusimägi, Anu Parts, Karl Hendrik Thomson ; intervjueerinud Raivo Juurak

    Index Scriptorium Estoniae

    Kruusimägi, Toomas, 1962-

    2010-01-01

    Uuest rahvusvahelisest International Baccalaureate'i (IB) õppekavast ja selle rakendamisest Tallinna Inglise Kolledži 11. klassis alates möödunud aastast räägivad kooli direktor Toomas Kruusimägi, õppedirektor Anu Parts ning õpilane Karl Hendrik Thomson

  11. Is There "Space" for International Baccalaureate? A Case Study Exploring Space and the Adoption of the IB Middle Year Programme

    Science.gov (United States)

    Monreal, Timothy

    2016-01-01

    Henri Lefebvre (1991) wrote, "[representational] space is alive: it speaks" (p. 42). This article explores how we might "listen" to space in education by examining the role of space in one school's decision to adopt the International Baccalaureate's Middle Years Programme [IB MYP]. It builds upon recent scholarship that applies…

  12. Inhibition of topoisomerase II activity in repair-proficient CHO K1 cells by 2-[(aminopropyl)amino]ethanethiol (WR-1065)

    International Nuclear Information System (INIS)

    Grdina, D.J.; Constantinou, A.; Shigematsu, N.

    1992-09-01

    The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied radioprotective agent S-2-(3-aminopropylamino) ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector under in vitro conditions when it is administered 30 min prior to radiation exposure at a concentration of 4 mM to repair-proficient Chinese hamster ovary Kl cells (i.e., a dose modification factor of 1.4). In contrast, the DNA double-strand break, repair-deficient Chinese hamster ovary xrs-5 cell line is not protected under these conditions (i.e., a dose modification factor of 1.0). Topoisomerase (topo) I and II activities and protein contents were measured in both Kl and xrs-5 cell lines and were found to be similar in magnitude. Neither exposure to radiation, to WR-1065, or to both affected these variables in xrs-5 cells. WR 1065 was effective, however, in reducing topo 11 activity by a factor of 2 in the repair-proficient Kl cell line. Topo II protein content, however, was not affected by these exposure conditions. One of several mechanisms of radiation protection attributed to aminothiol compounds has been their ability to affect enzymatic reactions involved in DNA synthesis, repair, and cell cycle progression. These results demonstrate a modifying effect by 2-[(aminopropyl)amino]ethanethiol on a specific nuclear enzyme (i.e., type H topoisomerase), which is involved in DNA synthesis. These results also suggest that differences do exist between the topo 11 enzymes isolated from the parent repair-proficient Kl and the DNA double-strand break, repair-deficient xrs-5 mutant cell lines

  13. Inhibition of topoisomerase II activity in repair-proficient CHO K1 cells by 2-[(aminopropyl)amino]ethanethiol (WR-1065)

    Energy Technology Data Exchange (ETDEWEB)

    Grdina, D.J.; Constantinou, A.; Shigematsu, N.

    1992-09-01

    The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied radioprotective agent S-2-(3-aminopropylamino) ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector under in vitro conditions when it is administered 30 min prior to radiation exposure at a concentration of 4 mM to repair-proficient Chinese hamster ovary Kl cells (i.e., a dose modification factor of 1.4). In contrast, the DNA double-strand break, repair-deficient Chinese hamster ovary xrs-5 cell line is not protected under these conditions (i.e., a dose modification factor of 1.0). Topoisomerase (topo) I and II activities and protein contents were measured in both Kl and xrs-5 cell lines and were found to be similar in magnitude. Neither exposure to radiation, to WR-1065, or to both affected these variables in xrs-5 cells. WR 1065 was effective, however, in reducing topo 11 activity by a factor of 2 in the repair-proficient Kl cell line. Topo II protein content, however, was not affected by these exposure conditions. One of several mechanisms of radiation protection attributed to aminothiol compounds has been their ability to affect enzymatic reactions involved in DNA synthesis, repair, and cell cycle progression. These results demonstrate a modifying effect by 2-[(aminopropyl)amino]ethanethiol on a specific nuclear enzyme (i.e., type H topoisomerase), which is involved in DNA synthesis. These results also suggest that differences do exist between the topo 11 enzymes isolated from the parent repair-proficient Kl and the DNA double-strand break, repair-deficient xrs-5 mutant cell lines.

  14. A Novel Inhibitor Of Topoisomerase I is Selectively Toxic For A Subset of Non-Small Cell Lung Cancer Cell Lines | Office of Cancer Genomics

    Science.gov (United States)

    SW044248, identified through a screen for chemicals that are selectively toxic for NSCLC cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was non-toxic to immortalized human bronchial cell lines.

  15. Lymphangiogenesis in cervical cancer evaluated by expression of the VEGF-C gene in clinical stage IB-IIIB

    Directory of Open Access Journals (Sweden)

    Magdalena Franc

    2015-02-01

    Full Text Available Introduction : The aim of the present study was to evaluate the profile of VEGF-C gene expression in particular stages of cervical cancer (IB-IIIB and to estimate the correlation between VEGF-C mRNA quantity profile and clinical stage. Material and methods : Material for molecular analysis consisted of cervical cancer tissue specimens collected from 38 women (10, 15, 13 cases were classified as IB, IIB and IIIB, respectively. The control group was composed of normal cervical tissues collected from 10 women who underwent hysterectomy for non-oncological reasons. The number of VEGF-C mRNA copies in particular groups was estimated by the reverse transcription quantitative polymerase chain reaction (RT-qPCR method. Results: In the control group the average number of mRNA copies was 134 ± 36 (median: 106, in a group with stage IB it was 16 077 ± 7090 (median: 580, for stage IIB – 35 019 ± 8945 (median: 40 870. The highest number of mRNA VEGF-C copies was derived in a group of patients with cervical cancer of stage IIIB. The average quantity was 56 155 ± 12 470, whereas median 55 981. A statistically significantly higher level of VEGF-C gene expression was disclosed in cervical cancer specimens with stage IIB and IIIB than in the control group. In stage IIIB, the VEGF-C gene expression was significantly higher than in specimens derived from individuals in stage IB. Conclusions : In squamous cell carcinoma of the uterine cervix of stage IB-IIIB genes involved in lymphangio­genesis, especially VEGF-C , are expressed, which expression increases as the clinical stage of cervical cancer is higher.

  16. Small intestinal bacterial overgrowth in irritable bowel syndrome: are there any predictors?

    Directory of Open Access Journals (Sweden)

    McCallum Richard W

    2010-02-01

    Full Text Available Abstract Background Small intestinal bacterial overgrowth (SIBO is a condition in which excessive levels of bacteria, mainly the colonic-type species are present in the small intestine. Recent data suggest that SIBO may contribute to the pathophysiology of Irritable bowel syndrome (IBS. The purpose of this study was to identify potential predictors of SIBO in patients with IBS. Methods Adults with IBS based on Rome II criteria who had predominance of bloating and flatulence underwent a glucose breath test (GBT to determine the presence of SIBO. Breath samples were obtained at baseline and at 30, 45, 60, 75 and 90 minutes after ingestion of 50 g of glucose dissolved in 150 mL of water. Results of the glucose breath test, which measures hydrogen and methane levels in the breath, were considered positive for SIBO if 1 the hydrogen or methane peak was >20 ppm when the baseline was Results Ninety-eight patients were identified who underwent a GBT (mean age, 49 y; 78% female. Thirty-five patients (36% had a positive GBT result suggestive of SIBO. A positive GBT result was more likely in patients >55 years of age (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.4-9.0 and in females (OR, 4.0; 95% CI, 1.1-14.5. Hydrogen was detected more frequently in patients with diarrhea-predominant IBS (OR, 8; 95% CI, 1.4-45, and methane was the main gas detected in patients with constipation-predominant IBS (OR, 8; 95% CI, 1.3-44. There was no significant correlation between the presence of SIBO and the predominant bowel pattern or concurrent use of tegaserod, proton pump inhibitors, or opiate analgesics. Conclusions Small intestinal bacterial overgrowth was present in a sizeable percentage of patients with IBS with predominance of bloating and flatulence. Older age and female sex were predictors of SIBO in patients with IBS. Identification of possible predictors of SIBO in patients with IBS could aid in the development of successful treatment plans.

  17. Gastrointestinal (GI) permeability correlates with trait anxiety and urinary norepinephrine/creatinine (CR)ratio in children with functional abdominal pain (FAP)and irritable bowel syndrome (IBS) but not in controls

    Science.gov (United States)

    FAP and IBS affect 10–15% of school age children and bear many similarities to irritable bowel syndrome (IBS) in adults (e.g., functional pain, visceral hyperalgesia). Animal models of IBS have suggested a relationship between neonatal stress/anxiety and increased GI permeability later in life. We h...

  18. TINGKAT KEPUASAN PENGGUNA APLIKASI INTERSYSTEM BUSINESS SOLUTION (IBS PADA PT CITAJAYA INFINITE SYSTEM

    Directory of Open Access Journals (Sweden)

    Anderes Gui

    2009-05-01

    Full Text Available Use of applications to assist business processes to be completed faster, saat have been very widely adopted by companies so that good performance yang applications and meet the needs of users will be very important. The purpose of this research is to find the application user expectations Intersystem Business Solution (IBS in PT Citajaya Infinite System and find out how the performance of these applications after implemented so that will be generated an output, which form the level of satisfaction from the use of applications by managers and employees at the company. Data collection methods used were observation, interviews, and questionnaires. Manual methods used in data processing, Microsoft Excel 2003, and SPSS version 13.0. While the analysis method using gap analysis to determine the scale and range of satisfaction levels. So, one conclusion that can be drawn from this study is the performance of this application is sufficient to meet user expectations.Keywords: level of satisfaction, users, IBS applicationABSTRAKPenggunaan aplikasi untuk membantu proses bisnis agar menjadi lebih cepat diselesaikan, saat ini sudah sangat banyak diterapkan oleh perusahaan-perusahaan sehingga kinerja aplikasi yang baik dan memenuhi kebutuhan dari pengguna akan sangat penting sekali. Tujuan dari penelitian ini adalah untuk mencari harapan pengguna aplikasi Intersystem Business Solution (IBS pada PT Citajaya Infinite System dan mengetahui bagaimana kinerja aplikasi ini setelah diimplementasikan sehingga akan dihasilkan sebuah output, yang berupa tingkat kepuasan dari penggunaan aplikasi oleh para manajer dan karyawan di perusahaan tersebut. Metode pengumpulan data yang digunakan adalah observasi, wawancara, dan kuesioner. Metode pengolahan datanya menggunakan manual, Microsoft Excel 2003, dan SPSS versi 13.0. Sedangkan metode analisisnya menggunakan gap analysis dan rentang skala untuk menentukan tingkat kepuasan. Jadi, salah satu simpulan yang dapat diambil

  19. MiR-144 Increases Intestinal Permeability in IBS-D Rats by Targeting OCLN and ZO1

    Directory of Open Access Journals (Sweden)

    Qiuke Hou

    2017-12-01

    Full Text Available Background/Aims: Irritable bowel syndrome with diarrhoea (IBS-D is a chronic, functional bowel disorder characterized by abdominal pain or diarrhoea and altered bowel habits, which correlate with intestinal hyperpermeability. MicroRNAs (miRNAs are involved in regulating intestinal permeability in IBS-D. However, the role of miRNAs in regulating intestinal permeability and protecting the epithelial barrier remains unclear. Our goals were to (i identify differential expression of miRNAs and their targets in the distal colon of IBS-D rats; (ii verify in vitro whether occludin (OCLN and zonula occludens 1 (ZO1/TJP1 were direct targets of miR-144 and were down-regulated in IBS-D rats; and (iii determine whether down-regulation of miR-144 in vitro could reverse the pathological hallmarks of intestinal hyperpermeability via targeting OCLN and ZO1. Methods: The IBS-D rat model was established using 4% acetic acid and evaluated by haematoxylin-eosin (HE staining. The distal colon was obtained in order to perform miRNA microarray analysis and to isolate and culture colonic epithelial cells. When differential expression of miRNA was found, the results were verified by qRT-PCR, and the target genes were further explored by bioinformatics analysis. Correlation analyses were carried out to compare the expression of miRNA and target genes. Then, mutants, miRNA mimics and inhibitors of the target genes were constructed and transfected to colonic epithelial cells. qRT-PCR, western blotting, enzyme-linked immunosorbent assays (ELISAs and dual-luciferase assays were used to investigate the expression of miR-144 and OCLN, ZO1 in IBS-D rats. Results: There were 8 up-regulated and 18 down-regulated miRNAs identified in the IBS-D rat model. Of these, miR-144 was markedly up-regulated and resulted in the down-regulation of OCLN and ZO1 expression. Overexpression of miR-144 by transfection of miR-144 precursor markedly inhibited the expression of OCLN and ZO1. Further

  20. Myasthenia gravis in a patient affected by glycogen storage disease type Ib: a further manifestation of an increased risk for autoimmune disorders?

    Science.gov (United States)

    Melis, D; Balivo, F; Della Casa, R; Romano, A; Taurisano, R; Capaldo, B; Riccardi, G; Monsurrò, M R; Parenti, G; Andria, G

    2008-12-01

    Glycogen storage disease type Ib (GSD Ib, OMIM 232220) is an inborn disorder of glucose metabolism, caused by mutations in the G6PT gene, encoding a glucose 6-phosphate transporter (G6PT). GSD Ib is mainly associated with fasting hypoglycaemia and hepatomegaly. Most GSD Ib patients also show neutropenia and neutrophil dysfunction and therefore are at risk of developing severe infections and inflammatory bowel disease (IBD). An increased risk for autoimmune disorders, such as thyroid autoimmunity and Crohn-like disease, has also been demonstrated, but no systematic study on the prevalence of autoimmune disorders in GSD Ib patients has ever been performed. We describe a 25-year-old patient affected by GSD Ib who developed 'seronegative' myasthenia gravis (MG), presenting with bilateral eyelid ptosis, diplopia, dysarthria, severe dysphagia, dyspnoea and fatigue. The repetitive stimulation of peripheral nerves test showed signs of exhaustion of neuromuscular transmission, particularly evident in the cranial area. Even in the absence of identifiable anti-acetylcholine receptor antibodies, seronegative MG is considered an autoimmune disorder and may be related to the disturbed immune function observed in GSD Ib patients.