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Sample records for telomerase negative counterpart

  1. Negative-strand RNA viruses: the plant-infecting counterparts.

    Science.gov (United States)

    Kormelink, Richard; Garcia, Maria Laura; Goodin, Michael; Sasaya, Takahide; Haenni, Anne-Lise

    2011-12-01

    While a large number of negative-strand (-)RNA viruses infect animals and humans, a relative small number have plants as their primary host. Some of these have been classified within families together with animal/human infecting viruses due to similarities in particle morphology and genome organization, while others have just recently been/or are still classified in floating genera. In most cases, at least two striking differences can still be discerned between the animal/human-infecting viruses and their plant-infecting counterparts which for the latter relate to their adaptation to plants as hosts. The first one is the capacity to modify plasmodesmata to facilitate systemic spread of infectious viral entities throughout the plant host. The second one is the capacity to counteract RNA interference (RNAi, also referred to as RNA silencing), the innate antiviral defence system of plants and insects. In this review an overview will be presented on the negative-strand RNA plant viruses classified within the families Bunyaviridae, Rhabdoviridae, Ophioviridae and floating genera Tenuivirus and Varicosavirus. Genetic differences with the animal-infecting counterparts and their evolutionary descendants will be described in light of the above processes. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. A Highly Sensitive Telomerase Activity Assay that Eliminates False-Negative Results Caused by PCR Inhibitors

    Directory of Open Access Journals (Sweden)

    Hidenobu Yaku

    2013-09-01

    Full Text Available An assay for telomerase activity based on asymmetric polymerase chain reaction (A-PCR on magnetic beads (MBs and subsequent application of cycling probe technology (CPT is described. In this assay, the telomerase reaction products are immobilized on MBs, which are then washed to remove PCR inhibitors that are commonly found in clinical samples. The guanine-rich sequences (5'-(TTAGGGn-3' of the telomerase reaction products are then preferentially amplified by A-PCR, and the amplified products are subsequently detected via CPT, where a probe RNA with a fluorophore at the 5' end and a quencher at the 3' end is hydrolyzed by RNase H in the presence of the target DNA. The catalyst-mediated cleavage of the probe RNA enhances fluorescence from the 5' end of the probe. The assay allowed us to successfully detect HeLa cells selectively over normal human dermal fibroblast (NHDF cells. Importantly, this selectivity produced identical results with regard to detection of HeLa cells in the absence and presence of excess NHDF cells; therefore, this assay can be used for practical clinical applications. The lower limit of detection for HeLa cells was 50 cells, which is lower than that achieved with a conventional telomeric repeat amplification protocol assay. Our assay also eliminated false-negative results caused by PCR inhibitors. Furthermore, we show that this assay is appropriate for screening among G-quadruplex ligands to find those that inhibit telomerase activity.

  3. Negative-strand RNA viruses: The plant-infecting counterparts

    NARCIS (Netherlands)

    Kormelink, R.J.M.; Garcia, M.L.; Goodin, M.; Sasaya, T.; Haenni, A.L.

    2011-01-01

    While a large number of negative-strand (-)RNA viruses infect animals and humans, a relative small number have plants as their primary host. Some of these have been classified within families together with animal/human infecting viruses due to similarities in particle morphology and genome

  4. Troglitazone suppresses telomerase activity independently of PPARγ in estrogen-receptor negative breast cancer cells

    International Nuclear Information System (INIS)

    Rashid-Kolvear, Fariborz; Taboski, Michael AS; Nguyen, Johnny; Wang, Dong-Yu; Harrington, Lea A; Done, Susan J

    2010-01-01

    Breast cancer is one the highest causes of female cancer death worldwide. Many standard chemotherapeutic agents currently used to treat breast cancer are relatively non-specific and act on all rapidly dividing cells. In recent years, more specific targeted therapies have been introduced. It is known that telomerase is active in over 90% of breast cancer tumors but inactive in adjacent normal tissues. The prevalence of active telomerase in breast cancer patients makes telomerase an attractive therapeutic target. Recent evidence suggests that telomerase activity can be suppressed by peroxisome proliferator activated receptor gamma (PPARγ). However, its effect on telomerase regulation in breast cancer has not been investigated. In this study, we investigated the effect of the PPARγ ligand, troglitazone, on telomerase activity in the MDA-MB-231 breast cancer cell line. Real time RT-PCR and telomerase activity assays were used to evaluate the effect of troglitazone. MDA-MB-231 cells had PPARγ expression silenced using shRNA interference. We demonstrated that troglitazone reduced the mRNA expression of hTERT and telomerase activity in the MDA-MB-231 breast cancer cell line. Troglitazone reduced telomerase activity even in the absence of PPARγ. In agreement with this result, we found no correlation between PPARγ and hTERT mRNA transcript levels in breast cancer patients. Statistical significance was determined using Pearson correlation and the paired Student's t test. To our knowledge, this is the first time that the effect of troglitazone on telomerase activity in breast cancer cells has been investigated. Our data suggest that troglitazone may be used as an anti-telomerase agent; however, the mechanism underlying this inhibitory effect remains to be determined

  5. Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Christensen, Rikke; Graakjaer, Jesper

    2007-01-01

    -detected alkaline DNA unwinding assay together with Western blot analyses for phosphorylated H2AX and Q-FISH was applied for investigation of telomeric damage. Our results indicate that hMSC and TERT-immortalized hMSCs can cope with relatively high doses of gamma-rays and that overall DNA repair is similar...... in the two cell lines. The telomeres were extensively destroyed after irradiation in both cell types suggesting that telomere caps are especially sensitive to radiation. The TERT-immortalized hMSCs showed higher stability at telomeric regions than primary hMSCs indicating that cells with long telomeres...

  6. [Telomerase activity in uveal melanomas].

    Science.gov (United States)

    Rohrbach, J M; Riedinger, C; Wild, M; Partsch, M

    2000-05-01

    The maximum number of cell divisions of a certain cell population is genetically fixed so that aging cells become non-dividing (senescent) at least. This replicative life span, also known as "Hayflick limit", is probably defined by a "critical" length of the telomeres. Telomeres are special DNA-sequences located at the four ends of the chromosomes which are shortened with each cell cycle. Cells of most, but not all malignant tumours have been shown to reactivate the enzyme telomerase so that telomeres can be reconstructed, "Hayflick limit" can be overcome, and unlimited cell division can be established. This study was undertaken to elucidate whether telomerase reactivation is used by uveal melanoma cells. Fresh tumour tissue was removed from 10 untreated uveal melanomas after enucleation. Telomerase activity was determined using a PCR ELISA according to the Telomeric Repeat Amplification Protocol (TRAP). Normal tissue of the skin and the conjunctiva served as control. Telomerase activity was detectable in 90% of the investigated uveal melanomas. All control specimens were telomerase negative. Uveal melanoma growth seems to depend on telomerase reactivation. Thus, telomerase inhibition could offer a new principle for uveal melanoma therapy in the future.

  7. Telomere elongation in immortal human cells without detectable telomerase activity.

    Science.gov (United States)

    Bryan, T M; Englezou, A; Gupta, J; Bacchetti, S; Reddel, R R

    1995-09-01

    Immortalization of human cells is often associated with reactivation of telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats onto telomeres and compensates for their shortening. We examined whether telomerase activation is necessary for immortalization. All normal human fibroblasts tested were negative for telomerase activity. Thirteen out of 13 DNA tumor virus-transformed cell cultures were also negative in the pre-crisis (i.e. non-immortalized) stage. Of 35 immortalized cell lines, 20 had telomerase activity as expected, but 15 had no detectable telomerase. The 15 telomerase-negative immortalized cell lines all had very long and heterogeneous telomeres of up to 50 kb. Hybrids between telomerase-negative and telomerase-positive cells senesced. Two senescent hybrids demonstrated telomerase activity, indicating that activation of telomerase is not sufficient for immortalization. Some hybrid clones subsequently recommenced proliferation and became immortalized either with or without telomerase activity. Those without telomerase activity also had very long and heterogeneous telomeres. Taken together, these data suggest that the presence of lengthened or stabilized telomeres is necessary for immortalization, and that this may be achieved either by the reactivation of telomerase or by a novel and as yet unidentified mechanism.

  8. Biological characteristics and clinical outcome of triple negative primary breast cancer in older women - comparison with their younger counterparts.

    Directory of Open Access Journals (Sweden)

    Binafsha M Syed

    Full Text Available Triple negative (ER, PgR and HER2 negative breast cancers (TNBCs are often considered as a poor prognostic phenotype. There is dearth of evidence showing the prevalence and biological behaviour of TNBCs in older women. This study aimed to analyse their biological characteristics in comparison with a well characterised younger series from a single centre with long term clinical follow-up. Over 37 years (1973-2010, 1,758 older (≥70 years women with early operable (<5 cm primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. A total of 127 patients (22.1% had TNBCs and full biological analysis of 15 biomarkers was performed. The results were compared with those of their younger (<70 years counterparts 342 (18.9% from a previously characterised, consecutive series of primary breast cancer treated in the same unit (1986-1998. The 127 older patients with TNBCs showed lower rates of Ki67 and CK 7/8 positivity and high rates of bcl2 and CK18 positivity when compared with their younger counterparts (p<0.05. There was no significant difference in the long term clinical outcome between the two age groups, despite the fact that 47% of the younger patients had adjuvant chemotherapy, while none in the older cohort received such treatment. EGFR, axillary stage and pathological size showed prognostic significance in older women with TNBCs on univariate analysis. Despite not having received adjuvant chemotherapy, the older series had clinical outcome similar to the younger patients almost half of whom had chemotherapy. This appears to be related to other biomarkers (in addition to ER/PgR/HER2 eg Ki67, bcl2 and cytokeratins which have different expression patterns influencing prognosis.

  9. Telomerase lost?

    Czech Academy of Sciences Publication Activity Database

    Mason, J. M.; Randall, T. A.; Čapková Frydrychová, Radmila

    2016-01-01

    Roč. 125, č. 1 (2016), s. 65-73 ISSN 0009-5915 R&D Projects: GA ČR GA14-07172S Grant - others:GA JU(CZ) 052/2013/P; GA JU(CZ) 038/2014/P; European Union Seventh Framework Programme(CZ) 316304 Program:FP7 Institutional support: RVO:60077344 Keywords : telomerase * DNA sequences * Bombyx mori Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.414, year: 2016 http://link.springer.com/article/10.1007%2Fs00412-015-0528-7

  10. An Alternate Splicing Variant of the Human Telomerase Catalytic Subunit Inhibits Telomerase Activity

    Directory of Open Access Journals (Sweden)

    Xiaoming Yi

    2000-09-01

    Full Text Available Telomerase, a cellular reverse transcriptase, adds telomeric repeats to chromosome ends. In normal human somatic cells, telomerase is repressed and telomeres progressively shorten, leading to proliferative senescence. Introduction of the telomerase (hTERT cDNA is sufficient to produce telomerase activity and immortalize normal human cells, suggesting that the repression of telomerase activity is transcriptional. The telomerase transcript has been shown to have at least six alternate splicing sites (four insertion sites and two deletion sites, and variants containing both or either of the deletion sites are present during development and in a panel of cancer cell lines we surveyed. One deletion (β site and all four insertions cause premature translation terminations, whereas the other deletion (α site is 36 by and lies within reverse transcriptase (RT motif A, suggesting that this deletion variant may be a candidate as a dominant-negative inhibitor of telomerase. We have cloned three alternately spliced hTERT variants that contain the α,β or both α and,β deletion sites. These alternate splicing variants along with empty vector and wild-type hTERT were introduced into normal human fibroblasts and several telomerase-positive immortal and tumor cell lines. Expression of the α site deletion variant (hTERT α− construct was confirmed by Western blotting. We found that none of the three alternate splicing variants reconstitutes telomerase activity in fibroblasts. However, hTERT α− inhibits telomerase activities in telomerase-positive cells, causes telomere shortening and eventually cell death. This alternately spliced dominant-negative variant may be important in understanding telomerase regulation during development, differentiation and in cancer progression.

  11. Meningiomas, dicentric chromosomes, gliomas, and telomerase activity.

    Science.gov (United States)

    Carroll, T; Maltby, E; Brock, I; Royds, J; Timperley, W; Jellinek, D

    1999-08-01

    Lack of telomere maintenance during cell replication leads to telomere erosion and loss of function. This can result in telomere associations which probably cause the dicentric chromosomes seen in some tumour cells. One mechanism of telomere maintenance in dividing cells is the action of telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats onto telomeres and compensates for their shortening during cell division. Over 90 per cent of extracranial malignant neoplasms have been found to have telomerase activity. This study sought to determine if there was a relationship between absence of telomerase activity and presence of dicentric chromosomes in meningiomas and to what extent the other main group of central nervous system tumours, the gliomas, expressed telomerase activity. Telomerase activity was measured on 25 meningiomas and 29 gliomas. Four of the meningiomas were atypical variants and 11 were positive for dicentric chromosomes. Twenty-five of 29 gliomas were glioblastoma multiforme tumours. Measures were taken to ensure absence of false positives due to primer-dimer interaction and false negatives due to protein degradation or the presence of Taq polymerase inhibitors. All 25 meningiomas and the four low-grade gliomas (WHO grade II) were telomerase activity-negative. Seven (28 per cent) of the 25 glioblastoma multiforme tumours showed telomerase activity. The absence of telomerase activity in meningiomas and the high frequency of telomere associations support the hypothesis that these tumours are benign, transformed but pre-crisis. The relatively low frequency of telomerase activity in the malignant glioblastoma multiforme suggests that most of these tumours may have other mechanisms of telomere maintenance and that the potentially therapeutic telomerase inhibitors will not be of great value in the future management of the majority of patients suffering from these tumours. Copyright 1999 John Wiley & Sons, Ltd.

  12. Telomerase Repeated Amplification Protocol (TRAP).

    Science.gov (United States)

    Mender, Ilgen; Shay, Jerry W

    2015-11-20

    analyzed by electrophoresis. TSNT is, an internal standard control, amplified by TS primer. NT is its own reverse primer, which is not a substrate for telomerase. These primers are used to identify false-negative results by if the gel lacks internal control bands.

  13. The inhibitory effect of Curcuma longa extract on telomerase activity ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-02-08

    Feb 8, 2010 ... curcumin, could have important effect on treatment of lung cancer. Curcumin ... study inhibitory effect of C. longa total extract on telomerase in A549 lung cancer cell line as in vitro model of ..... If A > 2× (OD of negative control), then, telomerase activity ... radiation, chemotherapy, laser therapy, photodynamic.

  14. Telomerases: chemistry, biology, and clinical applications

    National Research Council Canada - National Science Library

    Lue, Neal F; Autexier, Chantal

    2012-01-01

    .... Other topics include telomerase biogenesis, transcriptional and post-translational regulation, off-telomere functions of telomerase and the role of telomerase in cellular senescence, aging and cancer...

  15. Differences in telomerase activity between colon and rectal cancer.

    Science.gov (United States)

    Ayiomamitis, Georgios D; Notas, George; Zaravinos, Apostolos; Zizi-Sermpetzoglou, Adamantia; Georgiadou, Maria; Sfakianaki, Ourania; Kouroumallis, Elias

    2014-06-01

    Colorectal cancer is one of the most common cancers and the third leading cause of cancer death in both sexes. The disease progresses as a multistep process and is associated with genetic alterations. One of the characteristic features of cancer is telomerase activation. We sought to evaluate the differences in telomerase activity between colon cancer and adjacent normal tissue and to correlate the differences in telomerase activity between different locations with clinicopathological factors and survival. Matched colon tumour samples and adjacent normal mucosa samples 10 cm away from the tumour were collected during colectomy. We assessed telomerase activity using real time polymerase chain reaction. Several pathological characteristics of tumours, including p53, Ki-67, p21, bcl2 and MLH1 expression were also studied. We collected samples from 49 patients. There was a significantly higher telomerase activity in colon cancer tissue than normal tissue. Adenocarcinomas of the right colon express significantly higher telomerase than left-side cancers. Colon cancers and their adjacent normal tissue had significantly more telomerase and were more positive to MLH1 than rectal cancers. The expression of p53 negatively correlated to telomerase activity and was linked to better patient survival. Colon and rectal cancers seem to have different telomerase and MLH1 profiles, and this could be another factor for their different biologic and clinical behaviour and progression. These results support the idea that the large bowel cannot be considered a uniform organ, at least in the biology of cancer.

  16. Human telomerase activity regulation

    OpenAIRE

    Wojtyla, Aneta; Gladych, Marta; Rubis, Blazej

    2010-01-01

    Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control b...

  17. Telomerase activity in gastric cancer.

    Science.gov (United States)

    Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W; Matsuura, Y

    1995-08-01

    Although many genetic alterations have been reported in gastric cancer, it is not known whether all gastric tumors are capable of indefinite proliferative potential, e.g., immortality. The expression of telomerase and stabilization of telomeres are concomitant with the attainment of immortality in tumor cells; thus, the measurement of telomerase activity in clinically obtained tumor samples may provide important information useful both as a diagnostic marker to detect immortal cancer cells in clinical materials and as a prognostic indicator of patient outcome. Telomerase activity was analyzed in 66 primary gastric cancers with the use of a PCR-based assay. The majority of tumors (85%) displayed telomerase activity, but telomerase was undetectable in 10 tumors (15%), 8 of which were early stage tumors. Most of the tumors with telomerase activity were large and of advanced stages, including metastases. Survival rate of patients of tumors with detectable telomerase activity was significantly shorter than that of those without telomerase activity. Alterations of telomere length (reduced/elongated terminal restriction fragments) were detected in 14 of 66 (21%) gastric cancers, and all 14 had telomerase activity. Cellular DNA contents revealed that all 22 aneuploid tumors had detectable telomerase activity. The present results indicate that telomerase activation may be required as a critical step in the multigenetic process of tumorigenesis, and that telomerase is frequently but not always activated as a late event in gastric cancer progression.

  18. When Telomerase Causes Telomere Loss.

    Science.gov (United States)

    Glousker, Galina; Lingner, Joachim

    2018-02-05

    Telomerase counteracts telomere shortening, preventing cellular senescence. Telomerase deficiency causes telomere syndromes because of premature telomere exhaustion in highly proliferative cells. Paradoxically, in a recent issue of Cell, Margalef et al. (2018) demonstrate that telomerase causes telomere loss in cells lacking the RTEL1 helicase, which is defective in Hoyeraal-Hreidarsson syndrome (HHS). Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Association of telomerase activity with radio- and chemosensitivity of neuroblastomas

    Directory of Open Access Journals (Sweden)

    Willich Normann

    2010-07-01

    Full Text Available Abstract Background Telomerase activity compensates shortening of telomeres during cell division and enables cancer cells to escape senescent processes. It is also supposed, that telomerase is associated with radio- and chemoresistance. In the here described study we systematically investigated the influence of telomerase activity (TA and telomere length on the outcome of radio- and chemotherapy in neuroblastoma. Methods We studied the effects on dominant negative (DN mutant, wild type (WT of the telomerase catalytic unit (hTERT using neuroblastoma cell lines. The cells were irradiated with 60Co and treated with doxorubicin, etoposide, cisplatin and ifosfamide, respectively. Viability was determined by MTS/MTT-test and the GI50 was calculated. Telomere length was measured by southernblot analysis and TA by Trap-Assay. Results Compared to the hTERT expressing cells the dominant negative cells showed increased radiosensitivity with decreased telomere length. Independent of telomere length, telomerase negative cells are significantly more sensitive to irradiation. The effect of TA knock-down or overexpression on chemosensitivity were dependent on TA, the anticancer drug, and the chemosensitivity of the maternal cell line. Conclusions Our results supported the concept of telomerase inhibition as an antiproliferative treatment approach in neuroblastomas. Telomerase inhibition increases the outcome of radiotherapy while in combination with chemotherapy the outcome depends on drug- and cell line and can be additive/synergistic or antagonistic. High telomerase activity is one distinct cancer stem cell feature and the here described cellular constructs in combination with stem cell markers like CD133, Aldehyddehydrogenase-1 (ALDH-1 or Side population (SP may help to investigate the impact of telomerase activity on cancer stem cell survival under therapy.

  20. Telomerer og telomerase

    DEFF Research Database (Denmark)

    Bendix, Laila; Kølvraa, Steen

    2010-01-01

    In 2009 the Nobel Prize in Medicine was awarded to EH Blackburn, CW Greider and JW Szostak for their work on "How chromosomes are protected by telomeres and the enzyme telomerase". Telomeres are specialized DNA structures localized at the end of linear chromosomes. Telomeres are known as the biol......In 2009 the Nobel Prize in Medicine was awarded to EH Blackburn, CW Greider and JW Szostak for their work on "How chromosomes are protected by telomeres and the enzyme telomerase". Telomeres are specialized DNA structures localized at the end of linear chromosomes. Telomeres are known...

  1. Identification of cis-acting elements on positive-strand subgenomic mRNA required for the synthesis of negative-strand counterpart in bovine coronavirus.

    Science.gov (United States)

    Yeh, Po-Yuan; Wu, Hung-Yi

    2014-07-30

    It has been demonstrated that, in addition to genomic RNA, sgmRNA is able to serve as a template for the synthesis of the negative-strand [(-)-strand] complement. However, the cis-acting elements on the positive-strand [(+)-strand] sgmRNA required for (-)-strand sgmRNA synthesis have not yet been systematically identified. In this study, we employed real-time quantitative reverse transcription polymerase chain reaction to analyze the cis-acting elements on bovine coronavirus (BCoV) sgmRNA 7 required for the synthesis of its (-)-strand counterpart by deletion mutagenesis. The major findings are as follows. (1) Deletion of the 5'-terminal leader sequence on sgmRNA 7 decreased the synthesis of the (-)-strand sgmRNA complement. (2) Deletions of the 3' untranslated region (UTR) bulged stem-loop showed no effect on (-)-strand sgmRNA synthesis; however, deletion of the 3' UTR pseudoknot decreased the yield of (-)-strand sgmRNA. (3) Nucleotides positioned from -15 to -34 of the sgmRNA 7 3'-terminal region are required for efficient (-)-strand sgmRNA synthesis. (4) Nucleotide species at the 3'-most position (-1) of sgmRNA 7 is correlated to the efficiency of (-)-strand sgmRNA synthesis. These results together suggest, in principle, that the 5'- and 3'-terminal sequences on sgmRNA 7 harbor cis-acting elements are critical for efficient (-)-strand sgmRNA synthesis in BCoV.

  2. Identification of Cis-Acting Elements on Positive-Strand Subgenomic mRNA Required for the Synthesis of Negative-Strand Counterpart in Bovine Coronavirus

    Directory of Open Access Journals (Sweden)

    Po-Yuan Yeh

    2014-07-01

    Full Text Available It has been demonstrated that, in addition to genomic RNA, sgmRNA is able to serve as a template for the synthesis of the negative-strand [(−-strand] complement. However, the cis-acting elements on the positive-strand [(+-strand] sgmRNA required for (−-strand sgmRNA synthesis have not yet been systematically identified. In this study, we employed real-time quantitative reverse transcription polymerase chain reaction to analyze the cis-acting elements on bovine coronavirus (BCoV sgmRNA 7 required for the synthesis of its (−-strand counterpart by deletion mutagenesis. The major findings are as follows. (1 Deletion of the 5'-terminal leader sequence on sgmRNA 7 decreased the synthesis of the (−-strand sgmRNA complement. (2 Deletions of the 3' untranslated region (UTR bulged stem-loop showed no effect on (−-strand sgmRNA synthesis; however, deletion of the 3' UTR pseudoknot decreased the yield of (−-strand sgmRNA. (3 Nucleotides positioned from −15 to −34 of the sgmRNA 7 3'-terminal region are required for efficient (−-strand sgmRNA synthesis. (4 Nucleotide species at the 3'-most position (−1 of sgmRNA 7 is correlated to the efficiency of (−-strand sgmRNA synthesis. These results together suggest, in principle, that the 5'- and 3'-terminal sequences on sgmRNA 7 harbor cis-acting elements are critical for efficient (−-strand sgmRNA synthesis in BCoV.

  3. Telomerase in lung cancer diagnostics

    International Nuclear Information System (INIS)

    Kovkarova, E.; Stefanovski, T.; Dimov, A.; Naumovski, J.

    2003-01-01

    Background. Telomerase is a ribonucleoprotein that looks after the telomeric cap of the linear chromosomes maintaining its length. It is over expressed in tumour tissues, but not in normal somatic cells. Therefore the aim of this study was to determine the telomerase activity in lung cancer patients as novel marker for lung cancer detection evaluating the influence of tissue/cell obtaining technique. Material and methods. Using the TRAP (telomeric repeat amplification protocol), telomerase activity was determined in material obtained from bronchobiopsy (60 lung cancer patients compared with 20 controls) and washings from transthoracic fine needle aspiration biopsy performed in 10 patients with peripheral lung tumours. Results. Telomerase activity was detected in 75% of the lung cancer bronchobyopsies, and in 100% in transthoracic needle washings. Conclusions. Measurement of telomerase activity can contribute in fulfilling the diagnosis of lung masses and nodules suspected for lung cancer. (author)

  4. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent γ-H2AX and telomerase regulation in triple-negative breast cancer

    International Nuclear Information System (INIS)

    Kala, Rishabh; Shah, Harsh N.; Martin, Samantha L.; Tollefsbol, Trygve O.

    2015-01-01

    Nutrition is believed to be a primary contributor in regulating gene expression by affecting epigenetic pathways such as DNA methylation and histone modification. Resveratrol and pterostilbene are phytoalexins produced by plants as part of their defense system. These two bioactive compounds when used alone have been shown to alter genetic and epigenetic profiles of tumor cells, but the concentrations employed in various studies often far exceed physiologically achievable doses. Triple-negative breast cancer (TNBC) is an often fatal condition that may be prevented or treated through novel dietary-based approaches. HCC1806 and MDA-MB-157 breast cancer cells were used as TNBC cell lines in this study. MCF10A cells were used as control breast epithelial cells to determine the safety of this dietary regimen. CompuSyn software was used to determine the combination index (CI) for drug combinations. Combinatorial resveratrol and pterostilbene administered at close to physiologically relevant doses resulted in synergistic (CI <1) growth inhibition of TNBCs. SIRT1, a type III histone deacetylase (HDAC), was down-regulated in response to this combinatorial treatment. We further explored the effects of this novel combinatorial approach on DNA damage response by monitoring γ-H2AX and telomerase expression. With combination of these two compounds there was a significant decrease in these two proteins which might further resulted in significant growth inhibition, apoptosis and cell cycle arrest in HCC1806 and MDA-MB-157 breast cancer cells, while there was no significant effect on cellular viability, colony forming potential, morphology or apoptosis in control MCF10A breast epithelial cells. SIRT1 knockdown reproduced the effects of combinatorial resveratrol and pterostilbene-induced SIRT1 down-regulation through inhibition of both telomerase activity and γ-H2AX expression in HCC1806 breast cancer cells. As a part of the repair mechanisms and role of SIRT1 in recruiting DNMTs

  5. AZT as a telomerase inhibitor

    International Nuclear Information System (INIS)

    Gomez, Daniel E.; Armando, Romina G.; Alonso, Daniel F.

    2012-01-01

    Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  6. DETECTION OF TELOMERASE ACTIVITY IN BREAST CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    Yang Wentao; Xu Liangzhong; Zhang Taiming; Zhu weiping; Li Xiaomei; Jin Aiping

    1998-01-01

    Objective:To investigate the significance of telomerase activity in breast carcinoma with its respect to axillary lymph node status. Methods: Telomerase activity was analyzed in 88 breast carcinomas and 16benign breast lesions, using polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay. Results: Telomerase activity was detected in 75 (85%) of 88 breast carcinomas (including three breast carcinomas in situ which were all positive for telomerase activity), whereas in benign breast lesions analyzed only 2(12.5%) of 16 cases were positive for telomerase activity. The difference between the two groups was statistically significant (P<0.001). Besides,telomerase activity was expressed significantly higher in node-positive breast carcinoma (93%) than in nodenegative ones (77%) (P<0.05). Conclusion: Our results suggest that telomerase activation plays an important role during breast carcinoma development. It is possible that this enzyme may serve as an early indication of breast carcinoma.

  7. Telomerase Activity Detected by Quantitative Assay in Bladder Carcinoma and Exfoliated Cells in Urine

    Directory of Open Access Journals (Sweden)

    Roberta Fedriga

    2001-01-01

    Full Text Available Early diagnosis is one of the most determining factors for patient survival. The detection of telomerase activity is a potentially promising tool in the diagnosis of bladder and other types of cancer due to the high expression of this enzyme in tumor cells. We carried out a quantitative evaluation of telomerase activity in urine samples in an attempt to determine a cut-off capable of identifying cancer patients. Telomerase activity was quantified by fluorescence TRAP assay in urine from 50 healthy volunteers and in urine and bioptic tumor samples from 56 previously untreated bladder cancer patients and expressed in arbitrary enzymatic units (AEU. Telomerase activity in urine ranged from 0 to 106 AEU (median 0 in healthy donors and from 0 to 282 AEU (median 87 in patients with cancer. A telomerase expression higher than the cut off value determined by receiver operating characteristic (ROC analysis was observed in 78% of cases, regardless of tumor grade and in 71% (15/21 of cases of nonassessable or negative cytology. The quantitative analysis of telomerase activity in urine enabled us to define cut-off values characterized by different sensitivity and specificity. Cytologic and telomerase determination, used sequentially, enabled us to detect about 90% of tumors.

  8. Telomerase – future drug target enzyme?

    Directory of Open Access Journals (Sweden)

    Tomaž Langerholc

    2012-06-01

    Full Text Available Eucaryotic chromosome endings (telomeres replication problem was solved in the 1980’s by discovery of the telomerase enzyme. The Nobel Prize in Physiology or Medicine was awarded in 2009 for the discovery of telomerase. Altered telomerase expression in cancer, and human dream of eternal youth have accelerated the development of pharmacological telomerase inhibitors and activators. However, after 15 years of development they are still not available on the market. In the present article we reviewed pharmacological agents that target telomerase activity, which have entered clinical trials. Current drugs in development are mostly not intended to be used alone, as telomerase inhibitors under clinical trials are used in combination with the existing chemotherapeutics and anti-telomerase vaccines in combination with immuno-stimulants. Apart from cancer and aging, there are other diseases linked to deregulated activity of telomerase/telomeres and we also discuss technical and legal problems that researchers encounter in developing anti-telomerase therapy. Given the pace of development, first anti-telomerase drugs might appear on the market in the next 5 years.

  9. Telomere lengthening and other functions of telomerase.

    Science.gov (United States)

    Rubtsova, M P; Vasilkova, D P; Malyavko, A N; Naraikina, Yu V; Zvereva, M I; Dontsova, O A

    2012-04-01

    Telomerase is an enzyme that maintains the length of the telomere. The telomere length specifies the number of divisions a cell can undergo before it finally dies (i.e. the proliferative potential of cells). For example, telomerase is activated in embryonic cell lines and the telomere length is maintained at a constant level; therefore, these cells have an unlimited fission potential. Stem cells are characterized by a lower telomerase activity, which enables only partial compensation for the shortening of telomeres. Somatic cells are usually characterized by the absence of telomerase activity. Telomere shortening leads to the attainment of the Hayflick limit, the transition of cells to a state of senescence. The cells subsequently enter a state of crisis, accompanied by massive cell death. The surviving cells become cancer cells, which are capable both of dividing indefinitely and maintaining telomere length (usually with the aid of telomerase). Telomerase is a reverse transcriptase. It consists of two major components: telomerase RNA (TER) and reverse transcriptase (TERT). TER is a non-coding RNA, and it contains the region which serves as a template for telomere synthesis. An increasing number of articles focussing on the alternative functions of telomerase components have recently started appearing. The present review summarizes data on the structure, biogenesis, and functions of telomerase.

  10. Telomerase and mammalian ageing: a critical appraisal.

    Science.gov (United States)

    Goyns, M H; Lavery, W L

    2000-03-13

    The telomeres that occur at the end of chromosomes are maintained by the activity of telomerase and are thought to be important protective factors in maintaining the integrity of chromosomes. It now appears that in vitro replicative senescence, which has been observed in cultured somatic cells, is due to a loss of telomere length in those cells, caused by inactivity of telomerase. This has led to the proposition that telomerase activity is an important determinant in organismal ageing. However, many cells in the body do not proliferate regularly and therefore will not lose telomere length. Cells that do proliferate frequently have now been shown to have active telomerase. Other cells, such as fibroblasts, that do not have telomerase activity but proliferate only occasionally may not reach the Hayflick limit during the lifetime of an animal. There is also no correlation between telomere length and the maximal lifespan exhibited by different species. Studies of telomerase knock-out mice have reported some aspects of accelerated ageing after three generations, but the relevance of these observations to normal ageing remains unconvincing. The role of telomerase in producing immortal tumour cells and the possibility that activation of telomerase is an important event in malignant transformation is similarly controversial and open to alternative interpretations. The significance of these and other observations, and how they define the role of telomerase in ageing, is discussed.

  11. Prevalence of Telomerase Activity in Human Cancer

    Directory of Open Access Journals (Sweden)

    Chi-Hau Chen

    2011-05-01

    Full Text Available Telomerase activity has been measured in a wide variety of cancerous and non-cancerous tissue types, and the vast majority of clinical studies have shown a direct correlation between it and the presence of cancerous cells. Telomerase plays a key role in cellular immortality and tumorigenesis. Telomerase is activated in 80–90% of human carcinomas, but not in normal somatic cells, therefore, its detection holds promise as a diagnostic marker for cancer. Measurable levels of telomerase have been detected in malignant cells from various samples: tissue from gestational trophoblastic neoplasms; squamous carcinoma cells from oral rinses; lung carcinoma cells from bronchial washings; colorectal carcinoma cells from colonic luminal washings; bladder carcinoma cells from urine or bladder washings; and breast carcinoma or thyroid cancer cells from fine needle aspirations. Such clinical tests for telomerase can be useful as non-invasive and cost-effective methods for early detection and monitoring of cancer. In addition, telomerase activity has been shown to correlate with poor clinical outcome in late-stage diseases such as non-small cell lung cancer, colorectal cancer, and soft tissue sarcomas. In such cases, testing for telomerase activity can be used to identify patients with a poor prognosis and to select those who might benefit from adjuvant treatment. Our review of the latest medical advances in this field reveals that telomerase holds great promise as a biomarker for early cancer detection and monitoring, and has considerable potential as the basis for developing new anticancer therapies.

  12. Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells.

    Science.gov (United States)

    Armstrong, Christine A; Tomita, Kazunori

    2017-03-01

    Aberrant activation of telomerase occurs in 85-90% of all cancers and underpins the ability of cancer cells to bypass their proliferative limit, rendering them immortal. The activity of telomerase is tightly controlled at multiple levels, from transcriptional regulation of the telomerase components to holoenzyme biogenesis and recruitment to the telomere, and finally activation and processivity. However, studies using cancer cell lines and other model systems have begun to reveal features of telomeres and telomerase that are unique to cancer. This review summarizes our current knowledge on the mechanisms of telomerase recruitment and activation using insights from studies in mammals and budding and fission yeasts. Finally, we discuss the differences in telomere homeostasis between normal cells and cancer cells, which may provide a foundation for telomere/telomerase targeted cancer treatments. © 2017 The Authors.

  13. Telomerase and drug resistance in cancer

    OpenAIRE

    Lipinska, Natalia; Romaniuk, Aleksandra; Paszel-Jaworska, Anna; Toton, Ewa; Kopczynski, Przemyslaw; Rubis, Blazej

    2017-01-01

    It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gen...

  14. Acute myocardial infarction: 'telomerasing' for cardioprotection

    OpenAIRE

    Sanchís-Gomar, Fabián; Lucía Mulas, Alejandro

    2015-01-01

    Reactivating the telomerase gene through gene therapy after acute myocardial infarction (AMI) has been recently reported to improve survival in mice. Given that regular physical exercise also activates this gene, therapeutic and lifestyle interventions targeting telomerase need to be explored as possible additions to the current armamentarium for myocardial regeneration. 9.292 JCR (2015) Q1, 17/289 Biochemistry & mollecular biology, 17/187 Cell biology, 8/124 Medicine, research & experimen...

  15. Premature aging in telomerase-deficient zebrafish

    Directory of Open Access Journals (Sweden)

    Monique Anchelin

    2013-09-01

    The study of telomere biology is crucial to the understanding of aging and cancer. In the pursuit of greater knowledge in the field of human telomere biology, the mouse has been used extensively as a model. However, there are fundamental differences between mouse and human cells. Therefore, additional models are required. In light of this, we have characterized telomerase-deficient zebrafish (Danio rerio as the second vertebrate model for human telomerase-driven diseases. We found that telomerase-deficient zebrafish show p53-dependent premature aging and reduced lifespan in the first generation, as occurs in humans but not in mice, probably reflecting the similar telomere length in fish and humans. Among these aging symptoms, spinal curvature, liver and retina degeneration, and infertility were the most remarkable. Although the second-generation embryos died in early developmental stages, restoration of telomerase activity rescued telomere length and survival, indicating that telomerase dosage is crucial. Importantly, this model also reproduces the disease anticipation observed in humans with dyskeratosis congenita (DC. Thus, telomerase haploinsufficiency leads to anticipation phenomenon in longevity, which is related to telomere shortening and, specifically, with the proportion of short telomeres. Furthermore, p53 was induced by telomere attrition, leading to growth arrest and apoptosis. Importantly, genetic inhibition of p53 rescued the adverse effects of telomere loss, indicating that the molecular mechanisms induced by telomere shortening are conserved from fish to mammals. The partial rescue of telomere length and longevity by restoration of telomerase activity, together with the feasibility of the zebrafish for high-throughput chemical screening, both point to the usefulness of this model for the discovery of new drugs able to reactivate telomerase in individuals with DC.

  16. Evidence for a relief of repression mechanism for activation of the human telomerase reverse transcriptase promoter.

    Science.gov (United States)

    Wang, Shuwen; Zhu, Jiyue

    2003-05-23

    The transcriptional activation of human telomerase reverse transcriptase (hTERT) is an important step during cellular immortalization and tumorigenesis. To study how this activation occurs during immortalization, we have established a set of genetically related pre-crisis cells and their immortal progeny. As expected, hTERT mRNA was detected in our telomerase-positive immortal cells but not in pre-crisis cells or telomerase-negative immortal cells. However, transiently transfected luciferase reporters controlled by hTERT promoter sequences exhibited similar levels of luciferase activity in both telomerase-positive and -negative cells, suggesting that the endogenous chromatin context is likely required for hTERT regulation. Analysis of chromatin susceptibility to DNase I digestion consistently identified a DNase I hypersensitivity site (DHS) near the hTERT transcription initiation site in telomerase-positive cells. In addition, the histone deacetylase inhibitor trichostatin A (TSA) induced hTERT transcription and also a general increase in chromatin sensitivity to DNase treatment in telomerase-negative cells. The TSA-induced hTERT transcription in pre-crisis cells was accompanied by the formation of a DHS at the hTERT promoter. Furthermore, the TSA-induced hTERT transcription and chromatin alterations were not blocked by cycloheximide, suggesting that this induction does not require de novo protein synthesis and that TSA induces hTERT expression through the inhibition of histone deacetylation at the hTERT promoter. Taken together, our results suggest that the endogenous chromatin environment plays a critical role in the regulation of hTERT expression during cellular immortalization.

  17. Telomerase and Tel1p Preferentially Associate with Short Telomeres in S. cerevisiae

    Science.gov (United States)

    Sabourin, Michelle; Tuzon, Creighton T.; Zakian, Virginia A.

    2009-01-01

    SUMMARY In diverse organisms, telomerase preferentially elongates short telomeres. We generated a single short telomere in otherwise wild-type (WT) S. cerevisiae cells. The binding of the positive regulators Ku and Cdc13p was similar at short and WT-length telomeres. The negative regulators Rif1p and Rif2p were present at the short telomere, although Rif2p levels were reduced. Two telomerase holoenzyme components, Est1p and Est2p, were preferentially enriched at short telomeres in late S/G2 phase, the time of telomerase action. Tel1p, the yeast ATM-like checkpoint kinase, was highly enriched at short telomeres from early S through G2 phase and even into the next cell cycle. Nonetheless, induction of a single short telomere did not elicit a cell-cycle arrest. Tel1p binding was dependent on Xrs2p and required for preferential binding of telomerase to short telomeres. These data suggest that Tel1p targets telomerase to the DNA ends most in need of extension. PMID:17656141

  18. Telomerase Activation in Atherosclerosis and Induction of Telomerase Reverse Transcriptase Expression by Inflammatory Stimuli in Macrophages

    Science.gov (United States)

    Gizard, Florence; Heywood, Elizabeth B.; Findeisen, Hannes M.; Zhao, Yue; Jones, Karrie L.; Cudejko, Cèline; Post, Ginell R.; Staels, Bart; Bruemmer, Dennis

    2010-01-01

    Objective Telomerase serves as a critical regulator of tissue renewal. Although telomerase activity is inducible in response to various environmental cues, it remains unknown whether telomerase is activated during the inflammatory remodeling underlying atherosclerosis formation. To address this question, we investigated in the present study the regulation of telomerase in macrophages and during atherosclerosis development in LDL-receptor-deficient mice. Methods and Results We demonstrate that inflammatory stimuli activate telomerase in macrophages by inducing the expression of the catalytic subunit telomerase reverse transcriptase (TERT). Reporter and chromatin immunoprecipitation assays identified a previously unrecognized NF-κB response element in the TERT promoter, to which NF-κB is recruited during inflammation. Inhibition of NF-κB signaling completely abolished the induction of TERT expression, characterizing TERT as a bona fide NF-κB target gene. Furthermore, functional experiments revealed that TERT-deficiency results in a senescent cell phenotype. Finally, we demonstrate high levels of TERT expression in macrophages of human atherosclerotic lesions and establish that telomerase is activated during atherosclerosis development in LDL-receptor-deficient mice. Conclusion These results characterize TERT as a previously unrecognized NF-κB target gene in macrophages and demonstrate that telomerase is activated during atherosclerosis. This induction of TERT expression prevents macrophage senescence and may have important implications for the development of atherosclerosis. PMID:21106948

  19. Detection of telomerase activity using microchip electrophoresis.

    Science.gov (United States)

    Karasawa, Koji; Arakawa, Hidetoshi

    2015-07-01

    Telomerase participates in malignant transformation or immortalization of cells and thus has attracted attention as an anticancer drug target and diagnostic tumor marker. The telomeric repeat amplification protocol (TRAP) and improved TRAP methods (TRAP-fluorescence, TRAP-hybridization, etc.) are widely used forms of this telomerase assay. However, these approaches generally employ acrylamide gel electrophoresis after amplification of telomeric repeats by polymerase chain reaction (PCR), making these TRAP methods time consuming and technically demanding. In this study we developed a novel telomerase assay using microchip electrophoresis for rapid and highly sensitive detection of telomerase activity in cancer cells. The mixed gel of 0.8% hydroxypropyl methylcellulose (HPMC) and 0.3% polyethylene oxide (PEO) with SYBR Gold (fluorescent reagent) was used for microchip electrophoresis. As a result, the product amplified by a telomerase-positive cell could be measured in one cell per assay and detected with high reproducibility (CV=0.67%) in the short time of 100s. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Telomerase Activity Impacts on Epstein-Barr Virus Infection of AGS Cells

    Science.gov (United States)

    Rac, Jürgen; Haas, Florian; Schumacher, Andrina; Middeldorp, Jaap M.; Delecluse, Henri-Jacques; Speck, Roberto F.

    2015-01-01

    The Epstein-Barr virus (EBV) is transmitted from host-to-host via saliva and is associated with epithelial malignancies including nasopharyngeal carcinoma (NPC) and some forms of gastric carcinoma (GC). Nevertheless, EBV does not transform epithelial cells in vitro where it is rapidly lost from infected primary epithelial cells or epithelial tumor cells. Long-term infection by EBV, however, can be established in hTERT-immortalized nasopharyngeal epithelial cells. Here, we hypothesized that increased telomerase activity in epithelial cells enhances their susceptibility to infection by EBV. Using HONE-1, AGS and HEK293 cells we generated epithelial model cell lines with increased or suppressed telomerase activity by stable ectopic expression of hTERT or of a catalytically inactive, dominant negative hTERT mutant. Infection experiments with recombinant prototypic EBV (rB95.8), recombinant NPC EBV (rM81) with increased epithelial cell tropism compared to B95.8, or recombinant B95.8 EBV with BZLF1-knockout that is not able to undergo lytic replication, revealed that infection frequencies positively correlate with telomerase activity in AGS cells but also partly depend on the cellular background. AGS cells with increased telomerase activity showed increased expression mainly of latent EBV genes, suggesting that increased telomerase activity directly acts on the EBV infection of epithelial cells by facilitating latent EBV gene expression early upon virus inoculation. Thus, our results indicate that infection of epithelial cells by EBV is a very selective process involving, among others, telomerase activity and cellular background to allow for optimized host-to-host transmission via saliva. PMID:25856387

  1. Zoning of mucosal phenotype, dysplasia, and telomerase activity measured by telomerase repeat assay protocol in Barrett's esophagus

    NARCIS (Netherlands)

    Going, JJ; Fletcher-Monaghan, AJ; Neilson, L; Wisman, BA; van der Zee, A; Stuart, RC; Keith, WN

    2004-01-01

    Glandular dysplasia in Barrett's esophagus may regress spontaneously but can also progress to cancer. The human telomerase RNA template and the human telomerase reverse transcriptase enzyme which do not, of themselves, correlate strongly with telomerase activity, are too often overexpressed in

  2. ORIGINAL ARTICLE Detection of human telomerase reverse ...

    African Journals Online (AJOL)

    salah

    currently remains the gold standard procedure for diagnosis, yet, it is invasive and costly. Urinary cytopathology remains to be the only non-invasive alter- native method for diagnosis. Although it is tumour specific, yet it has a poor sensitivity, especially for low grade tumours. Detection of Telomerase enzyme in exfoliated ...

  3. Telomeres, telomerase and premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Renata Košir Pogačnik

    2011-11-01

    Full Text Available Telomeres are specialized structures at the ends of chromosomes, consisting of six repeated nucleotides in TTAGGG sequence. Genome stability is partly maintained by the architecture of telomeres and is gradually lost as telomeres progressively shorten with each cell replication. Critically shortened telomeres are recognized by DNA repair mechanisms as DNA damage and the cell replication cycle stops. The cell eventually dies or undergoes cell apoptosis. Telomere represents a cellular marker of biological age and are therefore also called cell mitotic clock. The enzyme that counteracts telomere shortening by adding nucleotides to the 3’ end of DNA strand is called telomerase. It is composed of the RNA subunit (TR, which is special type of messenger RNA (mRNA, the catalytic protein subunit (TERT, which works as a reverse transcriptase and numerous additional proteins. Telomerase is active in some germline, epithelial and haemopoietic cells, but in most somatic cells the activity is undetectable. In literature, the length of telomeres is closely connected with premature ovarian failure (POF. POF is generally defined as the onset of menopause before the age of 40. The causes of disease are genetical, autoimmune, iatrogenic or if we cannot establish the cause – idiopathic. A lot of studies examined correlation between idiopathic POF, length of telomeres and telomerase activity. The studies mostly show that women with POF have shortened telomeres and decreased activity of telomerase as compared to healthy women.

  4. Telomeres, telomerase and oral cancer (Review).

    Science.gov (United States)

    Sebastian, Sinto; Grammatica, Luciano; Paradiso, Angelo

    2005-12-01

    Oral squamous cell carcinoma (oral cancer) and many squamous cell carcinomas of the head and neck arise as a consequence of multiple molecular events induced by the effects of various carcinogens related to tobacco use, environmental factors, and viruses in some instances (e.g., mucosal oncogenic human papillomaviruses), against a background of inheritable resistance or susceptibility. Consequent genetic damage affects many chromosomes and genes, and it is the accumulation of these changes that appears to lead to carcinoma. Telomere maintenance by telomerase or, in its absence, alternative lengthening of telomeres protect this acquired altered genetic information ensuring immortality without losing eukaryotic linear DNA; when this does not occur DNA is lost and end-replication problems arise. Telomerase is reactivated in 80-90% of cancers thus attracting the attention of pathologists and clinicians who have explored its use as a target for anticancer therapy and to develop better diagnostic and prognostic markers. In the last few years, valuable research from various laboratories has provided major insights into telomerase and telomeres leading to their use as diagnostic and prognostic markers in several types of cancer. Moreover, many strategies have emerged which inhibit this complex enzyme for anticancer therapy and are one step ahead of clinical trials. This review explains the basic biology and the clinical implications of telomerase-based diagnosis and prognosis, the prospects for its use in anticancer therapy, and the limitations it presents in the context of oral cancer.

  5. In vitro reconstitution of the active T. castaneum telomerase.

    Science.gov (United States)

    Schuller, Anthony P; Harkisheimer, Michael J; Skordalakes, Emmanuel

    2011-07-14

    Efforts to isolate the catalytic subunit of telomerase, TERT, in sufficient quantities for structural studies, have been met with limited success for more than a decade. Here, we present methods for the isolation of the recombinant Tribolium castaneum TERT (TcTERT) and the reconstitution of the active T. castaneum telomerase ribonucleoprotein (RNP) complex in vitro. Telomerase is a specialized reverse transcriptase that adds short DNA repeats, called telomeres, to the 3' end of linear chromosomes that serve to protect them from end-to-end fusion and degradation. Following DNA replication, a short segment is lost at the end of the chromosome and without telomerase, cells continue dividing until eventually reaching their Hayflick Limit. Additionally, telomerase is dormant in most somatic cells in adults, but is active in cancer cells where it promotes cell immortality. The minimal telomerase enzyme consists of two core components: the protein subunit (TERT), which comprises the catalytic subunit of the enzyme and an integral RNA component (TER), which contains the template TERT uses to synthesize telomeres. Prior to 2008, only structures for individual telomerase domains had been solved. A major breakthrough in this field came from the determination of the crystal structure of the active, catalytic subunit of T. castaneum telomerase, TcTERT. Here, we present methods for producing large quantities of the active, soluble TcTERT for structural and biochemical studies, and the reconstitution of the telomerase RNP complex in vitro for telomerase activity assays. An overview of the experimental methods used is shown in Figure 1.

  6. DNA damaging bystander signalling from stem cells, cancer cells and fibroblasts after Cr(VI) exposure and its dependence on telomerase

    Energy Technology Data Exchange (ETDEWEB)

    Cogan, Nicola [Bristol Implant Research Centre, University of Bristol, Bristol, BS10 5NB (United Kingdom); Baird, Duncan M. [Department of Pathology School of Medicine, Cardiff University, Henry Wellcome Building for Biomedical Research in Wales, Heath Park, Cardiff, CF14 4XN (United Kingdom); Phillips, Ryan [Bristol Implant Research Centre, University of Bristol, Bristol, BS10 5NB (United Kingdom); Crompton, Lucy A.; Caldwell, Maeve A. [Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, BS1 3NY (United Kingdom); Rubio, Miguel A. [Center of Regenerative Medicine in Barcelona, CMRB Dr. Aiguader, 88, 7th Floor, 08003 Barcelona (Spain); Newson, Roger [Radiation and Environmental Science Centre, Focas Institute, Dublin Institute of Technology, Dublin 2 (Ireland); Lyng, Fiona [National Heart and Lung Institute, Imperial College London, London, SW7 2AZ (United Kingdom); Case, C. Patrick, E-mail: c.p.case@bristol.ac.uk [Bristol Implant Research Centre, University of Bristol, Bristol, BS10 5NB (United Kingdom)

    2010-01-05

    The bystander effect is a feature of low dose radiation exposure and is characterized by a signaling process from irradiated cells to non irradiated cells, which causes DNA and chromosome damage in these 'nearest neighbour' cells. Here we show that a low and short dose of Cr(VI) can induce stem cells, cancer cells and fibroblasts to chronically secrete bystander signals, which cause DNA damage in neighboring cells. The Cr(VI) induced bystander signaling depended on the telomerase status of either cell. Telomerase negative fibroblasts were able to receive DNA damaging signals from telomerase positive or negative fibroblasts or telomerase positive cancer cells. However telomerase positive fibroblasts were resistant to signals from Cr(VI) exposed telomerase positive fibroblasts or cancer cells. Human embryonic stem cells, with positive Oct4 staining as a marker of pluripotency, showed no significant increase of DNA damage from adjacent Cr and mitomycin C exposed fibroblasts whilst those cells that were negatively stained did. This selectivity of DNA damaging bystander signaling could be an important consideration in developing therapies against cancer and in the safety and effectiveness of tissue engineering and transplantation using stem cells.

  7. DNA damaging bystander signalling from stem cells, cancer cells and fibroblasts after Cr(VI) exposure and its dependence on telomerase

    International Nuclear Information System (INIS)

    Cogan, Nicola; Baird, Duncan M.; Phillips, Ryan; Crompton, Lucy A.; Caldwell, Maeve A.; Rubio, Miguel A.; Newson, Roger; Lyng, Fiona; Case, C. Patrick

    2010-01-01

    The bystander effect is a feature of low dose radiation exposure and is characterized by a signaling process from irradiated cells to non irradiated cells, which causes DNA and chromosome damage in these 'nearest neighbour' cells. Here we show that a low and short dose of Cr(VI) can induce stem cells, cancer cells and fibroblasts to chronically secrete bystander signals, which cause DNA damage in neighboring cells. The Cr(VI) induced bystander signaling depended on the telomerase status of either cell. Telomerase negative fibroblasts were able to receive DNA damaging signals from telomerase positive or negative fibroblasts or telomerase positive cancer cells. However telomerase positive fibroblasts were resistant to signals from Cr(VI) exposed telomerase positive fibroblasts or cancer cells. Human embryonic stem cells, with positive Oct4 staining as a marker of pluripotency, showed no significant increase of DNA damage from adjacent Cr and mitomycin C exposed fibroblasts whilst those cells that were negatively stained did. This selectivity of DNA damaging bystander signaling could be an important consideration in developing therapies against cancer and in the safety and effectiveness of tissue engineering and transplantation using stem cells.

  8. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types.

    Science.gov (United States)

    Kilian, A; Bowtell, D D; Abud, H E; Hime, G R; Venter, D J; Keese, P K; Duncan, E L; Reddel, R R; Jefferson, R A

    1997-11-01

    Telomerase is a multicomponent reverse transcriptase enzyme that adds DNA repeats to the ends of chromosomes using its RNA component as a template for synthesis. Telomerase activity is detected in the germline as well as the majority of tumors and immortal cell lines, and at low levels in several types of normal cells. We have cloned a human gene homologous to a protein from Saccharomyces cerevisiae and Euplotes aediculatus that has reverse transcriptase motifs and is thought to be the catalytic subunit of telomerase in those species. This gene is present in the human genome as a single copy sequence with a dominant transcript of approximately 4 kb in a human colon cancer cell line, LIM1215. The cDNA sequence was determined using clones from a LIM1215 cDNA library and by RT-PCR, cRACE and 3'RACE on mRNA from the same source. We show that the gene is expressed in several normal tissues, telomerase-positive post-crisis (immortal) cell lines and various tumors but is not expressed in the majority of normal tissues analyzed, pre-crisis (non-immortal) cells and telomerase-negative immortal (ALT) cell lines. Multiple products were identified by RT-PCR using primers within the reverse transcriptase domain. Sequencing of these products suggests that they arise by alternative splicing. Strikingly, various tumors, cell lines and even normal tissues (colonic crypt and testis) showed considerable differences in the splicing patterns. Alternative splicing of the telomerase catalytic subunit transcript may be important for the regulation of telomerase activity and may give rise to proteins with different biochemical functions.

  9. Telomerase and the search for the end of cancer.

    Science.gov (United States)

    Mocellin, Simone; Pooley, Karen A; Nitti, Donato

    2013-02-01

    Many of the fundamental molecular mechanisms underlying tumor biology remain elusive and, thus, developing specific anticancer therapies remains a challenge. The recently discovered relationships identified among telomeres, telomerase, aging, and cancer have opened a new avenue in tumor biology research that may revolutionize anticancer therapy. This review summarizes the critical aspects of telomerase biology that underpin the development of novel telomerase-targeting therapies for malignant diseases, and special regard is given to the aspects of telomerase that make it such an appealing target, such as the widespread expression of telomerase in cancers. Despite significant progress, issues remain to be addressed before telomerase-based therapies are truly effective and we include critical discussion of the results obtained thus far. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Nutrition and lifestyle in healthy aging: the telomerase challenge.

    Science.gov (United States)

    Boccardi, Virginia; Paolisso, Giuseppe; Mecocci, Patrizia

    2016-01-01

    Nutrition and lifestyle, known to modulate aging process and age-related diseases, might also affect telomerase activity. Short and dysfunctional telomeres rather than average telomere length are associated with longevity in animal models, and their rescue by telomerase maybe sufficient to restore cell and organismal viability. Improving telomerase activation in stem cells and potentially in other cells by diet and lifestyle interventions may represent an intriguing way to promote health-span in humans.

  11. Mechanism of Telomerase Inhibition Using a Small Inhibitory RNAs and Induction of Breast Tumor Cell Sensitization

    Science.gov (United States)

    2007-04-01

    immunoprecipitation; TnT- transcription and translation. References Cited Barik , S. 2004. Control of nonsegmented negative-strand RNA virus replication by siRNA...Virus Res. 102: 27-35. Barquinero, J . et al. 2004. Retroviral vectors: new applications for an old tool. Gene Ther. 11(suppl 1): S3-S9...proteins and heterochromatin. Oncogene. 21: 553-563. Chen, J -L., Blasco, M.A., and Greider, C.W. 2000. Secondary structure of vertebrate telomerase RNA

  12. Identification of Protein Components of Yeast Telomerase

    Science.gov (United States)

    2000-09-01

    cells past this limit senesce, or stop growing (reviewed in Hayflick 1997). This limit is imposed by the inactivity of telomerase, which results in...CLASSIFICATION OF THIS PAGE Unclassified 19. SECURITY CLASSIFICATION OF ABSTRACT Unclassified 15. NUMBER OF PAGES 55 16. PRICE CODE 20. LIMITATION ...one of which is the acquired capability of limitless replicative potential. Normal mammalian cells have an intrinsic limit to cellular division, and

  13. Telomere 1 (POT1) gene expression and its association with telomerase activity in colorectal tumor samples with different pathological features.

    Science.gov (United States)

    Izgi, Ahu; Gunal, Armagan; Yalcin, Serap; Gunduz, Ufuk

    2014-09-01

    The ends of chromosoms, telomeres are bound with a number of proteins which protect and stabilize telomeres against degredation, end to end fusion and aberrant recombinations. Telomeric DNA is bound of two groups of proteins, which are double-stranded telomeric DNA bindings proteins, and single stranded telomeric binding proteins. Among telomere binding proteins, protections of telomere 1 protein is a single stranded telomere binding proteins and suggested to be a significant player for telomere elongation and has an association with an enzyme called as telomerase which is an intrinsic reverse transcriptase. Telomerase synthesizes hexameric telomeric repeats onto the chromosomes thereby compansating telomere loss in immortal cells, such as tumor cells, whereas telomeres are shorthened with each division in normal cells. PCR-based TRAP (telomeric repeat amplification protocol) assay is a very sensitive assay for the detection of enzymatic activity of telomerase even if a few numbers of cancerous cells are available. The association between telomerase activity and hPOT1 expression in colorectal cancer is still unclear. Protein extraction was performed from specimens of matched normal and colorectal cancer specimens. Protein concentrations were determined by Bradford assay. Optimized protein concentrations were used for TRAP Assay. TRAP products were seperated by vertical gel electrophoresis on 12.5% polyacrylamide gels and visualized by silver staining. Gene expression of hPOT1 was determined by qPCR analysis. The results demonstrated that all tumor tissues were telomerase positive whereas all corresponding normal tissue was telomerase negative. Among clinicopathological findings, telomerase activity was found to be associated with stage, histology, localization, distant metastasis and lymph node metastasis of tumor in the current study. Although all of the clinicopathological findings differed in the expression of hPOT1 compared to normal tissues, they did not

  14. Re: Role of Telomeres and Telomerase in Cancer

    Directory of Open Access Journals (Sweden)

    Shay JW

    2016-03-01

    Full Text Available The most important difference between cancer and normall cells is the ability to continuous proliferation. This activation works due to telomeres and telomerase enzyme. Fifty years ago, Leonard Hayflick discovered that cultured normal humans cells have a limited capacity to divide. Today, this withdrawal from the cell cycle after a certain number of cellular divisions (replicative senescence is known to be triggered as a result of shortened telomeres. Studies on telomeres and telomerase have begun to provide additional information about aging and cancer development and have created new opportunities in the field of regenerative medicine for telomeropathies. Progressive telomere shortening from cell division (replicative aging provides a barrier for tumor progression. Continuous cell growth in malignancy correlates with the reactivation of telomerase. Telomerase is a cellular reverse transcriptase that adds new deoxyribonucleic acid (DNA onto the telomeres that are located at the ends of chromosomes. Telomeres consist of many kilobases of TTAGGG nucleotide repeats. The telomeric nucleotide repeats shorten with each cell division due to replication problems (DNA repair and oxidative damage. Quiescent/senescent state of the cell bypass can be accomplished by abrogating cell cycle checkpoint genes (such as TP53, p16INK4a, pRb. Telomerase is detected in approximately 90% of all malignant tumors. This telomerase activation has emerged as a target for cancer treatment. Telomerase therapeutics are classified as gene therapy (hTERT-telomerase catalytic protein component, hTR-telomerase functional, immunotherapy (Imetalstat-telomerase template antagonist, and small molecule inhibitors. In the near future, more specific researches on telomers and telomerase will contribute to aging/immortality studies (as stem cells and to discover new biomarkers for malignant tissue or anticancer therapeutics.

  15. Demonstration of constant upregulation of the telomerase RNA component in human gastric carcinomas using in situ hybridization.

    Science.gov (United States)

    Heine, B; Hummel, M; Demel, G; Stein, H

    1998-06-01

    Upregulation of the ribonucleoprotein telomerase seems to be a prerequisite for immortality, a feature of malignant cells. Using a polymerase chain reaction (PCR)-based assay, it is possible to demonstrate telomerase activity (TA) in specimens of most human malignancies, whereas it is absent from most normal tissues. It remains unclear, however, why between 5 and 50 per cent of various malignant tumour samples give negative results when TA is measured by the telomeric repeat amplification protocol (TRAP). The expectation that reverse transcription (RT)-PCR for detection of the telomerase RNA component (hTR) would be able to complement or to replace the TRAP assay failed, since malignant as well as non-malignant tissue samples gave positive results in most instances. In the present study, in situ hybridization (ISH) was developed to demonstrate the RNA component of human telomerase at the single cell level. With this method, 13 specimens of fresh frozen gastric carcinoma and four of normal, dysplastic, or inflamed gastric mucosa were investigated and the results were compared with those obtained by RT-PCR and the TRAP assay. In addition, ISH was performed on formalin-fixed sections of the same cases. The TRAP assay revealed positive results in 8 out of 13 gastric carcinomas and was negative in all non-malignant tissues. RT-PCR led to amplification of the telomerase RNA component in all specimens tested, irrespective of the presence or absence of malignant cells. By ISH, all gastric carcinomas showed strong telomerase RNA component-specific signals over malignant cells, whereas only a few grains were detectable over some types of normal somatic cells, including activated lymphocytes. In conclusion, high expression of the telomerase RNA component was restricted to the malignant cells of all the gastric carcinomas investigated, as shown by ISH. This indicates that the absence of TA in a proportion of carcinomas is due to methodological problems of the TRAP assay and is

  16. Telomerase Inhibitors from Natural Products and Their Anticancer Potential

    Directory of Open Access Journals (Sweden)

    Kumar Ganesan

    2017-12-01

    Full Text Available Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy—a hallmark of cancer—and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design.

  17. Protein composition of catalytically active human telomerase from immortal cells

    DEFF Research Database (Denmark)

    Cohen, Scott B; Graham, Mark E; Lovrecz, George O

    2007-01-01

    Telomerase is a ribonucleoprotein enzyme complex that adds 5'-TTAGGG-3' repeats onto the ends of human chromosomes, providing a telomere maintenance mechanism for approximately 90% of human cancers. We have purified human telomerase approximately 10(8)-fold, with the final elution dependent on th...

  18. Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers.

    Science.gov (United States)

    Pal, Deeksha; Sharma, Ujjawal; Khajuria, Ragini; Singh, Shrawan Kumar; Kakkar, Nandita; Prasad, Rajendra

    2015-05-15

    In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000) but not with the subtypes of RCC (P = 0.355). Notwithstanding, no correlation was found between telomerase activity and subtypes of RCC. Strikingly, the telomere length was found to be significantly shorter in RCC (P=0.000) to that of corresponding normal renal tissues and it is well correlated with grades (P=0.016) but not with stages (P=0.202) and subtypes (P=0.669) of RCC. In this study, telomere length was also negatively correlated with the age of patients (r(2)=0.528; P=0.000) which supports the notion that it could be used as a marker for biological aging. ALT associated PML bodies containing PML protein was found in telomerase negative cases of RCC. It suggests the presence of an ALT pathway mechanism to maintain the telomere length in telomerase negative RCC tissues which was associated with high stages of RCC, suggesting a prevalent mechanism for telomere maintenance in high stages. In conclusion, the telomerase activity and telomere length can be used as a diagnostic as well as a predictive marker in RCC. The prevalence of ALT mechanism in high stages of RCC is warranted for the development of anti-ALT inhibitors along with telomerase inhibitor against RCC as a therapeutic approach. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. A Smart DNA Tweezer for Detection of Human Telomerase Activity.

    Science.gov (United States)

    Xu, Xiaowen; Wang, Lei; Li, Kan; Huang, Qihong; Jiang, Wei

    2018-03-06

    Reliable and accurate detection of telomerase activity is crucial to better understand its role in cancer cells and to further explore its function in cancer diagnosis and treatment. Here, we construct a smart DNA tweezer (DT) for detection of telomerase activity. The DT is assembled by three specially designed single-stranded oligonucleotides: a central strand dually labeled with donor/acceptor fluorophores and two arm strands containing overhangs complementary to telomerase reaction products (TRPs). It can get closed through hybridization with TRPs and get reopen through strand displacement reaction by TRPs' complementary sequences. First, under the action of telomerase, telomerase binding substrates (TS) are elongated to generate TRPs ended with telomeric repeats (TTAGGG) n . TRPs hybridize with the two arm overhangs cooperatively and strain DT to closed state, inducing an increased fluorescence resonance energy transfer (FRET) efficiency, which is utilized for telomerase activity detection. Second, upon introduction of a removal strand (RS) complementary to TRPs, the closed DT is relaxed to open state via the toehold-mediated strand displacement, inducing a decreased FRET efficiency, which is utilized for determination of TRP length distribution. The detection limit of telomerase activity is equivalent to 141 cells/μL for HeLa cells, and telomerase-active cellular extracts can be differentiated from telomerase-inactive cellular extracts. Furthermore, TRPs owning 1, 2, 3, 4, and ≥5 telomeric repeats are identified to account for 25.6%, 20.5%, 15.7%, 12.5%, and 25.7%, respectively. The proposed strategy will offer a new approach for reliable, accurate detection of telomerase activity and product length distribution for deeper studying its role and function in cancer.

  20. Current Perspectives of Telomerase Structure and Function in Eukaryotes with Emerging Views on Telomerase in Human Parasites.

    Science.gov (United States)

    Dey, Abhishek; Chakrabarti, Kausik

    2018-01-24

    Replicative capacity of a cell is strongly correlated with telomere length regulation. Aberrant lengthening or reduction in the length of telomeres can lead to health anomalies, such as cancer or premature aging. Telomerase is a master regulator for maintaining replicative potential in most eukaryotic cells. It does so by controlling telomere length at chromosome ends. Akin to cancer cells, most single-cell eukaryotic pathogens are highly proliferative and require persistent telomerase activity to maintain constant length of telomere and propagation within their host. Although telomerase is key to unlimited cellular proliferation in both cases, not much was known about the role of telomerase in human parasites (malaria, Trypanosoma , etc.) until recently. Since telomerase regulation is mediated via its own structural components, interactions with catalytic reverse transcriptase and several factors that can recruit and assemble telomerase to telomeres in a cell cycle-dependent manner, we compare and discuss here recent findings in telomerase biology in cancer, aging and parasitic diseases to give a broader perspective of telomerase function in human diseases.

  1. The Emerging Roles for Telomerase in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Meng-Ying Liu

    2018-05-01

    Full Text Available Telomerase, a specialized ribonucleoprotein enzyme complex, maintains telomere length at the 3′ end of chromosomes, and functions importantly in stem cells, cancer and aging. Telomerase exists in neural stem cells (NSCs and neural progenitor cells (NPCs, at a high level in the developing and adult brains of humans and rodents. Increasing studies have demonstrated that telomerase in NSCs/NPCs plays important roles in cell proliferation, neuronal differentiation, neuronal survival and neuritogenesis. In addition, recent works have shown that telomerase reverse transcriptase (TERT can protect newborn neurons from apoptosis and excitotoxicity. However, to date, the link between telomerase and diseases in the central nervous system (CNS is not well reviewed. Here, we analyze the evidence and summarize the important roles of telomerase in the CNS. Understanding the roles of telomerase in the nervous system is not only important to gain further insight into the process of the neural cell life cycle but would also provide novel therapeutic applications in CNS diseases such as neurodegenerative condition, mood disorders, aging and other ailments.

  2. Quantum experiments without classical counterparts

    International Nuclear Information System (INIS)

    Pavicic, M.

    2005-01-01

    Full text: We present a generalized and exhaustive method of finding the directions of the quantization axes of the measured eigenstates within experiments which have no classical counterparts. The method relies on a constructive and exhaustive definition of sets of such directions (which we call Kochen-Specker vectors) in a Hilbert space of any dimension as well as of all the remaining vectors of the space. Kochen-Specker vectors are elements of any set of orthonormal states, i.e., vectors in n-dim Hilbert space, Hn, n > 2 to which it is impossible to assign 1s and 0s in such a way that no two mutually orthogonal vectors from the set are both assigned 1 and that not all mutually orthogonal vectors are assigned 0. Our constructive definition of such Kochen-Specker vectors is based on algorithms that generate MMP diagrams corresponding to blocks of orthogonal vectors in Rn, on algorithms that single out those diagrams on which algebraic to 0-1 states cannot be defined, and on algorithms that solve nonlinear equations describing the orthogonalities of the vectors by means of statistically polynomially complex interval analysis and self-teaching programs. The algorithms are limited neither by the number of dimensions nor by the number of vectors. To demonstrate the power of the algorithms, all 4-dim KS vector systems containing up to 24 vectors were generated and described, all 3-dim vector systems containing up to 30 vectors were scanned, and several general properties of KS vectors were found. (author)

  3. Telomerase level increase is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: Secondary outcome analysis of the OFFER randomized clinical trial.

    Science.gov (United States)

    Pawełczyk, Tomasz; Grancow-Grabka, Marta; Trafalska, Elżbieta; Szemraj, Janusz; Żurner, Natalia; Pawełczyk, Agnieszka

    2018-04-20

    Schizophrenia is associated with shortening of the lifespan mainly due to cardiovascular events, cancer and chronic obstructive pulmonary disease. Both telomere attrition and decrease of telomerase levels were observed in schizophrenia. Polyunsaturated fatty acids (PUFA) influence multiple biochemical mechanisms which are postulated to accelerate telomere shortening and limit the longevity of patients with schizophrenia. Intervention studies based on add-on therapy with n-3 polyunsaturated fatty acids (n-3 PUFA) in patients with schizophrenia did not assess the changes in telomerase levels. A randomized placebo-controlled trial named OFFER was designed to compare the efficacy of a 26-week intervention composed of either 2.2g/day of n-3 PUFA or olive oil placebo with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between the clinical effect of n-3 PUFA and changes in telomerase levels. Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the study arms. The Positive and Negative Syndrome Scale (PANSS) was used to assess the change in symptom severity. Telomerase levels of peripheral blood mononuclear cells (PBMC) were assessed at three points: at baseline and at weeks 8 and 26 of the intervention. A significantly greater increase in PBMC telomerase levels in the intervention group compared to placebo was observed (p<0.001). Changes in telomerase levels significantly and inversely correlated with improvement in depressive symptoms and severity of the illness. The efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to an increase in telomerase levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Tetrahymena telomerase protein p65 induces conformational changes throughout telomerase RNA (TER) and rescues telomerase reverse transcriptase and TER assembly mutants.

    Science.gov (United States)

    Berman, Andrea J; Gooding, Anne R; Cech, Thomas R

    2010-10-01

    The biogenesis of the Tetrahymena telomerase ribonucleoprotein particle (RNP) is enhanced by p65, a La family protein. Single-molecule and biochemical studies have uncovered a hierarchical assembly of the RNP, wherein the binding of p65 to stems I and IV of telomerase RNA (TER) causes a conformational change that facilitates the subsequent binding of telomerase reverse transcriptase (TERT) to TER. We used purified p65 and variants of TERT and TER to investigate the conformational rearrangements that occur during RNP assembly. Nuclease protection assays and mutational analysis revealed that p65 interacts with and stimulates conformational changes in regions of TER beyond stem IV. Several TER mutants exhibited telomerase activity only in the presence of p65, revealing the importance of p65 in promoting the correct RNP assembly pathway. In addition, p65 rescued TERT assembly mutants but not TERT activity mutants. Taken together, these results suggest that p65 stimulates telomerase assembly and activity in two ways. First, by sequestering stems I and IV, p65 limits the ensemble of structural conformations of TER, thereby presenting TERT with the active conformation of TER. Second, p65 acts as a molecular buttress within the assembled RNP, mutually stabilizing TER and TERT in catalytically active conformations.

  5. Detection of telomerase on upconversion nanoparticle modified cellulose paper.

    Science.gov (United States)

    Wang, Faming; Li, Wen; Wang, Jiasi; Ren, Jinsong; Qu, Xiaogang

    2015-07-25

    Herein we report a convenient and sensitive method for the detection of telomerase activity based on upconversion nanoparticle (UCNP) modified cellulose paper. Compared with many solution-phase systems, this paper chip is more stable and easily stores the test results. What's more, the low background fluorescence of the UCNPs increases the sensitivity of this method, and the low telomerase levels in different cell lines can clearly be discriminated by the naked eye.

  6. Clinical Outcomes of Lung Transplantation in Patients with Telomerase Mutations

    Science.gov (United States)

    Tokman, Sofya; Singer, Jonathan P.; Devine, Megan S.; Westall, Glen P.; Aubert, John-David; Tamm, Michael; Snell, Gregory I.; Lee, Joyce S.; Goldberg, Hilary J.; Kukreja, Jasleen; Golden, Jeffrey A.; Leard, Lorriana E.; Garcia, Christine K.; Hays, Steven R.

    2017-01-01

    Background Successful lung transplantation (LT) for patients with pulmonary fibrosis from telomerase mutations is limited by systemic complications of telomerase dysfunction including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes among 14 LT recipients with telomerase mutations. Methods Subjects underwent LT between February 2005 and April 2014 at 5 LT centers. We abstracted data from medical records, focusing on outcomes reflecting post-LT treatment effects likely to be complicated by telomerase mutations. Results The median age of subjects was 60.5 years (IQR 52.0–62.0), 64.3% were male, and the mean post-LT observation time was 3.2 years (SD ±2.9). Eleven subjects had a mutation in telomerase reverse transcriptase, 2 in telomerase RNA component, and 1 had an uncharacterized mutation. Ten subjects were leukopenic post-LT; leukopenia prompted cessation of mycophenolate mofetil in 5 and treatment with filgrastim in 4. Six subjects had recurrent lower respiratory tract infections (LRTI), 7 had acute cellular rejection (ACR) (A1), and 4 developed chronic lung allograft dysfunction (CLAD). Ten LT recipients developed chronic renal insufficiency and 8 experienced acute, reversible renal failure. Three developed cancer, none had cirrhosis. Thirteen subjects were alive at data censorship. Conclusions The clinical course for LT recipients with telomerase mutations is complicated by renal disease, leukopenia prompting a change in the immunosuppressive regimen, and recurrent LTRI. In contrast, cirrhosis was absent, ACR was mild, and development of CLAD was comparable to other LT populations. While posing challenges, lung transplantation may be feasible for patients with pulmonary fibrosis due to telomerase mutations. PMID:26169663

  7. [Telomerase in lung cancer. Testing the activity of the "immortaligy enzyme" bronchial biopsies increases the diagnostic yield in cases of suspected peripheral bronchogenic carcinomas].

    Science.gov (United States)

    Freitag, L; Litterst, P; Obertrifter, B; Velehorschi, V; Kemmer, H P; Linder, A; Brightman, I

    2000-11-01

    The proliferative capability is time-limited in normal somatic cells by the shortening of their chromosomal ends, the telomeres (Hayflick limit). An important feature of malignant cells is their immortality. The probably most common mechanism of tumour cells to achieve unlimited replicability is the activation of the enzyme telomerase. The reverse transcriptase can compensate the loss of telomeres. Using a PCR-based TRAP assay we found telomerase activity in tumour biopsies, exsudates and bronchial washings in various thoracic malignancies. In 38 of 47 patients with suspected peripheral lung cancer eventually surgery or invasive procedures proved a malignancy. In fluoroscopically guided bronchial brushings from 25 of these 38 patients (66%) the TRAP assay revealed telomerase activity. There was a single false positive case (tuberculosis) and with a single exception, the simultaneously taken brushes of the contralateral lobes were all telomerase negative. In 23 patients (61%) tumour cells were found in the cytological examination. In 33 patients at least one marker was positive. Thus the combination of cytology and telomerase test in bronchial brush biopsies attained a diagnostic yield of 87%.

  8. The differentiation status of primary gonadal germ cell tumors correlates inversely with telomerase activity and the expression level of the gene encoding the catalytic subunit of telomerase

    International Nuclear Information System (INIS)

    Schrader, Mark; Burger, Angelika M; Müller, Markus; Krause, Hans; Straub, Bernd; Schostak, Martin; Schulze, Wolfgang; Lauke, Heidrun; Miller, Kurt

    2002-01-01

    The activity of the ribonucleoprotein enzyme telomerase is detectable in germ, stem and tumor cells. One major component of telomerase is human telomerase reverse transcriptase (hTERT), which encodes the catalytic subunit of telomerase. Here we investigate the correlation of telomerase activity and hTERT gene expression and the differentiation status of primary testicular germ cell tumors (TGCT). Telomerase activity (TA) was detected by a quantitative telomerase PCR ELISA, and hTERT mRNA expression was quantified by online RT-PCR in 42 primary testicular germ cell tumors. The control group consisted of benign testicular biopsies from infertile patients. High levels of telomerase activity and hTERT expression were detected in all examined undifferentiated TGCTs and in the benign testicular tissue specimens with germ cell content. In contrast, differentiated teratomas and testicular control tissue without germ cells (Sertoli-cell-only syndrome) showed no telomerase activity and only minimal hTERT expression. These findings demonstrate an inverse relationship between the level of telomerase activity and hTERT mRNA expression and the differentiation state of germ cell tumors. Quantification of telomerase activity and hTERT mRNA expression enables a new molecular-diagnostic subclassification of germ cell tumors that describes their proliferation potential and differentiation status

  9. The differentiation status of primary gonadal germ cell tumors correlates inversely with telomerase activity and the expression level of the gene encoding the catalytic subunit of telomerase

    Directory of Open Access Journals (Sweden)

    Schulze Wolfgang

    2002-11-01

    Full Text Available Abstract Background The activity of the ribonucleoprotein enzyme telomerase is detectable in germ, stem and tumor cells. One major component of telomerase is human telomerase reverse transcriptase (hTERT, which encodes the catalytic subunit of telomerase. Here we investigate the correlation of telomerase activity and hTERT gene expression and the differentiation status of primary testicular germ cell tumors (TGCT. Methods Telomerase activity (TA was detected by a quantitative telomerase PCR ELISA, and hTERT mRNA expression was quantified by online RT-PCR in 42 primary testicular germ cell tumors. The control group consisted of benign testicular biopsies from infertile patients. Results High levels of telomerase activity and hTERT expression were detected in all examined undifferentiated TGCTs and in the benign testicular tissue specimens with germ cell content. In contrast, differentiated teratomas and testicular control tissue without germ cells (Sertoli-cell-only syndrome showed no telomerase activity and only minimal hTERT expression. Conclusions These findings demonstrate an inverse relationship between the level of telomerase activity and hTERT mRNA expression and the differentiation state of germ cell tumors. Quantification of telomerase activity and hTERT mRNA expression enables a new molecular-diagnostic subclassification of germ cell tumors that describes their proliferation potential and differentiation status.

  10. Down-regulation of telomerase activity in DLD-1 human colorectal adenocarcinoma cells by tocotrienol

    International Nuclear Information System (INIS)

    Eitsuka, Takahiro; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2006-01-01

    As high telomerase activity is detected in most cancer cells, inhibition of telomerase by drug or dietary food components is a new strategy for cancer prevention. Here, we investigated the inhibitory effect of vitamin E, with particular emphasis on tocotrienol (unsaturated vitamin E), on human telomerase in cell-culture study. As results, tocotrienol inhibited telomerase activity of DLD-1 human colorectal adenocarcinoma cells in time- and dose-dependent manner, interestingly, with δ-tocotrienol exhibiting the highest inhibitory activity. Tocotrienol inhibited protein kinase C activity, resulting in down-regulation of c-myc and human telomerase reverse transcriptase (hTERT) expression, thereby reducing telomerase activity. In contrast to tocotrienol, tocopherol showed very weak telomerase inhibition. These results provide novel evidence for First time indicating that tocotrienol acts as a potent candidate regulator of telomerase and supporting the anti-proliferative function of tocotrienol

  11. Telomerase activity as a marker for malignancy in feline tissues.

    Science.gov (United States)

    Cadile, C D; Kitchell, B E; Biller, B J; Hetler, E R; Balkin, R G

    2001-10-01

    To establish the diagnostic significance of the telomeric repeat amplification protocol (TRAP) assay in detecting feline malignancies. Solid tissue specimens collected from 33 client-owned cats undergoing diagnostic or therapeutic procedures at the University of Illinois Veterinary Medical Teaching Hospital between July 1997 and September 1999 and an additional 20 tissue samples were collected from 3 clinically normal control cats euthanatized at the conclusion of an unrelated study. The TRAP assay was used for detection of telomerase activity. Each result was compared to its respective histopathologic diagnosis. Twenty-nine of 31 malignant and 1 of 22 benign or normal tissue samples had telomerase activity, indicating 94% sensitivity and 95% specificity of the TRAP assay in our laboratory. The diagnostic significance of telomerase activity has been demonstrated in humans and recently in dogs by our laboratory. We tested feline samples to determine whether similar patterns of telomerase activity exist. On the basis of our results, the TRAP assay may be clinically useful in providing a rapid diagnosis of malignancy in cats. The telomerase enzyme may also serve as a therapeutic target in feline tumors.

  12. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    International Nuclear Information System (INIS)

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo; Yoo, Young-Do; Park, Won-Bong; Cho, Myung-Haing; Park, Gil Hong; Lee, Kee-Ho

    2010-01-01

    Research highlights: → In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. → The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. → The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. → P53 status is not associated with the occurrence of unsensitized clone. → Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC -/- cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC -/- clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  13. Global gene expression response to telomerase in bovine adrenocortical cells

    International Nuclear Information System (INIS)

    Perrault, Steven D.; Hornsby, Peter J.; Betts, Dean H.

    2005-01-01

    The infinite proliferative capability of most immortalized cells is dependent upon the presence of the enzyme telomerase and its ability to maintain telomere length and structure. However, telomerase may be involved in a greater system than telomere length regulation, as recent evidence has shown it capable of increasing wound healing in vivo, and improving cellular proliferation rate and survival from apoptosis in vitro. Here, we describe the global gene expression response to ectopic telomerase expression in an in vitro bovine adrenocortical cell model. Telomerase-immortalized cells showed an increased ability for proliferation and survival in minimal essential medium above cells transgenic for GFP. cDNA microarray analyses revealed an altered cell state indicative of increased adrenocortical cell proliferation regulated by the IGF2 pathway and alterations in members of the TGF-B family. As well, we identified alterations in genes associated with development and wound healing that support a model that high telomerase expression induces a highly adaptable, progenitor-like state

  14. Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe.

    Science.gov (United States)

    Margalef, Pol; Kotsantis, Panagiotis; Borel, Valerie; Bellelli, Roberto; Panier, Stephanie; Boulton, Simon J

    2018-01-25

    Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1 -/- cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  15. The PPARα/p16INK4a Pathway inhibits Vascular Smooth Muscle Cell Proliferation by repressing Cell Cycle-dependent Telomerase Activation

    Science.gov (United States)

    Gizard, Florence; Nomiyama, Takashi; Zhao, Yue; Findeisen, Hannes M.; Heywood, Elizabeth B.; Jones, Karrie L.; Staels, Bart; Bruemmer, Dennis

    2009-01-01

    Peroxisome Proliferator-Activated Receptor (PPAR) α, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARα activation suppresses G1→S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16INK4a (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARα is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARα activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect which was dependent on p16. The inhibition of cell proliferation by PPARα activation was lost in VSMC following TERT overexpression or knock-down, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARα. Finally, we demonstrate that PPARα agonists suppress telomerase activation during the proliferative response following vascular injury indicating that these findings are applicable in vivo. In concert, these results demonstrate that the anti-proliferative effects of PPARα in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade. PMID:18818403

  16. Evidence for ovarian granulosa stem cells: telomerase activity and localization of the telomerase ribonucleic acid component in bovine ovarian follicles.

    Science.gov (United States)

    Lavranos, T C; Mathis, J M; Latham, S E; Kalionis, B; Shay, J W; Rodgers, R J

    1999-08-01

    We have previously postulated that granulosa cells of developing follicles arise from a population of stem cells. Stem cells and cancer cells can divide indefinitely partly because they express telomerase. Telomerase is a ribonucleoprotein enzyme that repairs the ends of telomeres that otherwise shorten progressively upon each successive cell division. In this study we carried out cell cycle analyses and examined telomerase expression to examine our hypothesis. Preantral (60-100 microm) and small (1 mm) follicles, as well as granulosa cells from medium-sized (3 mm) and large (6-8 mm) follicles, were isolated. Cell cycle analyses and expression of Ki-67, a cell cycle-related protein, were undertaken on follicles of each size (n = 3) by flow cytometry; 12% to 16% of granulosa cells in all follicles were in the S phase, and less than 2% were in the G(2)/M phase. Telomerase activity (n = 3) was highest in the small preantral follicles, declining at the 1-mm stage and even further at the 3-mm stage. In situ hybridization histochemistry was carried out on bovine ovaries, and telomerase RNA was detected in the granulosa cells of growing follicles but not primordial follicles. Two major patterns of staining were observed in the membrana granulosa of antral follicles: staining in the middle and antral layers, and staining in the middle and basal layers. No staining was detected in oocytes. Our results strongly support our hypothesis that granulosa cells arise from a population of stem cells.

  17. Telomere stability and telomerase in mesenchymal stem cells

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Graakjaer, Jesper; Kølvrå, Steen

    2008-01-01

    Telomeres are repetitive genetic material that cap and thereby protect the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in high concentrations in the embryonic stem cells and in fast growing...... embryonic cells, and declines with age. It is still unclear to what extent there is telomerase in adult stem cells, but since these are the founder cells of cells of all the tissues in the body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important....... In the present communication we focus on telomere expression and telomere length in stem cells, with a special focus on mesenchymal stem cells. We consider different mechanisms by which stem cells can maintain telomeres and also focus on the dynamics of telomere length in mesenchymal stem cells, both the overall...

  18. Genotoxicity studies on DNA-interactive telomerase inhibitors with application as anti-cancer agents.

    Science.gov (United States)

    Harrington, Dean J; Cemeli, Eduardo; Carder, Joanna; Fearnley, Jamie; Estdale, Sian; Perry, Philip J; Jenkins, Terence C; Anderson, Diana

    2003-01-01

    Telomerase-targeted strategies have aroused recent interest in anti-cancer chemotherapy, because DNA-binding drugs can interact with high-order tetraplex rather than double-stranded (duplex) DNA targets in tumour cells. However, the protracted cell-drug exposure times necessary for clinical application require that telomerase inhibitory efficacy must be accompanied by both low inherent cytotoxicity and the absence of mutagenicity/genotoxicity. For the first time, the genotoxicity of a number of structurally diverse DNA-interactive telomerase inhibitors is examined in the Ames test using six Salmonella typhimurium bacterial strains (TA1535, TA1537, TA1538, TA98, TA100, and TA102). DNA damage induced by each agent was also assessed using the Comet assay with human lymphocytes. The two assay procedures revealed markedly different genotoxicity profiles that are likely to reflect differences in metabolism and/or DNA repair between bacterial and mammalian cells. The mutational spectrum for a biologically active fluorenone derivative, shown to be mutagenic in the TA100 strain, was characterised using a novel and rapid assay method based upon PCR amplification of a fragment of the hisG46 allele, followed by RFLP analysis. Preliminary analysis indicates that the majority (84%) of mutations induced by this compound are C --> A transversions at position 2 of the missense proline codon of the hisG46 allele. However, despite its genotoxic bacterial profile, this fluorenone agent gave a negative response in the Comet assay, and demonstrates how unwanted systemic effects (e.g., cytotoxicity and genotoxicity) can be prevented or ameliorated through suitable molecular fine-tuning of a candidate drug in targeted human tumour cells. Copyright 2003 Wiley-Liss, Inc.

  19. Leptin upregulates telomerase activity and transcription of human telomerase reverse transcriptase in MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Ren, He, E-mail: herenrh@yahoo.com.cn [Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin Medical University Cancer Hospital, Tianjin (China); Zhao, Tiansuo; Wang, Xiuchao; Gao, Chuntao; Wang, Jian; Yu, Ming [Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin Medical University Cancer Hospital, Tianjin (China); Hao, Jihui, E-mail: jihuihao@yahoo.com [Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin Medical University Cancer Hospital, Tianjin (China)

    2010-03-26

    The aim was to analyze the mechanism of leptin-induced activity of telomerase in MCF-7 breast cancer cells. We found that leptin activated telomerase in a dose-dependent manner; leptin upregulated the expression of Human Telomerase Reverse Transcriptase (hTERT) at mRNA and protein levels; blockade of signal transducer and activator of transcription 3 (STAT3) phosphorylation significantly counteracted leptin-induced hTERT transcription and protein expression; chromatin immunoprecipitation analysis showed that leptin enhanced the binding of STAT3 to the hTERT promoter. This study uncovers a new mechanism of the proliferative effect of leptin on breast cancer cells and provides a new explanation of obesity-related breast cancer.

  20. Native gel electrophoresis of human telomerase distinguishes active complexes with or without dyskerin

    Science.gov (United States)

    Gardano, Laura; Holland, Linda; Oulton, Rena; Le Bihan, Thierry; Harrington, Lea

    2012-01-01

    Telomeres, the ends of linear chromosomes, safeguard against genome instability. The enzyme responsible for extension of the telomere 3′ terminus is the ribonucleoprotein telomerase. Whereas telomerase activity can be reconstituted in vitro with only the telomerase RNA (hTR) and telomerase reverse transcriptase (TERT), additional components are required in vivo for enzyme assembly, stability and telomere extension activity. One such associated protein, dyskerin, promotes hTR stability in vivo and is the only component to co-purify with active, endogenous human telomerase. We used oligonucleotide-based affinity purification of hTR followed by native gel electrophoresis and in-gel telomerase activity detection to query the composition of telomerase at different purification stringencies. At low salt concentrations (0.1 M NaCl), affinity-purified telomerase was ‘supershifted’ with an anti-dyskerin antibody, however the association with dyskerin was lost after purification at 0.6 M NaCl, despite the retention of telomerase activity and a comparable yield of hTR. The interaction of purified hTR and dyskerin in vitro displayed a similar salt-sensitive interaction. These results demonstrate that endogenous human telomerase, once assembled and active, does not require dyskerin for catalytic activity. Native gel electrophoresis may prove useful in the characterization of telomerase complexes under various physiological conditions. PMID:22187156

  1. Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype.

    Science.gov (United States)

    Al-Ajmi, Nouf; Saretzki, Gabriele; Miles, Colin; Spyridopoulos, Ioakim

    2014-10-01

    Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC(-/-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT(-/-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA.

    Science.gov (United States)

    Wang, Na; Liu, Tiantian; Sofiadis, Anastasios; Juhlin, C Christofer; Zedenius, Jan; Höög, Anders; Larsson, Catharina; Xu, Dawei

    2014-10-01

    The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis. The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit. The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival. TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup. © 2014 American Cancer Society.

  3. Expression of telomerase reverse transcriptase in radiation-induced chronic human skin ulcer

    International Nuclear Information System (INIS)

    Zhao Po; Li Zhijun; Lu Yali; Zhong Mei; Gu Qingyang; Wang Dewen

    2001-01-01

    Objective: To investigate the expression of the catalytic subunit of telomerase, telomerase reverse transcriptase (TRT) and the possible relationship between the TRT and cancer transformation or poor healing in radiation-induced chronic ulcer of human skin. Methods: Rabbit antibody against human TRT and SP immunohistochemical method were used to detect TRT expression in 24 cases of formalin-fixed, paraffin-embed human skin chronic ulcer tissues induced by radiation, 5 cases of normal skin, 2 of burned skin, and 8 of carcinoma. Results: The positive rate for TRT was 58.3%(14/24) in chronic radiation ulcers, of which the strongly positive rate was 41.7%(10/24) and the weakly positive 16.7%(4/24), 0% in normal (0/5) and burned skin (0/2), and 100% in carcinoma (8/8). The strongly positive expression of TRT was observed almost always in the cytoplasm and nucleus of squamous epithelial cells of proliferative epidermis but the negative and partly weakly positive expression in the smooth muscles, endothelia of small blood vessels and capillaries, and fibroblasts. Chronic inflammtory cells, plasmacytes and lymphocytes also showed weakly positive for TRT. Conclusion: TRT expression could be involved in the malignant transformation of chronic radiation ulcer into squamous carcinoma, and in the poor healing caused by sclerosis of small blood vessels and lack of granulation tissue consisting of capillaries and fibroblasts

  4. Telomerase levels control the lifespan of human T lymphocytes

    NARCIS (Netherlands)

    Roth, Alexander; Yssel, Hans; Pene, Jerome; Chavez, Elizabeth A.; Schertzer, Mike; Lansdorp, Peter M.; Spits, Hergen; Luiten, Rosalie M.

    2003-01-01

    The loss of telomeric DNA with each cell division contributes to the limited replicative lifespan of human T lymphocytes. Although telomerase is transiently expressed in T lymphocytes upon activation, it is insufficient to confer immortality. We have previously shown that immortalization of human

  5. The inhibitory effect of Curcuma longa extract on telomerase activity ...

    African Journals Online (AJOL)

    Telomerase is reactivated in lung cancer cells, the most prevalent cancer worldwide, but not normal cells. Therefore, targeting it, preferably with natural compounds derive from medicinal plant such as curcumin, could have important effect on treatment of lung cancer. Curcumin, derived from Curcuma longa rhizome, has ...

  6. Telomerase activity and apoptosis genes as parameters of ...

    African Journals Online (AJOL)

    Ekram Abdel-Salam

    2013-01-23

    Jan 23, 2013 ... ORIGINAL ARTICLE. Telomerase ... The Egyptian Journal of Medical Human Genetics www.ejmhg.eg.net ... membrane protein that belongs to the tumor necrosis factor superfamily and ... revision of the 1975 Helsinki Declaration. Methods ... Determination of Soluble Fas was in duplicate plasma sam- ples.

  7. β-Cyclodextrin-curcumin complex inhibit telomerase gene ...

    African Journals Online (AJOL)

    Yomi

    2011-12-21

    Dec 21, 2011 ... have various applications in cancer therapy. But, its low water solubility and bioavailability is possible for poor drug delivery of curcumin. In this study, we prepared β-cyclodextrin-curcumin complex to determine the inhibitory effect of this drug on telomerase gene expression. Curcumin was encapsulated.

  8. Urine Telomerase for Diagnosis and Surveillance of Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Angela Lamarca

    2012-01-01

    Full Text Available Bladder cancer has increased incidence during last decades. For those patients with nonmuscle involved tumors, noninvasive diagnosis test and surveillance methods must be designed to avoid current cystoscopies that nowadays are done regularly in a lot of patients. Novel urine biomarkers have been developed during last years. Telomerase is important in cancer biology, improving the division capacity of cancer cells. Even urinary telomerase could be a potentially useful urinary tumor marker; its use for diagnosis of asymptomatic and symptomatic patients or its impact during surveillance is still unknown. Moreover, there will need to be uniformity and standardization in the assays before it can become useful in clinical practice. It does not seem to exist a real difference between the most classical assays for the detection of urine telomerase (TRAP and hTERT. However, the new detection methods with modified TeloTAGGG telomerase or with gold nanoparticles must also be taken into consideration for the correct development of this diagnosis method. Maybe the target population would be the high-risk groups within screening programs. To date there is no enough evidence to use it alone and to eliminate cystoscopies from the diagnosis and surveillance of these patients. The combination with cytology or FISH is still preferred.

  9. TRAPping telomerase within the intestinal stem cell niche

    OpenAIRE

    Pech, Matthew F; Artandi, Steven E

    2011-01-01

    Recent work from Hans Clevers' lab reveals high telomerase activity and telomere length in dividing LGR5-positive intestinal stem cells. They further report random chromosome segregation and thus challenge the ‘immortal strand' hypothesis at least for this stem cell population.

  10. P. berghei telomerase subunit TERT is essential for parasite survival.

    Directory of Open Access Journals (Sweden)

    Agnieszka A Religa

    Full Text Available Telomeres define the ends of chromosomes protecting eukaryotic cells from chromosome instability and eventual cell death. The complex regulation of telomeres involves various proteins including telomerase, which is a specialized ribonucleoprotein responsible for telomere maintenance. Telomeres of chromosomes of malaria parasites are kept at a constant length during blood stage proliferation. The 7-bp telomere repeat sequence is universal across different Plasmodium species (GGGTTT/CA, though the average telomere length varies. The catalytic subunit of telomerase, telomerase reverse transcriptase (TERT, is present in all sequenced Plasmodium species and is approximately three times larger than other eukaryotic TERTs. The Plasmodium RNA component of TERT has recently been identified in silico. A strategy to delete the gene encoding TERT via double cross-over (DXO homologous recombination was undertaken to study the telomerase function in P. berghei. Expression of both TERT and the RNA component (TR in P. berghei blood stages was analysed by Western blotting and Northern analysis. Average telomere length was measured in several Plasmodium species using Telomere Restriction Fragment (TRF analysis. TERT and TR were detected in blood stages and an average telomere length of ∼ 950 bp established. Deletion of the tert gene was performed using standard transfection methodologies and we show the presence of tert- mutants in the transfected parasite populations. Cloning of tert- mutants has been attempted multiple times without success. Thorough analysis of the transfected parasite populations and the parasite obtained from extensive parasite cloning from these populations provide evidence for a so called delayed death phenotype as observed in different organisms lacking TERT. The findings indicate that TERT is essential for P. berghei cell survival. The study extends our current knowledge on telomere biology in malaria parasites and validates further

  11. Modulation of Telomerase Activity in Cancer Cells by Dietary Compounds: A Review

    Directory of Open Access Journals (Sweden)

    Takahiro Eitsuka

    2018-02-01

    Full Text Available Telomerase is expressed in ~90% of human cancer cell lines and tumor specimens, whereas its enzymatic activity is not detectable in most human somatic cells, suggesting that telomerase represents a highly attractive target for selective cancer treatment. Accordingly, various classes of telomerase inhibitors have been screened and developed in recent years. We and other researchers have successfully found that some dietary compounds can modulate telomerase activity in cancer cells. Telomerase inhibitors derived from food are subdivided into two groups: one group directly blocks the enzymatic activity of telomerase (e.g., catechin and sulfoquinovosyldiacylglycerol, and the other downregulates the expression of human telomerase reverse transcriptase (hTERT, the catalytic subunit of human telomerase, via signal transduction pathways (e.g., retinoic acid and tocotrienol. In contrast, a few dietary components, including genistein and glycated lipid, induce cellular telomerase activity in several types of cancer cells, suggesting that they may be involved in tumor progression. This review summarizes the current knowledge about the effects of dietary factors on telomerase regulation in cancer cells and discusses their molecular mechanisms of action.

  12. The influence of the telomere-telomerase system on diabetes mellitus and its vascular complications.

    Science.gov (United States)

    Qi Nan, Wu; Ling, Zhang; Bing, Chen

    2015-06-01

    The telomere-telomerase system plays an important role in the pathogenesis and disease progression of diabetes mellitus as well as in its vascular complications. Recent studies suggest that telomere shortening and abnormal telomerase activity occur in patients with diabetes mellitus, and targeting the telomere-telomerase system has become a prospective treatment for diabetes mellitus and its vascular complications. This review highlights the significance of the telomere-telomerase system and supports its role as a possible therapeutic target for patients with diabetes mellitus and its vascular complications Areas covered: This review covers the advances in understanding the telomere-telomerase system over the last 30 years and its significance in diabetes mellitus. In addition, it provides knowledge regarding the significance of the telomere-telomerase system in diabetes mellitus and its vascular complications as well as its role and mechanisms in oxidative stress, cell therapy and antioxidant activity Expert opinion: The telomere-telomerase system may be a potential therapeutic target that can protect against DNA damage and apoptosis in patients with diabetes mellitus and its vascular complications. DNA damage and apoptosis are associated with oxidative stress and are involved in the dysfunction of pancreatic β cells, insulin resistance, and its vascular complications. Abnormalities in the telomere-telomerase system may be associated with diabetes mellitus and its vascular complications. Therapies targeting telomere-telomerase system, telomerase reverse transcriptase transfection and alterative telomere lengthening must be identified before gene therapy can commence.

  13. The AAA-ATPase NVL2 is a telomerase component essential for holoenzyme assembly

    Energy Technology Data Exchange (ETDEWEB)

    Her, Joonyoung [Departments of Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749 (Korea, Republic of); Chung, In Kwon, E-mail: topoviro@yonsei.ac.kr [Departments of Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2012-01-20

    Highlights: Black-Right-Pointing-Pointer Identification of the AAA-ATPase NVL2 as a novel hTERT-interacting protein. Black-Right-Pointing-Pointer NVL2 associates with catalytically active telomerase via an interaction with hTERT. Black-Right-Pointing-Pointer NVL2 is a telomerase component essential for holoenzyme assembly. Black-Right-Pointing-Pointer ATP-binding activity of NVL2 is required for hTERT binding and telomerase assembly. -- Abstract: Continued cell proliferation requires telomerase to maintain functional telomeres that are essential for chromosome integrity. Although the core enzyme includes a telomerase reverse transcriptase (TERT) and a telomerase RNA component (TERC), a number of auxiliary proteins have been identified to regulate telomerase assembly, localization, and enzymatic activity. Here we describe the characterization of the AAA-ATPase NVL2 as a novel hTERT-interacting protein. NVL2 interacts and co-localizes with hTERT in the nucleolus. NLV2 is also found in association with catalytically competent telomerase in cell lysates through an interaction with hTERT. Depletion of endogenous NVL2 by small interfering RNA led to a decrease in hTERT without affecting the steady-state levels of hTERT mRNA, thereby reducing telomerase activity, suggesting that NVL2 is an essential component of the telomerase holoenzyme. We also found that ATP-binding activity of NVL2 is required for hTERT binding as well as telomerase assembly. Our findings suggest that NVL2, in addition to its role in ribosome biosynthesis, is essential for telomerase biogenesis and provides an alternative approach for inhibiting telomerase activity in cancer.

  14. ACCOUNTING TREATMENTS SPECIFIC TO COUNTERPART COMMERCIAL TRANSACTIONS

    Directory of Open Access Journals (Sweden)

    Lucia PALIU - POPA

    2010-12-01

    Full Text Available Given the lack of availability of funds in foreign currency, felt in many countries, especially in the developing and developed countries and the economic or financial crisis in the global foreign exchange, counterpart commercial transactions were imposed as a “disarming” condition of the international trade. In the counterpart a purchase transaction is combined with a sale transaction, an import with an export in order to ensure balanced trade between the partners, trade that involves eliminating or reducing the currency as a payment source and its replacement with trade of goods and services. Thus, in the context of an acute need to export of greatly industrialized countries, where the overproduction phenomenon tends to have a chronic character, the counterpart has become a highly complex and sustainable phenomenon, which has seen a steady increase in the volume of amounts, with a geographical area and large variety of forms and mechanisms of implementation. Based on the characteristics and structure of counterpart transactions, we shall describe in this paper the accounting models specific to international trade, as part of the combined foreign trade transactions without neglecting the tax treatments that influence the entry in the accounts

  15. Serum telomerase levels in smokers and smokeless tobacco users as Maras powder.

    Science.gov (United States)

    Bozkuş, Fulsen; Atilla, Nurhan; Şimşek, Seçil; Kurutaş, Ergül; Samur, Anıl; Arpağ, Hüseyin; Kahraman, Hasan

    2017-09-01

    To the best of our knowledge, no previous study regarding the serum telomerase levels in Maras powder users (MPUs) has been founded. The aim of the current study was to investigate serum telomerase levels in smokers and MPUs. The study was carried out with 98 patients (36 MPUs, 32 smokers and 30 non-smokers). Blood samples were collected, and after having measured the serum telomerase and malondialdehyde (MDA) levels of the patients, comparison were made between the groups. It has been observed that the serum telomerase and MDA levels of smokers (pnon-smoker control subjects. In addition, the levels of serum telomerase and MDA were observed to be higher in the MPU group compared to those of the smoker group (psmokers. In this context, it may be useful to further measure and assess telomerase activity in such patients in order to better determine the harmful effects associated with these habits.

  16. Telomerase as a potential anticancer target: growth inhibition and genomic instability.

    Science.gov (United States)

    Faraoni, Isabella; Graziani, Grazia

    2000-02-01

    Stabilization of telomere length in chromosomes by an RNA-dependent DNA polymerase (telomerase) appears to be responsible for the replicative immortality of cancer cells. These findings provide the rational basis for generating experimental models to develop anti-telomerase drugs. However, there is conflicting evidence in the literature about the outcome of telomerase inhibition. While tumor cytostatic and cytotoxic effects associated with telomerase inhibition have been described, absence of telomerase has been associated with genetic instability and tumor development. Therefore, a therapeutic strategy based on telomerase inhibition will likely have to cope with problems related to innate or acquired mechanisms of drug resistance and possibly to therapy-related tumors. Copyright 2000 Harcourt Publishers Ltd.

  17. Electromagnetic Counterparts to Black Hole Mergers

    Science.gov (United States)

    Schnittman, Jeremy D.

    2011-01-01

    During the final moments of a binary black hole (BH) merger, the gravitational wave (GW) luminosity of the system is greater than the combined electromagnetic (EM) output of the entire observable universe. However, the extremely weak coupling between GWs and ordinary matter makes these waves very difficult to detect directly. Fortunately, the inspirating BH system will interact strongly-on a purely Newtonian level-with any surrounding material in the host galaxy, and this matter can in turn produce unique EM signals detectable at Earth. By identifying EM counterparts to GW sources, we will be able to study the host environments of the merging BHs, in turn greatly expanding the scientific yield of a mission like LISA. Here we present a comprehensive review of the recent literature on the subject of EM counterparts, as well as a discussion of the theoretical and observational advances required to fully realize the scientific potential of the field.

  18. Biological formal counterparts of logical machines

    Energy Technology Data Exchange (ETDEWEB)

    Moreno-diaz, R; Hernandez Guarch, F

    1983-01-01

    The significance of the McCulloch-Pitts formal neural net theory (1943) is still nowadays frequently misunderstood, and their basic units are wrongly considered as factual models for neurons. As a consequence, the whole original theory and its later addenda are unreasonably criticized for their simplicity. But, as it was proved then and since, the theory is after the modular neurophysiological counterpart of logical machines, so that it actually provides biologically plausible models for automata, turing machines, etc., and not vice versa. In its true context, no theory has surpassed its proposals. In McCulloch and Pitts memoriam and for the sake of future theoretical research, the authors stress this important historical point, including also some recent results on the neurophysiological counterparts of modular arbitrary probabilistic automata. 16 references.

  19. Telomerase activity in patients with stage 2–5D chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Veysel Kidir

    2017-11-01

    Full Text Available Background: Molecular mechanisms of increased cardiovascular mortality in chronic kidney disease (CKD associated with biological age are not well understood. Recent studies support the hypothesis that common factors responsible for this phenomenon are cellular aging and telomere dysfunction. Objectives: The purpose of this study was to investigate the relation between telomerase activity and CKD stages. Methods: The study included 120 patients who were followed-up for CKD stage 2–5D, composed of 30 patients of each stage and 30 healthy volunteers without any known disease who were admitted to our hospital for routine check-ups. Telomerase activity in peripheral blood mononuclear cells (PBMC was measured using the TRAP assay. Results: A significant difference was observed for telomerase activity in PBMC between groups. The detected levels were lowest in the healthy control group (0.15 ± 0.02, and highest in CKD stage 5D patients (0.23 ± 0.04. In CKD patients, telomerase activity in PBMC was positively correlated with the CKD stage, serum creatinine, potassium and parathormone levels, and negatively correlated with estimated glomerular filtration rate (eGFR, body mass index (BMI, platelet count and serum calcium levels. According to the linear regression analysis, independent predictors for high telomerase activity in CKD patients were eGFR and BMI. Conclusion: Telomerase activity in PBMC increases with advancing CKD stage in CKD patients. Increased telomerase activity in PBMC is associated with eGFR and BMI. Resumen: Antecedentes: Los mecanismos moleculares responsables del aumento de la mortalidad cardiovascular en la enfermedad renal crónica (ERC asociada a la edad biológica no se conocen bien. Los estudios recientes apoyan la hipótesis de que los factores comunes responsables de este fenómeno son el envejecimiento celular y la disfunción telomérica. Objetivos: El objetivo de este estudio fue investigar

  20. Detection of telomerase activity in Plasmodium falciparum using a nonradioactive method

    Directory of Open Access Journals (Sweden)

    Rubiano Claudia C

    2003-01-01

    Full Text Available A simple, quick and sensitive method was used to detect telomerase activity in Plasmodium falciparum. The telomeric repeat amplification protocol (TRAP assay was modified using electrophoresis and staining with SYBR-green I to detect telomerase activity in a range of 10² to 10(7 parasites. This might be a useful way to ascertain telomerase activity in different types of nontumor cells.

  1. A telomerase em células-tronco hematopoéticas Telomerase in hematopoietic stem cells

    Directory of Open Access Journals (Sweden)

    Silvana Perini

    2008-02-01

    Full Text Available A proliferação das células-tronco hematopoéticas sofre a perda dos telômeros a cada divisão celular. Alguns autores discordam quanto à perda ou não do potencial proliferativo e capacidade de auto-renovação das células mais diferenciadas. Revisaremos aqui o papel da telomerase na biologia do sistema hematopoético, na diferenciação normal ou maligna, assim como no envelhecimento das células-tronco hematopoéticas. A constante renovação celular requerida pela hematopoese confere às células-tronco embrionárias, assim como à maioria das células tumorais, um aumento da capacidade proliferativa marcada pela detecção da enzima telomerase e possível manutenção dos telômeros. Estudos clínicos se farão necessários para esclarecer melhor a atividade da telomerase em células-tronco hematopoéticas, seu possível uso como marcador de diagnóstico e seu uso a fim de propósitos prognósticos.Hematopoietic stem cell proliferation leads to telomere length decreases at each cellular division. Some authors disagree about the telomere influence on the reduction of the proliferative potential and capacity of self renewal. Here we review telomerase function in the biology of the hematopoietic system, in normal or differentiation and its influence on the ageing of hematopoietic stem cells. The constant cellular renewal required to maintain the hematopoietic system, provides embryonic stem cells, as well as malignant cells, an increased proliferative capacity. This is marked by the detection of telomerase enzyme activity and possible telomere maintenance. Clinical trials will be required to clarify telomerase activity in hematopoietic stem cells, its possible use as a diagnostic marker and its use for prognostic purposes.

  2. Correlation between telomerase activity and matrix metalloproteinases 2 expression in gastric cancer.

    Science.gov (United States)

    Wang, Gang; Wang, Wenling; Zhou, Jianjiang; Yang, Xiaofeng

    2013-01-01

    To investigate the relationship between telomerase activity (TA) and matrix metallo proteinases 2 (MMP-2) on malignant behavior and prognosis predictable value in gastric cancer. Telomerase activity and MMP-2 protein expressions were tested in 40 gastric surgical resected cancer samples and the clinicopathological data of enrolled patients were obtained to get correlation analysis results. The expression of telomerase was up-regulated with infiltrating depth, lymph node metastasis and stage (P correlated with infiltrating depth (P < 0.05). Combined detections of telomerase activity and MMP2 protein could identify patients at high risk in disease recurrence and prognosis more efficiently.

  3. Ciliate telomerase RNA loop IV nucleotides promote hierarchical RNP assembly and holoenzyme stability.

    Science.gov (United States)

    Robart, Aaron R; O'Connor, Catherine M; Collins, Kathleen

    2010-03-01

    Telomerase adds simple-sequence repeats to chromosome 3' ends to compensate for the loss of repeats with each round of genome replication. To accomplish this de novo DNA synthesis, telomerase uses a template within its integral RNA component. In addition to providing the template, the telomerase RNA subunit (TER) also harbors nontemplate motifs that contribute to the specialized telomerase catalytic cycle of reiterative repeat synthesis. Most nontemplate TER motifs function through linkage with the template, but in ciliate and vertebrate telomerases, a stem-loop motif binds telomerase reverse transcriptase (TERT) and reconstitutes full activity of the minimal recombinant TERT+TER RNP, even when physically separated from the template. Here, we resolve the functional requirements for this motif of ciliate TER in physiological RNP context using the Tetrahymena thermophila p65-TER-TERT core RNP reconstituted in vitro and the holoenzyme reconstituted in vivo. Contrary to expectation based on assays of the minimal recombinant RNP, we find that none of a panel of individual loop IV nucleotide substitutions impacts the profile of telomerase product synthesis when reconstituted as physiological core RNP or holoenzyme RNP. However, loop IV nucleotide substitutions do variably reduce assembly of TERT with the p65-TER complex in vitro and reduce the accumulation and stability of telomerase RNP in endogenous holoenzyme context. Our results point to a unifying model of a conformational activation role for this TER motif in the telomerase RNP enzyme.

  4. Detection of telomerase activity by the TRAP assay and its variants and alternatives.

    Science.gov (United States)

    Fajkus, Jirí

    2006-09-01

    Telomerase activity is closely connected to problems of cellular immortality, proliferative capacity, differentiation, cancer and aging. Correspondingly, techniques for its detection have been essential for progress in telomere biology and are of still increasing importance in molecular diagnostics and therapy of cancer. This article reviews the development of the telomere repeat amplification protocol (TRAP) and its various modifications as the most widespread assay to detect and measure telomerase activity. Alternative possibilities of telomerase activity detection are also discussed which make it possible to omit the PCR-mediated amplification of telomerase products. These approaches are based on recent advances in highly sensitive detection systems.

  5. Activity of telomerase and telomeric length in Aphis mellifera

    Czech Academy of Sciences Publication Activity Database

    Korandová, Michala; Čapková Frydrychová, Radmila

    2016-01-01

    Roč. 125, č. 3 (2016), s. 405-411 ISSN 0009-5915 R&D Projects: GA ČR GA14-07172S Grant - others:GA JU(CZ) 052/2013/P; European Union Seventh Framework(CZ) 316304 Program:FP7 Institutional support: RVO:60077344 Keywords : telomere * telomerase * Apis mellifera Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.414, year: 2016

  6. Targeting telomerase and DNA repair in human cancers

    International Nuclear Information System (INIS)

    Prakash Hande, M.

    2014-01-01

    Telomerase reactivation is essential for telomere maintenance in human cancer cells ensuring indefinite proliferation. Targeting telomere homeostasis has become one of the promising strategies in the therapeutic management of tumours. One major potential drawback, however, is the time lag between telomerase inhibition and critically shortened telomeres triggering cell death, allowing cancer cells to acquire drug resistance. Numerous studies over the last decade have highlighted the role of DNA repair proteins such as Poly (ADP-Ribose) Polymerase-1 (PARP-1), and DNA-dependent protein kinase (DNA-PKcs) in the maintenance of telomere homoeostasis. Dysfunctional telomeres, resulting from the loss of telomeric DNA repeats or the loss of function of telomere-associated proteins trigger DNA damage responses similar to that observed for double strand breaks. We have been working on unravelling such synthetic lethality in cancer cells and this talk would be on one such recently concluded study that demonstrates that inhibition of DNA repair pathways, i.e., NHEJ pathway and that of telomerase could be an alternative strategy to enhance anti-tumour effects and circumvent the possibility of drug resistance. (author)

  7. Telomerase activity-independent function of telomerase reverse transcriptase is involved in acrylamide-induced neuron damage.

    Science.gov (United States)

    Zhang, P; Pan, H; Wang, J; Liu, X; Hu, X

    2014-07-01

    Polyacrylamide is used widely in industry, and its decomposition product, acrylamide (ACR), readily finds its way into commonly consumed cosmetics and baked and fried foods. ACR exerts potent neurotoxic effects in human and animal models. Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, traditionally has been considered to play an important role in maintaining telomere length. Emerging evidence has shown, however, that TERT plays an important role in neuroprotection by inhibiting apoptosis and excitotoxicity, and by promoting angiogenesis, neuronal survival and neurogenesis, which are closely related to the telomere-independent functions of TERT. We investigated whether and how the TERT pathway is involved in ACR induced neurotoxicity in rat cortical neurons. We found that ACR 1) significantly reduced the viability of cortical neurons as measured by MTT assay, 2) induced neuron apoptosis as revealed by FITC-conjugated Annexin V/PI double staining and flow cytometry (FACS) analysis, 3) elevated expression of cleaved caspase-3, and 4) decreased bcl-2 expression of cortical neurons. ACR also increased intracellular ROS levels in cortical neurons, increased MDA levels and reduced GSH, SOD and GSH-Px levels in mitochondria in a dose-dependent manner. We found that TERT expression in mitochondria was increased by ACR at concentrations of 2.5 and 5.0 mM, but TERT expression was decreased by 10 mM ACR. Telomerase activity, however, was undetectable in rat cortical neurons. Our results suggest that the TERT pathway is involved in ACR induced apoptosis of cortical neurons. TERT also may exert its neuroprotective role in a telomerase activity-independent way, especially in mitochondria.

  8. Gamma Ray Bursts-Afterglows and Counterparts

    Science.gov (United States)

    Fishman, Gerald J

    1998-01-01

    Several breakthrough discoveries were made last year of x-ray, optical and radio afterglows and counterparts to gamma-ray bursts, and a redshift has been associated with at least one of these. These discoveries were made possible by the fast, accurate gamma-ray burst locations of the BeppoSAX satellite. It is now generally believed that the burst sources are at cosmological distances and that they represent the most powerful explosions in the Universe. These observations also open new possibilities for the study of early star formation, the physics of extreme conditions and perhaps even cosmology. This session will concentrate on recent x-ray, optical and radio afterglow observations of gamma-ray bursts, associated redshift measurements, and counterpart observations. Several review and theory talks will also be presented, along with a summary of the astrophysical implications of the observations. There will be additional poster contributions on observations of gamma-ray burst source locations at wavelengths other than gamma rays. Posters are also solicited that describe new observational capabilities for rapid follow-up observations of gamma-ray bursts.

  9. Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas.

    Directory of Open Access Journals (Sweden)

    Yuwei Zhang

    Full Text Available Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT and telomerase RNA component (TERC in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability.Sequencing analysis revealed one deletion involving TERC (TERC del 341-360, and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous; A1062T (4 heterozygous]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01. Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-β-catenin complex, markedly depleted β-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs following Zeocin

  10. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy

    DEFF Research Database (Denmark)

    Bruedigam, Claudia; Bagger, Frederik Otzen; Heidel, Florian H.

    2014-01-01

    (-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia...... progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs....

  11. Improved Inhibition of Telomerase by Short Twisted Intercalating Nucleic Acids under Molecular Crowding Conditions

    DEFF Research Database (Denmark)

    Agarwal, Tani; Pradhan, Devranjan; Géci, Imrich

    2012-01-01

    Human telomeric DNA has the ability to fold into a 4-stranded G-quadruplex structure. Several G-quadruplex ligands are known to stabilize the structure and thereby inhibit telomerase activity. Such ligands have demonstrated efficient telomerase inhibition in dilute conditions, but under molecular...

  12. Downregulation of telomerase activity in human promyelocytic cell line using RNA interference.

    Science.gov (United States)

    Miri-Moghaddam, E; Deezagi, A; Soheili, Z S

    2009-12-01

    Telomerase is a ribonucleoprotein complex. It consists of two main components, human telomerase reverse transcriptase (hTERT) and human telomerase RNA. High telomerase activity is present in most malignant cells, but it is barely detectable in majority of somatic cells. The direct correlation between telomerase reactivation and carcinogens has made hTERT a key target for anticancer therapeutic studies. In this study, for the first time, we evaluated the ability of the new generation of short interfering RNA (siRNA) to regulate telomerase activity in the human promyelocytic leukemia cell line (HL-60). Transient transfection cell line by hTERT siRNAs resulted in statistically significant suppression of hTERT messenger RNAs which were detected by quantitative real-time polymerase chain reaction, while the expressed hTERT protein levels were measured by flow cytometry. The results of telomeric repeat amplification protocol showed that telomerase activity was significantly reduced upon transfection of the HL-60 cell line with hTERT siRNAs. The results of this study showed that telomerase activity and cell proliferation were efficiently inhibited in the hTERT siRNA-treated leukemic cell line.

  13. Progressive Increase in Telomerase Activity From Benign Melanocytic Conditions to Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Ruben D. Ramirez

    1999-04-01

    Full Text Available The expression of telomerase activity and the in situ localization of the human telomerase RNA component (hTR in melanocytic skin lesions was evaluated in specimens from sixty-three patients. Specimens of melanocytic nevi, primary melanomas and subcutaneous metastases of melanoma were obtained from fifty-eight patients, whereas metastasized lymph nodes were obtained from five patients. Telomerase activity was determined in these specimens by using a Polymerase Chain Reaction—based assay (TRAP. High relative mean telomerase activity levels were detected in metastatic melanoma (subcutaneous metastasess = 54.5, lymph node metastasess = 56.5. Much lower levels were detected in primary melanomas, which increased with advancing levels of tumor cell penetration (Clark II = 0.02, Clark III = 1.1, and Clark IV = 1.9. Twenty-six formalin-fixed, paraffin-embedded melanocytic lesions were sectioned and analyzed for telomerase RNA with a radioactive in situ hybridization assay. In situ hybridization studies with a probe to the template RNA component of telomerase confirmed that expression was almost exclusively confined to tumor cells and not infiltrating lymphocytes. These results indicate that levels of telomerase activity and telomerase RNA in melanocytic lesions correlate well with clinical stage and could potentially assist in the diagnosis of borderline lesions.

  14. Quantitative and qualitative analysis of telomerase activity in benign and malignant thyroid tissues

    International Nuclear Information System (INIS)

    Zheng Rongxiu; Fang Peihua; Tan Jian; Lu Mei; Li Yigong

    2002-01-01

    Objective: To study the status of telomerase activity during the development of thyroid tumors, and to determine whether telomerase activity can be used clinically as a molecular marker in the differential diagnosis of thyroid cancer. Methods: Telomerase activity was measured in 37 thyroid carcinomas, 33 benign thyroid lesions and 30 normal thyroid tissue samples by means of a modified TRAP-PCR. The assay was also applied to 15 fine needle aspirates (FNAs) of thyroid carcinomas to test its sensitivity. Results: Thirty-one of 37 thyroid carcinomas (83.8%), 7 of 33 benign thyroid lesions (21.2%), and 4 of 30 adjacent normal thyroid tissue samples expressed telomerase activity, 15 FNAs also had positive telomerase activity, just as their corresponding tissue specimens. The quantitative analysis showed that the telomerase activity was significantly higher in thyroid carcinomas than that in benign thyroid tissue samples. And medullary carcinomas and anaplastic carcinomas had higher levels of telomerase activity than papillary carcinomas. Conclusions: Telomerase activity is a good marker for thyroid carcinomas. The quantitative TRAP-PCR might have more potential application in the differential diagnosis of tumors and the estimation of tumor progression and prognosis. And this sensitive assay could become a useful new modality for supplementing microscopic cytopathology in the detection of cancer cells in small tissue samples and FNAs

  15. Highly sensitive electrochemical detection of human telomerase activity based on bio-barcode method.

    Science.gov (United States)

    Li, Ying; Liu, Bangwei; Li, Xia; Wei, Qingli

    2010-07-15

    In the present study, an electrochemical method for highly sensitive detection of human telomerase activity was developed based on bio-barcode amplification assay. Telomerase was extracted from HeLa cells, then the extract was mixed with telomerase substrate (TS) primer to perform extension reaction. The extension product was hybridized with the capture DNA immobilized on the Au electrode and then reacted with the signal DNA on Au nanoparticles to form a sandwich hybridization mode. Electrochemical signals were generated by chronocoulometric interrogation of [Ru(NH(3))(6)](3+) that quantitatively binds to the DNA on Au nanoparticles via electrostatic interaction. This method can detect the telomerase activity from as little as 10 cultured cancer cells without the polymerase chain reaction (PCR) amplification of telomerase extension product. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  16. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing.

    Science.gov (United States)

    Aono, Jun; Ruiz-Rodriguez, Ernesto; Qing, Hua; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-01-01

    The present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase. Proliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated. We first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus. Inhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC

  17. Telomerase activation by genomic rearrangements in high-risk neuroblastoma

    Science.gov (United States)

    Peifer, Martin; Hertwig, Falk; Roels, Frederik; Dreidax, Daniel; Gartlgruber, Moritz; Menon, Roopika; Krämer, Andrea; Roncaioli, Justin L.; Sand, Frederik; Heuckmann, Johannes M.; Ikram, Fakhera; Schmidt, Rene; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Vogel, Wenzel; Altmüller, Janine; Nürnberg, Peter; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Mariappan, Aruljothi; Heynck, Stefanie; Mariotti, Erika; Henrich, Kai-Oliver; Glöckner, Christian; Bosco, Graziella; Leuschner, Ivo; Schweiger, Michal R.; Savelyeva, Larissa; Watkins, Simon C.; Shao, Chunxuan; Bell, Emma; Höfer, Thomas; Achter, Viktor; Lang, Ulrich; Theissen, Jessica; Volland, Ruth; Saadati, Maral; Eggert, Angelika; de Wilde, Bram; Berthold, Frank; Peng, Zhiyu; Zhao, Chen; Shi, Leming; Ortmann, Monika; Büttner, Reinhard; Perner, Sven; Hero, Barbara; Schramm, Alexander; Schulte, Johannes H.; Herrmann, Carl; O’Sullivan, Roderick J.; Westermann, Frank; Thomas, Roman K.; Fischer, Matthias

    2016-01-01

    Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system1. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2–4. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type1,2,5. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours. PMID:26466568

  18. Telomerase Activity in Chicken EmbryoFibroblast Cell Cultures Infected withMarek's Disease Virus

    Directory of Open Access Journals (Sweden)

    Gregory A. Tannock

    2010-07-01

    Full Text Available Background:Telomerase is a ribonucleoprotein, which adds telomeric repeats onto the 3’end of existing telomers at the end of chromosomes ineukaryotes. One hypothesis states that telomere length may function as a mitoticclock, therefore expression of telomerase activity in cancer cells may be a necessary and essential step for tumor development and progression.Methods:The detectability of telomerase activity in chicken embryofibroblast (CEF cells infected with different passages of Marek's disease virus(MDV was tested with the TRAPEZE® telomerase detection kit at passages14 (P14, P80/1 and P120 for the Woodland strain, and passage 9 (P9 for theMPF57 strain. Results:The results showed increased telomerase activity in MDV Woodlands strain at P14 and MPF57 strain at P9. Conclusion:Our results suggest that MDV-transformed cells at low passage are a suitable system for the study of telomerases in tumor developmentand for testing telomerase-inhibiting drugs.

  19. Active Yeast Telomerase Shares Subunits with Ribonucleoproteins RNase P and RNase MRP.

    Science.gov (United States)

    Lemieux, Bruno; Laterreur, Nancy; Perederina, Anna; Noël, Jean-François; Dubois, Marie-Line; Krasilnikov, Andrey S; Wellinger, Raymund J

    2016-05-19

    Telomerase is the ribonucleoprotein enzyme that replenishes telomeric DNA and maintains genome integrity. Minimally, telomerase activity requires a templating RNA and a catalytic protein. Additional proteins are required for activity on telomeres in vivo. Here, we report that the Pop1, Pop6, and Pop7 proteins, known components of RNase P and RNase MRP, bind to yeast telomerase RNA and are essential constituents of the telomerase holoenzyme. Pop1/Pop6/Pop7 binding is specific and involves an RNA domain highly similar to a protein-binding domain in the RNAs of RNase P/MRP. The results also show that Pop1/Pop6/Pop7 function to maintain the essential components Est1 and Est2 on the RNA in vivo. Consistently, addition of Pop1 allows for telomerase activity reconstitution with wild-type telomerase RNA in vitro. Thus, the same chaperoning module has allowed the evolution of functionally and, remarkably, structurally distinct RNPs, telomerase, and RNases P/MRP from unrelated progenitor RNAs. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. RPA facilitates telomerase activity at chromosome ends in budding and fission yeasts.

    Science.gov (United States)

    Luciano, Pierre; Coulon, Stéphane; Faure, Virginie; Corda, Yves; Bos, Julia; Brill, Steven J; Gilson, Eric; Simon, Marie-Noelle; Géli, Vincent

    2012-04-18

    In Saccharomyces cerevisiae, the telomerase complex binds to chromosome ends and is activated in late S-phase through a process coupled to the progression of the replication fork. Here, we show that the single-stranded DNA-binding protein RPA (replication protein A) binds to the two daughter telomeres during telomere replication but only its binding to the leading-strand telomere depends on the Mre11/Rad50/Xrs2 (MRX) complex. We further demonstrate that RPA specifically co-precipitates with yKu, Cdc13 and telomerase. The interaction of RPA with telomerase appears to be mediated by both yKu and the telomerase subunit Est1. Moreover, a mutation in Rfa1 that affects both the interaction with yKu and telomerase reduces the dramatic increase in telomere length of a rif1Δ, rif2Δ double mutant. Finally, we show that the RPA/telomerase association and function are conserved in Schizosaccharomyces pombe. Our results indicate that in both yeasts, RPA directly facilitates telomerase activity at chromosome ends.

  1. NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells

    Directory of Open Access Journals (Sweden)

    Pengying Li

    2016-08-01

    Full Text Available Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity. The over-elimination of ROS by NAC resulted in the inhibition of Akt pathway. Our results suggest that ROS is involved in the regulation of cancer telomerase activity through Akt pathway. The different intracellular redox homeostasis and antioxidant system in normal cells and tumor cells may be the cause of the opposite effect on telomerase activity in response to NAC treatment. Our results provide a theoretical base of using antioxidants selectively inhibit cancer telomerase activity. Findings of the present study may provide insights into novel approaches for cancer treatment.

  2. Colorimetry and SERS dual-mode detection of telomerase activity: combining rapid screening with high sensitivity.

    Science.gov (United States)

    Zong, Shenfei; Wang, Zhuyuan; Chen, Hui; Hu, Guohua; Liu, Min; Chen, Peng; Cui, Yiping

    2014-01-01

    As an important biomarker and therapeutic target, telomerase has attracted considerable attention concerning its detection and monitoring. Here, we present a colorimetry and surface enhanced Raman scattering (SERS) dual-mode telomerase activity detection method, which has several distinctive advantages. First, colorimetric functionality allows rapid preliminary discrimination of telomerase activity by the naked eye. Second, the employment of SERS technique results in greatly improved detection sensitivity. Third, the combination of colorimetry and SERS into one detection system can ensure highly efficacious and sensitive screening of numerous samples. Besides, the avoidance of polymerase chain reaction (PCR) procedures further guarantees fine reliability and simplicity. Generally, the presented method is realized by an "elongate and capture" procedure. To be specific, gold nanoparticles modified with Raman molecules and telomeric repeat complementary oligonucleotide are employed as the colorimetric-SERS bifunctional reporting nanotag, while magnetic nanoparticles functionalized with telomerase substrate oligonucleotide are used as the capturing substrate. Telomerase can synthesize and elongate telomeric repeats onto the capturing substrate. The elongated telomeric repeats subsequently facilitate capturing of the reporting nanotag via hybridization between telomeric repeat and its complementary strand. The captured nanotags can cause a significant difference in the color and SERS intensity of the magnetically separated sediments. Thus both the color and SERS can be used as indicators of the telomerase activity. With fast screening ability and outstanding sensitivity, we anticipate that this method would greatly promote practical application of telomerase-based early-stage cancer diagnosis.

  3. Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

    Directory of Open Access Journals (Sweden)

    Theresa Vasko

    2017-10-01

    Full Text Available Leukocyte telomere length (TL has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML, indicates clinical outcomes in chronic lymphocytic leukemia (CLL, and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS. In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.

  4. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  5. RAD51 and RTEL1 compensate telomere loss in the absence of telomerase.

    Science.gov (United States)

    Olivier, Margaux; Charbonnel, Cyril; Amiard, Simon; White, Charles I; Gallego, Maria E

    2018-03-16

    Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions. Imposing replication stress through knockout of RNaseH2 increases numbers of chromosome fusions and reduces the survival of these plants deficient for telomerase and homologous recombination. This finding suggests that RAD51-dependent homologous recombination acts as an essential backup to the telomerase for compensation of replicative telomere loss to ensure genome stability. Furthermore, we show that this positive role of RAD51 in telomere stability is dependent on the RTEL1 helicase. We propose that a RAD51 dependent break-induced replication process is activated in cells lacking telomerase activity, with RTEL1 responsible for D-loop dissolution after telomere replication.

  6. Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

    Directory of Open Access Journals (Sweden)

    Jun Aono, MD, PhD

    2016-01-01

    Full Text Available Proliferation of smooth muscle cells (SMCs during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT, indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT.

  7. A second chance for telomerase reverse transcriptase in anticancer immunotherapy.

    Science.gov (United States)

    Zanetti, Maurizio

    2017-02-01

    Telomerase reverse transcriptase (TERT) is a self-antigen that is expressed constitutively in many tumours, and is, therefore, an important target for anticancer immunotherapy. In the past 10 years, trials of immunotherapy with TERT-based vaccines have demonstrated only modest benefits. In this Perspectives, I discuss the possible immunological reasons for this limited antitumour efficacy, and propose that advances in our understanding of the genetics and biology of the involvement of TERT in cancer provides the basis for renewed interest in TERT- based immunotherapy. Telomerase and TERT are expressed in cancer cells at every stage of tumour evolution, from the cancer stem cell to circulating tumour cells and tumour metastases. Many cancer types also harbour cells with mutations in the TERT promoter region, which increase transcriptional activation of this gene. These new findings should spur new interest in the development of TERT-based immunotherapies that are redesigned in line with established immunological considerations and working principles, and are tailored to patients stratified on the basis of TERT-promoter mutations and other underlying tumour characteristics. Thus, despite the disappointment of previous clinical trials, TERT offers the potential for personalized immunotherapy, perhaps in combination with immune-checkpoint inhibition.

  8. Telomerase as an emerging target to fight cancer--opportunities and challenges for nanomedicine.

    Science.gov (United States)

    Philippi, C; Loretz, B; Schaefer, U F; Lehr, C M

    2010-09-01

    Telomerase as an enzyme is responsible for the renewal of the chromosomal ends, the so-called telomeres. By preventing them from shortening with each cell cycle, telomerase is able to inhibit cellular senescence and apoptosis. Telomerase activity, which is detectable in the majority of cancer cells, allows them to maintain their proliferative capacity. The thus obtained immortality of those cells again is a key to their malignancy. Based on these discoveries, it is obvious that telomerase inhibitors would represent an innovative approach to fight cancer, and a variety of such candidate molecules are currently in the pipeline. Telomerase inhibitors largely fall in two classes of compounds: small synthetic molecules and nucleotide-based biologicals. For several candidates, some proof of concept studies have been demonstrated, either on cell cultures or in animal models. But the same studies also revealed that inefficient delivery is largely limiting the translational step into the clinic. The most appealing feature of telomerase inhibitors, which distinguishes them from conventional anticancer drugs, is probably seen in their intrinsic non-toxicity to normal cells. Nevertheless, efficient delivery to the target cells, i.e. to the tumor, is still required. Here, some well-known biopharmaceutical problems such as insufficient solubility, permeability or even metabolic stability are frequently encountered. To address these challenges, there is a clear need for adequate delivery technologies, for example by using nanomedicines, that would allow to overcome their biopharmaceutical shortcomings and to warrant a sufficient bioavailability at the target side. This review first briefly explains the concept of telomerase and telomerase inhibition in cancer therapy. It secondly aims to provide an overview of the different currently known telomerase inhibitors. Finally, the biopharmaceutical limitations of these molecules are discussed as well as the possibilities to overcome

  9. Elevation of telomerase activity in chronic radiation ulcer of human skin

    International Nuclear Information System (INIS)

    Li Xiaoying; Zhao Po; Wang Dewen; Yang Zhixiang

    1997-01-01

    Objective: To investigate the levels of telomerase activity in chronic radiation ulcers of human skin and the possible relationship between the enzyme and cancer transformation. Method: Using nonisotopic telomere repeat amplification protocol (TRAP), detections were performed in 20 cases of chronic radiation ulcers of human skin, 5 cases of normal skin tissues and 5 cases of carcinoma. Results: The positive rates for telomerase activity were 30.0%(6/20), 0(0/5) and 100%(5/5) in chronic radiation ulcers of human skin, normal skin and carcinoma, respectively. The telomerase activity in radiation ulcer was weaker than in carcinoma. Conclusion: The telomerase activity assay might be used as a marker for predicting the prognosis and the effect of treatment in chronic radiation ulcer of human skin

  10. Identification of the Types Properties and Functional Characteristics of Telomerase Expressing Cells in Breast Cancer

    National Research Council Canada - National Science Library

    Hines, William

    2003-01-01

    ... biochemical and functional properties may be characterized. Through examining the role of telomerase in cancer, this project also fosters the education of the candidate through the interaction with several experts in breast cancer pathology, epidemiology, bio...

  11. The roles of telomeres and telomerase in cellular immortalization and the development of cancer.

    Science.gov (United States)

    Klingelhutz, A J

    1999-01-01

    Normal human cells have a limited lifespan in culture called the Hayflick limit. Recent studies have indicated that telomere shortening is one of the important meters utilized by cells to determine the Hayflick limit, and that activation of a mechanism to maintain telomere length is essential for cells to become immortal. It is generally believed that cells must have a means to maintain telomeres in order to progress to malignancy. Most cancers do this by activating an enzyme called telomerase which adds telomeric repeats to the telomere ends. Recently, expression of this enzyme has been shown to extend the lifespan of cells. This review discusses the research that led to the discovery of telomerase, the characteristics of telomerase complex, and how recent and future advances in the telomerase field may lead to better diagnostic and treatment protocols for many different cancer types.

  12. Effect of Mifepristone on the Telomerase Activity in Chorion and Decidua during Early Pregnancy

    Institute of Scientific and Technical Information of China (English)

    Ge-qing XIA; Ya-li XIONG; Yong-hong SUN

    2004-01-01

    Objective To investigate telomerase activity in chorion and decidua from abortion induced by mifepristone incorporated with misoprostol at early pregnancy Methods TRAP-SYBR Green assay was used to detect the expression of telomerase. Forty specimen were obtained from medicinal abortion (experiment group) and forty were from normal induced abortion (control group).Results Positive expression, of chorion telomerase was significantly different between the experimental group (28%, 11/40) and the control group (73%, 29/40) (P<0. 05).While in decidua, the positive rate was 28% (11/40) in the experimental group and 20% (9/40) in the control group, there was no significant difference (P>0. 05).Conclusion It is suggested that miferistone may significantly decrease the telomerase activity in chorion but not in decidua.

  13. Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

    Directory of Open Access Journals (Sweden)

    Yi Liu

    2018-02-01

    Full Text Available Shwachman-Diamond syndrome (SDS is a rare pediatric disease characterized by various systemic disorders, including hematopoietic dysfunction. The mutation of Shwachman-Bodian-Diamond syndrome (SBDS gene has been proposed to be a major causative reason for SDS. Although SBDS patients were reported to have shorter telomere length in granulocytes, the underlying mechanism is still unclear. Here we provide data to elucidate the role of SBDS in telomere protection. We demonstrate that SBDS deficiency leads to telomere shortening. We found that overexpression of disease-associated SBDS mutants or knockdown of SBDS hampered the recruitment of telomerase onto telomeres, while the overall reverse transcriptase activity of telomerase remained unaffected. Moreover, we show that SBDS could specifically bind to TPP1 during the S phase of cell cycle, likely functioning as a stabilizer for TPP1-telomerase interaction. Our findings suggest that SBDS is a telomere-protecting protein that participates in regulating telomerase recruitment.

  14. Telomerase activity and its association with psychological stress, mental disorders, lifestyle factors and interventions: A systematic review.

    Science.gov (United States)

    Deng, W; Cheung, S T; Tsao, S W; Wang, X M; Tiwari, A F Y

    2016-02-01

    To summarise and discuss the association between telomerase activity and psychological stress, mental disorders and lifestyle factors. A systematic review was carried out to identify prospective or retrospective studies and interventions published up to June 2015 that reported associations between telomerase activity and psychological stress, mental disorders and lifestyle factors. Electronic data bases of PubMed, ProQuest, CINAHL and Google Scholar were searched. Twenty six studies on humans measured telomerase activity in peripheral blood mononuclear cells (PBMCs) or leukocytes and examined its association with psychological stress, mental disorders and lifestyle factors. Of those studies, three reported significantly decreased telomerase activity in individuals under chronic psychological stress. Interestingly, one of the three studies found that acute laboratory psychological stress significantly increased telomerase activity. Nine studies reported mixed results on association between mental disorders and telomerase activity. Of the nine studies, five reported that major depressive disorder (MDD) was associated with significantly increased telomerase activity. In thirteen out of fourteen studies on lifestyle factors, it was reported that physical exercise, diet micronutrient supplementation, mindfulness meditation, Qigong practice or yoga mediation resulted in increase in telomerase activity. In addition, two studies on animal models showed that depression-like behaviour was associated with decreased hippocampus telomerase activity. Five animal studies showed that physical exercise increased telomerase activity by cell-type-specific and genotype-specific manners. Although multi-facet results were reported on the association between telomerase activity and psychological stress, mental disorders and lifestyle factors, there were some consistent findings in humans such as (1) decreased telomerase activity in individuals under chronic stress, (2) increased

  15. Behaviour of telomere and telomerase during aging and regeneration in zebrafish.

    Directory of Open Access Journals (Sweden)

    Monique Anchelin

    Full Text Available Telomere length and telomerase activity are important factors in the pathobiology of human diseases. Age-related diseases and premature aging syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. The zebrafish (Danio rerio offers multiple experimental manipulation advantages over other vertebrate models and, therefore, it has been recently considered as a potential model for aging, cancer, and regeneration studies. However, it has only partially been exploited to shed light on these fundamental biological processes. The aim of this study was, therefore, to investigate telomere length and telomerase expression and activity in different strains of zebrafish obtained from different stock centres to determine whether they undergo any changes during aging and regeneration. We found that although both telomerase expression and telomere length increased from embryo to adulthood stages, they drastically declined in aged fish despite telomerase activity was detected in different tissues of old fish. In addition, we observed a weaker upregulation of telomerase expression in regenerating fins of old fish, which well correlates with their impaired regeneration capacity. Strikingly, telomeres were elongated or maintained during the fin regeneration process at all ages and after repeated amputations, likely to support high cell proliferation rates. We conclude that the expression of telomerase and telomere length are closely related during the entire life cycle of the fish and that these two parameters can be used as biomarkers of aging in zebrafish. Our results also reveal a direct relationship between the expression of telomerase, telomere length and the efficiency of tissue regeneration.

  16. Behaviour of telomere and telomerase during aging and regeneration in zebrafish.

    Science.gov (United States)

    Anchelin, Monique; Murcia, Laura; Alcaraz-Pérez, Francisca; García-Navarro, Esther M; Cayuela, María L

    2011-02-09

    Telomere length and telomerase activity are important factors in the pathobiology of human diseases. Age-related diseases and premature aging syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. The zebrafish (Danio rerio) offers multiple experimental manipulation advantages over other vertebrate models and, therefore, it has been recently considered as a potential model for aging, cancer, and regeneration studies. However, it has only partially been exploited to shed light on these fundamental biological processes. The aim of this study was, therefore, to investigate telomere length and telomerase expression and activity in different strains of zebrafish obtained from different stock centres to determine whether they undergo any changes during aging and regeneration. We found that although both telomerase expression and telomere length increased from embryo to adulthood stages, they drastically declined in aged fish despite telomerase activity was detected in different tissues of old fish. In addition, we observed a weaker upregulation of telomerase expression in regenerating fins of old fish, which well correlates with their impaired regeneration capacity. Strikingly, telomeres were elongated or maintained during the fin regeneration process at all ages and after repeated amputations, likely to support high cell proliferation rates. We conclude that the expression of telomerase and telomere length are closely related during the entire life cycle of the fish and that these two parameters can be used as biomarkers of aging in zebrafish. Our results also reveal a direct relationship between the expression of telomerase, telomere length and the efficiency of tissue regeneration.

  17. Nonradioactive telomerase activity assay by microchip electrophoresis: privileges to the classical gel electrophoresis assay.

    Science.gov (United States)

    Zhelev, Zhivko; Bakalova, Rumiana; Ewis, Ashraf; Ohba, Hideki; Ishikawa, Mitsuru; Baba, Yoshinobu

    2005-08-01

    The present study accents on the privileges of microchip-based electrophoresis to the conventional gel electrophoresis in separation of telomerase repeat amplification protocol/polymerase chain reaction (PCR) ladder products obtained in telomerase-catalyzed reaction in cancer cells. We try to clarify the interpretation of the results obtained by both electrophoretic procedures and to avoid misinterpretation as a result of PCR-dependent artefacts.

  18. A Cajal body-independent pathway for telomerase trafficking in mice

    International Nuclear Information System (INIS)

    Tomlinson, Rebecca L.; Li, Jian; Culp, Bradley R.; Terns, Rebecca M.; Terns, Michael P.

    2010-01-01

    The intranuclear trafficking of human telomerase involves a dynamic interplay between multiple nuclear sites, most notably Cajal bodies and telomeres. Cajal bodies are proposed to serve as sites of telomerase maturation, storage, and assembly, as well as to function in the cell cycle-regulated delivery of telomerase to telomeres in human cells. Here, we find that telomerase RNA does not localize to Cajal bodies in mouse cells, and instead resides in separate nuclear foci throughout much of the cell cycle. However, as in humans, mouse telomerase RNA (mTR) localizes to subsets of telomeres specifically during S phase. The localization of mTR to telomeres in mouse cells does not require coilin-containing Cajal bodies, as mTR is found at telomeres at similar frequencies in cells from wild-type and coilin knockout mice. At the same time, we find that human TR localizes to Cajal bodies (as well as telomeres) in mouse cells, indicating that the distinct trafficking of mTR is attributable to an intrinsic property of the RNA (rather than a difference in the mouse cell environment such as the properties of mouse Cajal bodies). We also find that during S phase, mTR foci coalesce into short chains, with at least one of the conjoined mTR foci co-localizing with a telomere. These findings point to a novel, Cajal body-independent pathway for telomerase biogenesis and trafficking in mice.

  19. A Cajal body-independent pathway for telomerase trafficking in mice

    Energy Technology Data Exchange (ETDEWEB)

    Tomlinson, Rebecca L.; Li, Jian; Culp, Bradley R.; Terns, Rebecca M., E-mail: rterns@bmb.uga.edu; Terns, Michael P., E-mail: mterns@bmb.uga.edu

    2010-10-15

    The intranuclear trafficking of human telomerase involves a dynamic interplay between multiple nuclear sites, most notably Cajal bodies and telomeres. Cajal bodies are proposed to serve as sites of telomerase maturation, storage, and assembly, as well as to function in the cell cycle-regulated delivery of telomerase to telomeres in human cells. Here, we find that telomerase RNA does not localize to Cajal bodies in mouse cells, and instead resides in separate nuclear foci throughout much of the cell cycle. However, as in humans, mouse telomerase RNA (mTR) localizes to subsets of telomeres specifically during S phase. The localization of mTR to telomeres in mouse cells does not require coilin-containing Cajal bodies, as mTR is found at telomeres at similar frequencies in cells from wild-type and coilin knockout mice. At the same time, we find that human TR localizes to Cajal bodies (as well as telomeres) in mouse cells, indicating that the distinct trafficking of mTR is attributable to an intrinsic property of the RNA (rather than a difference in the mouse cell environment such as the properties of mouse Cajal bodies). We also find that during S phase, mTR foci coalesce into short chains, with at least one of the conjoined mTR foci co-localizing with a telomere. These findings point to a novel, Cajal body-independent pathway for telomerase biogenesis and trafficking in mice.

  20. Inhibition of telomerase by linear-chain fatty acids: a structural analysis.

    Science.gov (United States)

    Oda, Masako; Ueno, Takamasa; Kasai, Nobuyuki; Takahashi, Hirotada; Yoshida, Hiromi; Sugawara, Fumio; Sakaguchi, Kengo; Hayashi, Hideya; Mizushina, Yoshiyuki

    2002-01-01

    In the present study, we have found that mono-unsaturated linear-chain fatty acids in the cis configuration with C(18) hydrocarbon chains (i.e. oleic acid) strongly inhibited the activity of human telomerase in a cell-free enzymic assay, with an IC(50) value of 8.6 microM. Interestingly, fatty acids with hydrocarbon chain lengths below 16 or above 20 carbons substantially decreased the potency of inhibition of telomerase. Moreover, the cis-mono-unsaturated C(18) linear-chain fatty acid oleic acid was the strongest inhibitor of all the fatty acids tested. A kinetic study revealed that oleic acid competitively inhibited the activity of telomerase ( K (i)=3.06 microM) with respect to the telomerase substrate primer. The energy-minimized three-dimensional structure of the linear-chain fatty acid was calculated and modelled. A molecule width of 11.53-14.26 A (where 1 A=0.1 nm) in the C(16) to C(20) fatty acid structure was suggested to be important for telomerase inhibition. The three-dimensional structure of the telomerase active site (i.e. the substrate primer-binding site) appears to have a pocket that could bind oleic acid, with the pocket being 8.50 A long and 12.80 A wide. PMID:12121150

  1. Telomerase activation by the E6 gene product of human papillomavirus type 16.

    Science.gov (United States)

    Klingelhutz, A J; Foster, S A; McDougall, J K

    1996-03-07

    Activation of telomerase, a ribonucleoprotein complex that synthesizes telomere repeat sequences, is linked to cell immortalization and is characteristic of most cell lines and tumours. Here we show that expression of the human papillomavirus type 16 (HPV-16) E6 protein activates telomerase in early-passage human keratinocytes and mammary epithelial cells. This activation was observed in cells pre-crisis, that is, before they became immortal, and occurred within one passage of retroviral infection with vectors expressing HPV-16 E6. Studies using HPV-16 E6 mutants showed that there was no correlation between the ability of the mutants to activate telomerase and their ability to target p53 for degradation, suggesting that telomerase activation by HPV-16 E6 is p53 independent. Keratinocytes expressing wild-type HPV-16 E6 have an extended lifespan, but do not become immortal, indicating that telomerase activation and E6-mediate degradation of p53 are insufficient for their immortalization. These results show that telomerase activation is an intrinsic, but insufficient, component of transformation by HPV.

  2. Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population

    International Nuclear Information System (INIS)

    He, Xianli; Qiao, Qing; Ge, Naijian; Nan, Jing; Shen, Shuqun; Wang, Zizhong; Yang, Yefa; Bao, Guoqiang

    2010-01-01

    Telomerase expression is one of the characteristics of gastric cancer (GC) cells and telomerase activity is frequently up-regulated by a variety of mechanisms during GC development. Therefore, we hypothesized that elevated levels of activated telomerase might enhance GC risk due to increased propagation of cells with DNA damage, such as induced by γ-radiation. To explore this hypothesis, 246 GC cases and 246 matched controls were recruited in our case-control study. TRAP-ELISA was used to assess the levels of telomerase activity at baseline and after γ-radiation and the γ-radiation-induced telomerase activity (defined as after γ-irradiation/baseline) in cultured peripheral blood lymphocytes (PBLs). Our data showed that there was no significant difference for the baseline telomerase activity between GC cases and controls (10.17 ± 7.21 vs. 11.02 ± 8.03, p = 0.168). However, after γ-radiation treatment, γ-radiation-induced telomerase activity was significantly higher in the cases than in the controls (1.51 ± 0.93 vs. 1.22 ± 0.66, p < 0.001). Using the median value of γ-radiation-induced telomerase activity in the controls as a cutoff point, we observed that high γ-radiation-induced telomerase activity was associated with a significantly increased GC risk (adjusted odds ratio, 2.45; 95% confidence interval, 1.83-3.18). Moreover, a dose response association was noted between γ-radiation-induced telomerase activity and GC risk. Age, but not sex, smoking and drinking status seem to have a modulating effect on the γ-radiation-induced telomerase activities in both cases and controls. Overall, our findings for the first time suggest that the increased γ-radiation-induced telomerase activity in PBLs might be associated with elevated GC risk. Further confirmation of this association using a prospective study design is warranted

  3. Alterations of telomerase activity and terminal restriction fragment in gastric cancer and its premalignant lesions.

    Science.gov (United States)

    Yang, S M; Fang, D C; Luo, Y H; Lu, R; Battle, P D; Liu, W W

    2001-08-01

    In order to explore the role of alterations of telomerase activity and terminal restriction fragment (TRF) length in the development and progression of gastric cancer. Telomerase activity was detected in 176 specimens of gastric mucosa obtained through an operation or endoscopical biopsy by using the telomeric repeat amplification protocol (TRAP) assay. Meanwhile, the mean length of TRF was measured with the use of a Southern blot in part of those samples. Telomerase activity was detected in 14 of 57 (24.6%) chronic atrophy gastritis patients, six of 18 (33.3%) intestinal metaplasia patients, three of eight (37.5%) dysplasia patients and 60 of 65 (92.3%) gastric cancer patients, respectively. Normal gastric mucosa revealed no telomerase activity. No association was found between telomerase activity and any clinicopathological parameters. The mean TRF length was decreased gradually with age in normal mucosa and in gastric cancer tissue. Regression analysis demonstrated that the reduction rate in these tissues was 41 +/- 12 base pairs/year. Among 35 gastric cancers, TRF length was shown to be shorter in 20 cases (57.1%), similar in 12 cases (34.3%) and elongated in three cases (7.6%), compared to the corresponding adjacent tissues. The mean TRF length tended to decrease as the mucosa underwent chronic atrophy gastritis, intestinal metaplasia, dysplasia and into gastric cancer. The mean TRF length in gastric cancer was not statistically correlated with clinicopathological parameters and telomerase activity. Our results suggest that telomerase is expressed during the early stage of gastric carcinogenesis, and that the clinical significance of TRF length appears to be limited in gastric cancer.

  4. The Telomerase Inhibitor MST-312 Interferes with Multiple Steps in the Herpes Simplex Virus Life Cycle.

    Science.gov (United States)

    Haberichter, Jarod; Roberts, Scott; Abbasi, Imran; Dedthanou, Phonphanh; Pradhan, Prajakta; Nguyen, Marie L

    2015-10-01

    The life cycle of herpes simplex virus (HSV) has the potential to be further manipulated to yield novel, more effective therapeutic treatments. Recent research has demonstrated that HSV-1 can increase telomerase activity and that expression of the catalytic component of telomerase, telomerase reverse transcriptase (TERT), alters sensitivity to HSV-dependent apoptosis. Telomerase is a cellular enzyme that synthesizes nucleotide repeats at the ends of chromosomes (telomeres), which prevents shortening of the 3' ends of DNA with each cell division. Once telomeres reach a critical length, cells undergo senescence and apoptosis. Here, we used a cell-permeable, reversible inhibitor of the telomerase enzyme, MST-312, to investigate telomerase activity during HSV infection. Human mammary epithelial cells immortalized through TERT expression and human carcinoma HEp-2 cells were infected with the KOS1.1 strain of HSV-1 in the presence of MST-312. MST-312 treatment reduced the number of cells displaying a cytopathic effect and the accumulation of immediate early and late viral proteins. Moreover, the presence of 20 μM to 100 μM MST-312 during infection led to a 2.5- to 5.5-log10 decrease in viral titers. MST-312 also inhibited the replication of HSV-2 and a recent clinical isolate of HSV-1. Additionally, we determined that MST-312 has the largest impact on viral events that take place prior to 5 h postinfection (hpi). Furthermore, MST-312 treatment inhibited virus replication, as measured by adsorption assays and quantification of genome replication. Together, these findings demonstrate that MST-312 interferes with the HSV life cycle. Further investigation into the mechanism for MST-312 is warranted and may provide novel targets for HSV therapies. Herpes simplex virus (HSV) infections can lead to cold sores, blindness, and brain damage. Identification of host factors that are important for the virus life cycle may provide novel targets for HSV antivirals. One such factor

  5. Comparison of telomerase activity in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic hyperplasia

    Directory of Open Access Journals (Sweden)

    Soleiman Mahjoub

    2006-11-01

    Full Text Available BACKGROUND: Telomerase is a reverse transcriptase enzyme that synthesizes telomeric DNA on chromosome ends. The enzyme is important for the immortalization of cancer cells because it maintains the telomeres. METHODS: Telomerase activity (TA was measured by fluorescence-based telomeric repeat amplification protocol (FTRAP assay in prostate carcinoma and benign prostatic hyperplasia (BPH. RESULTS: TA was present in 91.4% of 70 prostate cancers, 68.8% of 16 prostatic intraepithelial neoplasia (PIN, 43.3% of 30 BPH*, 21.4% of 14 atrophy and 20% of 15 normal samples adjacent to tumor. There was not any significant correlation between TA, histopathological tumor stage or gleason score. In contrast to high TA in the BPH* tissue from the cancer-bearing gland, only 6.3% of 32 BPH specimens from patients only diagnosed with BPH were telomerase activity-positive. CONCLUSIONS: These results indicate that TA is present in most prostate cancers. The high rate of TA in tissue adjacent to tumor may be attributed either to early molecular alteration of cancer that was histologically unapparent, or to the presence of occult cancer cells. Our findings suggest that the re-expression of telomerase activity could be one step in the transformation of BPH to PIN. KEY WORDS: Telomerase activity, prostate cancer, prostatic intraepithelial neoplasia, benign prostatic hyperplasia.

  6. Effects of Curcuma longa Extract on Telomerase Activity in Lung and Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Nosratollah Zarghami

    2014-10-01

    Full Text Available Background: The purpose of this study is to evaluate the effect of Curcuma longa extract on the telomerase gene expression in QU-DB lung cancer and T47D breast cancer cell lines. Materials and Methods: The present study is an experimental research. Using 3 different phases n-hexane, dichloromethane and methanol, total extract of Curcuma longa in a serial dilution was prepared and three phases was analyzed for determining which phase has more curcuminoids. Then the extract cytotoxicity effect was tested on breast cancer cell line (T47D, and lung cancer cell line (QU-DB by 24, 48 and 72 h MTT (Dimethyl thiazolyl diphenyl tetrazolium assay. Then, the cells were treated with serial concentrations of the extract. Finally, total protein was extracted from the control and test groups, its quantity was determined and telomeric repeat amplification protocol (TRAP assay was performed for measurement of possible inhibition of the telomerase activity. Results: Cell viability and MTT-based cytotoxicity assay show that the total extract of Curcuma longa has cytotoxic effect with different IC50s in breast and lung cancer cell lines. Analysis of TRAP assay also shows a significant reduction in telomerase activity on both cancer cells with different levels. Conclusion: Curcuma longa extract has anti-proliferation and telomerase inhibitory effects on QU-DB lung cancer and T47D breast cancer cells with differences in levels of telomerase inhibition.

  7. Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine

    Directory of Open Access Journals (Sweden)

    Sakineh Kazemi Noureini

    2018-04-01

    Full Text Available Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB, a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC50 value of about 0.17 ± 0.1 µM for BSB, roughly 400 times stronger than boldine, while the LD50 in the cytotoxicity assays were 12.5 and 21.88 µM, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC50 for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations.

  8. Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process.

    Science.gov (United States)

    Ducray, C; Pommier, J P; Martins, L; Boussin, F D; Sabatier, L

    1999-07-22

    Loss of telomeric repeats during cell proliferation could play a role in senescence. It has been generally assumed that activation of telomerase prevents further telomere shortening and is essential for cell immortalization. In this study, we performed a detailed cytogenetic and molecular characterization of four SV40 transformed human fibroblastic cell lines by regularly monitoring the size distribution of terminal restriction fragments, telomerase activity and the associated chromosomal instability throughout immortalization. The mean TRF lengths progressively decreased in pre-crisis cells during the lifespan of the cultures. At crisis, telomeres reached a critical size, different among the cell lines, contributing to the peak of dicentric chromosomes, which resulted mostly from telomeric associations. We observed a direct correlation between short telomere length at crisis and chromosomal instability. In two immortal cell lines, although telomerase was detected, mean telomere length still continued to decrease whereas the number of dicentric chromosomes associated was stabilized. Thus telomerase could protect specifically telomeres which have reached a critical size against end-to-end dicentrics, while long telomeres continue to decrease, although at a slower rate as before crisis. This suggests a balance between elongation by telomerase and telomere shortening, towards a stabilized 'optimal' length.

  9. Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension.

    Science.gov (United States)

    Porreca, Rosa M; Glousker, Galina; Awad, Aya; Matilla Fernandez, Maria I; Gibaud, Anne; Naucke, Christian; Cohen, Scott B; Bryan, Tracy M; Tzfati, Yehuda; Draskovic, Irena; Londoño-Vallejo, Arturo

    2018-05-18

    Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase.

  10. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    International Nuclear Information System (INIS)

    Uziel, Orit; Kanfer, Gil; Beery, Einat; Yelin, Dana; Shepshelovich, Daniel; Bakhanashvili, Mary; Nordenberg, Jardena; Lahav, Meir

    2014-01-01

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway

  11. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    Energy Technology Data Exchange (ETDEWEB)

    Uziel, Orit, E-mail: Oritu@clalit.org.il [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Kanfer, Gil [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Beery, Einat [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Yelin, Dana; Shepshelovich, Daniel [Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Bakhanashvili, Mary [Unit of Infectious Diseases, Sheba Medical Center, Tel-Hashomer (Israel); Nordenberg, Jardena [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Endocrinology Laboratory, Beilinson Medical Center, Petah-Tikva (Israel); Lahav, Meir [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel)

    2014-07-18

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

  12. Reconstitution of active telomerase in primary human foreskin fibroblasts : effects on proliferative characteristics and response to ionizing radiation

    NARCIS (Netherlands)

    Kampinga, H.H.; Waarde-Verhagen, M.A.W.H. van; Assen-Bolt, A.J. van; Rodemann, H.P.; Prowse, K.R.; Linskens, M.H.K.

    2004-01-01

    Purpose: Telomere shortening has been proposed to trigger senescence, and since most primary cells do not express active telomerase, reactivation of telomerase activity was proposed as a safe and non-transforming way of immortalizing cells. However, to study radiation responses, it is as yet unclear

  13. The telomerase reverse transcriptase subunit from the dimorphic fungus Ustilago maydis.

    Directory of Open Access Journals (Sweden)

    Dolores Bautista-España

    Full Text Available In this study, we investigated the reverse transcriptase subunit of telomerase in the dimorphic fungus Ustilago maydis. This protein (Trt1 contains 1371 amino acids and all of the characteristic TERT motifs. Mutants created by disrupting trt1 had senescent traits, such as delayed growth, low replicative potential, and reduced survival, that were reminiscent of the traits observed in est2 budding yeast mutants. Telomerase activity was observed in wild-type fungus sporidia but not those of the disruption mutant. The introduction of a self-replicating plasmid expressing Trt1 into the mutant strain restored growth proficiency and replicative potential. Analyses of trt1 crosses in planta suggested that Trt1 is necessary for teliospore formation in homozygous disrupted diploids and that telomerase is haploinsufficient in heterozygous diploids. Additionally, terminal restriction fragment analysis in the progeny hinted at alternative survival mechanisms similar to those of budding yeast.

  14. Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway

    DEFF Research Database (Denmark)

    Saeed, Hamid; Qiu, Weimin; Li, Chen

    2015-01-01

    -regulation of several components of insulin-like growth factor (IGF) signaling. Specifically, a significant increase in IGF-induced AKT phosphorylation and alkaline phosphatase (ALP) activity were observed in hMSC-TERT. Enhanced ALP activity was reduced in presence of IGF1 receptor inhibitor: picropodophyllin....... In addition, telomerase deficiency caused significant reduction in IGF signaling proteins in osteoblastic cells cultured from telomerase deficient mice (Terc (-/-)). The low bone mass exhibited by Terc (-/-) mice was associated with significant reduction in serum levels of IGF1 and IGFBP3 as well as reduced...... skeletal mRNA expression of Igf1, Igf2, Igf2r, Igfbp5 and Igfbp6. IGF1-induced osteoblast differentiation was also impaired in Terc (-/-) MSC. In conclusion, our data demonstrate that impaired IGF/AKT signaling contributes to the observed decreased bone mass and bone formation exhibited by telomerase...

  15. [Methods of measuring telomere length and telomerase activity--practice and problems].

    Science.gov (United States)

    Saito, Y; Suda, T; Hatakeyama, K

    1998-05-01

    The development of a highly sensitive method for detection of telomerase activity, telomeric repeat amplification protocol (TRAP), has provided knowledge on telomerase activity in normal and cancer tissues. Subsequent several modifications have been achieved, including an introduction of the internal standard and hybridization protection technique that leads to simplicity and improvement of reproducibility and linearity of this method, and application of TRAP to in situ analysis to identify the cells responsible for telomerase activity. As for measurement of telomere length, fluorescence in situ hybridization technique appeared to give an information of telomere length on an individual chromosome in contrast to analysis of terminal restriction fragment, a conventional method which can express mean telomere length of all chromosomes. Further methodological improvement in this field is ongoing and showing a new sight on cell mortality and immortality.

  16. Peroxiredoxin 1 Protects Telomeres from Oxidative Damage and Preserves Telomeric DNA for Extension by Telomerase

    Directory of Open Access Journals (Sweden)

    Eric Aeby

    2016-12-01

    Full Text Available Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage have not been described. We analyzed telomeric chromatin composition during the cell cycle and show that the antioxidant enzyme peroxiredoxin 1 (PRDX1 is enriched at telomeres during S phase. Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage at telomeres. We also show that the oxidized nucleotide 8-oxo-2′deoxyguanosine-5′-triphosphate (8oxodGTP causes premature chain termination when incorporated by telomerase and that some DNA substrates terminating in 8oxoG prevent extension by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase.

  17. Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition.

    Science.gov (United States)

    Qing, Hua; Aono, Jun; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-06-01

    Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. © 2015 Wiley Periodicals, Inc.

  18. Radiation-induced progressive decreasing in the expression of reverse transcriptase gene of hEST2 and telomerase activity

    International Nuclear Information System (INIS)

    Zhu Hanneng; Chen Wenying; Xiong Sidong

    2000-01-01

    Telomerase is a ribonucleoprotein complex that adds heximeric repeats called telomeres to the growing ends of chromosomal DNA. Telomerase activity is present in a vast majority of tumors but is repressed in most normal tissues. Human telomerase catalytic subunit gene (hEST2) reverse transcriptase (RT) segment was cloned by PCR according to the sequence published in GeneBank. PCR was used to investigate the expression of the hEST2 RT segment in diverse tumors as well as in various normal tissues. Results indicated that hEST2 RT segment was detectable in tumor cells lines but not in normal cells and tissues. In order to identify the relationship between telomerase and the biological effect of radiation injury, HeLa cells, KB cells and A431 cells were employed to measure the change in telomerase activity after 60 Co-ray irradiation at RNA level and protein level. Quantitative PCR determined that expression of hEST2 RT segment that encodes seven motifs of the human telomeras decreased with increasing dosage of radiation. In addition, a PCR-based telomeric repeat amplification protocol was used to assay telomerase activity after exposure to radiation. The results strongly support the experiments we had made: Telomerase activity decreases with increasing dosage of radiation. We conclude that detection of the hEST2 RT segment by Northern blotting is a new method for detecting telomerase activity. Furthermore, radiation can cause a dose-dependent decrease in telomerase activity. The effect of radiation on telomerase is one possible reason for the death of cancer cells after irradiation. (author)

  19. Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Flávia S Donaires

    Full Text Available Telomeres are repetitive DNA sequences at linear chromosome termini, protecting chromosomes against end-to-end fusion and damage, providing chromosomal stability. Telomeres shorten with mitotic cellular division, but are maintained in cells with high proliferative capacity by telomerase. Loss-of-function mutations in telomere-maintenance genes are genetic risk factors for cirrhosis development in humans and murine models. Telomerase deficiency provokes accelerated telomere shortening and dysfunction, facilitating genomic instability and oncogenesis. Here we examined whether telomerase mutations and telomere shortening were associated with hepatocellular carcinoma (HCC secondary to cirrhosis. Telomere length of peripheral blood leukocytes was measured by Southern blot and qPCR in 120 patients with HCC associated with cirrhosis and 261 healthy subjects. HCC patients were screened for telomerase gene variants (in TERT and TERC by Sanger sequencing. Age-adjusted telomere length was comparable between HCC patients and healthy subjects by both Southern blot and qPCR. Four non-synonymous TERT heterozygous variants were identified in four unrelated patients, resulting in a significantly higher mutation carrier frequency (3.3% in patients as compared to controls (p = 0.02. Three of the four variants (T726M, A1062T, and V1090M were previously observed in patients with other telomere diseases (severe aplastic anemia, acute myeloid leukemia, and cirrhosis. A novel TERT variant, A243V, was identified in a 65-year-old male with advanced HCC and cirrhosis secondary to chronic hepatitis C virus (HCV and alcohol ingestion, but direct assay measurements in vitro did not detect modulation of telomerase enzymatic activity or processivity. In summary, constitutional variants resulting in amino acid changes in the telomerase reverse transcriptase were found in a small proportion of patients with cirrhosis-associated HCC.

  20. Antimetastatic Effects of a Novel Telomerase Inhibitor, GRN163L, on Human Prostate Cancer

    Science.gov (United States)

    2010-05-01

    Human Papilloma Virus Type 18 (HPV-18) DNA. PZ-HPV-7 cells are generally considered as non-tumorigenic in subcutaneous xenograft animal models...6481. [39] H.J. Sommerfeld, A.K. Meeker, M.A. Piatyszek, G.S. Bova, J.W. Shay, D.S. Coffey, Telomerase activity: a prevalent marker of malignant human ...6:192–8. 31. Sommerfeld HJ, Meeker AK, Piatyszek MA, Bova GS, Shay JW, Coffey DS. Telomerase activity: a prevalent marker of malignant human prostate

  1. Telomeres and Telomerase in the Radiation Response: implications for instability, reprogramming, and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Brock James Sishc

    2015-11-01

    Full Text Available Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks; DSBs and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles telomeres and telomerase play in the response of human cells to ionizing radiations of different qualities, we tracked changes in telomeric end-capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET gamma(γ-rays or high LET high charge, high energy (HZE particles, delivered either acutely or at low dose rates (LDR. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprogramming. Taken together, the results reported here establish the critical importance of

  2. New prognostic factor telomerase reverse transcriptase promotor mutation presents without MR imaging biomarkers in primary glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ersoy, Tunc F.; Simon, Matthias [University Hospital Bonn, Department of Neurosurgery and Stereotaxy, Bonn (Germany); Ev. Krankenhaus Bielefeld, Department of Neurosurgery, Bielefeld (Germany); Keil, Vera C.; Hadizadeh, Dariusch R.; Schild, Hans H. [University Hospital Bonn, Department of Radiology, Bonn (Germany); Gielen, Gerrit H.; Waha, Andreas [University Hospital Bonn, Institute of Neuropathology, Bonn (Germany); Fimmers, Rolf [IMBIE, University Hospital Bonn, Bonn (Germany); Heidenreich, Barbara; Kumar, Rajiv [DFKZ, Department of Molecular Genetic Epidemiology, Heidelberg (Germany)

    2017-12-15

    Magnetic resonance (MR) imaging biomarkers can assist in the non-invasive assessment of the genetic status in glioblastomas (GBMs). Telomerase reverse transcriptase (TERT) promoter mutations are associated with a negative prognosis. This study was performed to identify MR imaging biomarkers to forecast the TERT mutation status. Pre-operative MRIs of 64/67 genetically confirmed primary GBM patients (51/67 TERT-mutated with rs2853669 polymorphism) were analyzed according to Visually AcceSAble Rembrandt Images (VASARI) (https: //wiki.cancerimagingarchive.net/display/Public/VASARI+Research+Project) imaging criteria by three radiological raters. TERT mutation and O{sup 6}-methylguanine-DNA methyltransferase (MGMT) hypermethylation data were obtained through direct and pyrosequencing as described in a previous study. Clinical data were derived from a prospectively maintained electronic database. Associations of potential imaging biomarkers and genetic status were assessed by Fisher and Mann-Whitney U tests and stepwise linear regression. No imaging biomarkers could be identified to predict TERT mutational status (alone or in conjunction with TERT promoter polymorphism rs2853669 AA-allele). TERT promoter mutations were more common in patients with tumor-associated seizures as first symptom (26/30 vs. 25/37, p = 0.07); these showed significantly smaller tumors [13.1 (9.0-19.0) vs. 24.0 (16.6-37.5) all cm{sup 3}; p = 0.007] and prolonged median overall survival [17.0 (11.5-28.0) vs. 9.0 (4.0-12.0) all months; p = 0.02]. TERT-mutated GBMs were underrepresented in the extended angularis region (p = 0.03), whereas MGMT-methylated GBMs were overrepresented in the corpus callosum (p = 0.03) and underrepresented temporomesially (p = 0.01). Imaging biomarkers for prediction of TERT mutation status remain weak and cannot be derived from the VASARI protocol. Tumor-associated seizures are less common in TERT mutated glioblastomas. (orig.)

  3. TERRA mimicking ssRNAs prevail over the DNA substrate for telomerase in vitro due to interactions with the alternative binding site.

    Science.gov (United States)

    Azhibek, Dulat; Skvortsov, Dmitry; Andreeva, Anna; Zatsepin, Timofei; Arutyunyan, Alexandr; Zvereva, Maria; Dontsova, Olga

    2016-06-01

    Telomerase is a key component of the telomere length maintenance system in the majority of eukaryotes. Telomerase displays maximal activity in stem and cancer cells with high proliferative potential. In humans, telomerase activity is regulated by various mechanisms, including the interaction with telomere ssDNA overhangs that contain a repetitive G-rich sequence, and with noncoding RNA, Telomeric repeat-containing RNA (TERRA), that contains the same sequence. So these nucleic acids can compete for telomerase RNA templates in the cell. In this study, we have investigated the ability of different model substrates mimicking telomere DNA overhangs and TERRA RNA to compete for telomerase in vitro through a previously developed telomerase inhibitor assay. We have shown in this study that RNA oligonucleotides are better competitors for telomerase that DNA ones as RNA also use an alternative binding site on telomerase, and the presence of 2'-OH groups is significant in these interactions. In contrast to DNA, the possibility of forming intramolecular G-quadruplex structures has a minor effect for RNA binding to telomerase. Taking together our data, we propose that TERRA RNA binds better to telomerase compared with its native substrate - the 3'-end of telomere DNA overhang. As a result, some specific factor may exist that participates in switching telomerase from TERRA to the 3'-end of DNA for telomere elongation at the distinct period of a cell cycle in vivo. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  4. Optimizing searches for electromagnetic counterparts of gravitational wave triggers

    Science.gov (United States)

    Coughlin, Michael W.; Tao, Duo; Chan, Man Leong; Chatterjee, Deep; Christensen, Nelson; Ghosh, Shaon; Greco, Giuseppe; Hu, Yiming; Kapadia, Shasvath; Rana, Javed; Salafia, Om Sharan; Stubbs11, Christopher

    2018-04-01

    With the detection of a binary neutron star system and its corresponding electromagnetic counterparts, a new window of transient astronomy has opened. Due to the size of the sky localization regions, which can span hundreds to thousands of square degrees, there are significant benefits to optimizing tilings for these large sky areas. The rich science promised by gravitational-wave astronomy has led to the proposal for a variety of proposed tiling and time allocation schemes, and for the first time, we make a systematic comparison of some of these methods. We find that differences of a factor of 2 or more in efficiency are possible, depending on the algorithm employed. For this reason, with future surveys searching for electromagnetic counterparts, care should be taken when selecting tiling, time allocation, and scheduling algorithms to optimize counterpart detection.

  5. The effect of β-ionone on telomerase activity in the human leukemia cell line K562

    Directory of Open Access Journals (Sweden)

    Zohreh Faezizadeh

    2015-06-01

    Full Text Available Background: Telomerase is highly activated in most human cancer cells, therefore, its inhibition has been proposed as a novel and promising strategy for cancer therapy. Many plant-derived anticancer agents act through inhibition of telomerase activity and induction of apoptosis. β-ionone, a carotenoid compound isolated from Roseaceae, has been reported to possess anticancer properties. The present study was undertaken to examine the mechanism of β-ionone-induced apoptosis in human leukemia cell line K562 with special emphasis on its role in telomerase inhibition. Method: In this study the anti-proliferation effect of β-ionone on K562 cells was evaluated by MTT assay. Apoptosis rate was detected by Hoechst staining and flow cytometry analysis. Telomerase activity was measured by (TRAP ELISA assay. Results: Exposure of K562 cells to β-ionone caused a dose-dependent decrease in proliferation. Flow cytometry analysis and Hoechst staining showed that percentage of apoptotic cells markedly increased with an increase in β-ionone concentration. Compared to control cells, treatment of K562 cells with β-ionone resulted in a significant decrease of telomerase activity. Moreover, a positive correlation was detected between telomerase inhibition and apoptosis induction in the treated K562 cells. Conclusion: Based on these results, β-ionone is an appropriate candidate for inhibiting telomerase activity in K562 cells. Therefore, it may be utilized as a novel drug against some leukemia cell lines.

  6. Antiaging Effects of an Intensive Mind and Body Therapeutic Program through Enhancement of Telomerase Activity and Adult Stem Cell Counts.

    Science.gov (United States)

    Rao, Krishna S; Chakraharti, Swarup K; Dongare, Vaishali S; Chetana, K; Ramirez, Christina M; Koka, Prasad S; Deb, Kaushik D

    2015-01-01

    Key modalities of integrative medicine known to rejuvenate the mind and body are meditation, yoga, and controlled diet. It has been shown previously that intensive or prolonged mind and body therapies (MBT) may have beneficial effects on the well-being of healthy people and in patients. Telomerase activity and levels of peripheral blood adult pluripotent stem cells (PB-APSC) are reliable markers of long-term well-being that are known to decrease with age. The objective of this study is to understand the effect of our MBT program on telomerase activity and stem cells in blood collected from the participants. Here, we have investigated the effects of an intensive three weeks MBT retreat on telomerase activity and the peripheral blood stem cells in participants before and after the MBT. A total of 108 people were enrolled in the study; 38 men and 70 women (aged 18-90) randomly assigned for the study. Telomerase activity was greater in retreat participants at the end of the MBT retreat. About 45% of people showed more than one-fold increase of telomerase activity after our MBT program. Furthermore, about 27% of people showed more pronounced fold increase (2-fold) in telomerase activity after the MBT. In addition, a substantial percentage of people (about 90%) exhibited increased stem cell counts after the MBT. The data suggest increased telomerase activity and stem cells count in peripheral blood from MBT retreat participants that may lead to increased longevity and better quality of life at latter age.

  7. MicroRNA Regulation of Telomerase Reverse Transcriptase (TERT: Micro Machines Pull Strings of Papier-Mâché Puppets

    Directory of Open Access Journals (Sweden)

    Ammad Ahmad Farooqi

    2018-04-01

    Full Text Available Substantial fraction of high-quality information is continuously being added into the existing pool of knowledge related to the biology of telomeres. Based on the insights gleaned from decades of research, it is clear that chromosomal stability needs a highly controlled and dynamic balance of DNA gain and loss in each terminal tract of telomeric repeats. Telomeres are formed by tandem repeats of TTAGGG sequences, which are gradually lost with each round of division of the cells. Targeted inhibition of telomerase to effectively induce apoptosis in cancer cells has attracted tremendous attention and overwhelmingly increasingly list of telomerase inhibitors truthfully advocates pharmacological significance of telomerase. Telomerase reverse transcriptase (TERT is a multi-talented and catalytically active component of the telomerase-associated protein machinery. Different proteins of telomerase-associated machinery work in a synchronized and orchestrated manner to ensure proper maintenance of telomeric length of chromosomes. Rapidly emerging scientific findings about regulation of TERT by microRNAs has revolutionized our understanding related to the biology of telomeres and telomerase. In this review, we have comprehensively discussed how different miRNAs regulate TERT in different cancers. Use of miRNA-based therapeutics against TERT in different cancers needs detailed research in preclinical models for effective translation of laboratory findings to clinically effective therapeutics.

  8. [Diagnostic significance of serum free DNA human telomerase reverse transcriptase quantitative determination on spinal cord injury].

    Science.gov (United States)

    Yang, M K; Tang, J; Xiang, Z; Zhang, X; Wang, J; Li, Z; Li, Y; Sheng, W B

    2018-02-06

    Objective: To investigate the relationship between the content of human telomerase reverse transcriptase (hTERT) and its clinical features in serum free DNA in patients with different degree of spinal cord injury. Methods: From December 2013 to December 2016, inpatients of the Central Hospital of Bazhong, Sichuan Province were enrolledand divided into the experimental group, the disease control group and the negative control group. For the experimental group: 46 patients with spinal cord injury were graded according to the criteria of the American Association of Spinal Cord Injury (ASIA), including 12 cases of grade A, 10 cases of grade B, 10 cases of grade C, 7 cases of grade D and 7 cases of grade E; for the disease control group: 15 patients with spinal fractures (without spinal cord injury) at the same period were included; and for the negative control group: 20 healthy adult volunteers aged 18-50 years were selected.Real-time fluorescence quantitative PCR and immunoblotting were performed to detect the content of hTERT in serum free DNA both in patients and healthy controls and to compare the difference between them. The results of the somatosensory evoked potential (SEP) of all patients were compared and analyzed.The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of hTERT content in serum free DNA in patients with spinal cord injury. Results: Comparison of serum free DNA hTERT content: in the experimental group, the serum free DNA hTERT content of grade A, B, C, D, E was (99.63±8.23), (76.24±4.37), (46.07±5.43), (16.30±0.95) and (15.74±1.12)μg/L, respectively.While it was (15.01±1.39)μg/L in the disease control group and (14.54±1.03)μg/L in the negative control group. The total difference was statistically significant between patients of each group and the control group ( F =857.917, P spinal cord injury has a certain guiding significance for the diagnosis of spinal cord injury and the degree of injury.

  9. A possible human counterpart of the principle of increasing entropy

    International Nuclear Information System (INIS)

    Liang, Y.; An, K.N.; Yang, G.; Huang, J.P.

    2014-01-01

    It is well-known that the principle of increasing entropy holds for isolated natural systems that contain non-adaptive molecules. Here we present, for the first time, an experimental evidence for a possible human counterpart of the principle in an isolated social system that involves adaptive humans. Our work shows that the human counterpart is valid even though interactions among humans in social systems are distinctly different from those among molecules in natural systems. Thus, it becomes possible to understand social systems from this natural principle, at least to some extent.

  10. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

    Science.gov (United States)

    Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

    2016-04-07

    Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomerase Tert gene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- and Tert-deficient mice). We find that a high dose of AAV9-Tert targets the bone marrow compartment, including hematopoietic stem cells. AAV9-Tert treatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres. © 2016 by The American Society of Hematology.

  11. Telomerase Activity in Breast Tumor Tissues and its Possible use for Detection of Circulating Carcinoma Cells

    Czech Academy of Sciences Publication Activity Database

    Šimíčková, M.; Nekulová, M.; Pecen, Ladislav; Vagundová, M.; Maláska, J.; Obermannová, R.; Lauerová, L.

    2002-01-01

    Roč. 5, - (2002), s. 98 ISSN 1211-8869. [Central European Conference on Human Tumor Markers /4./. 13.02.2003-16.02.2003, Karlovy Vary] Institutional research plan: CEZ:AV0Z1030915 Keywords : telomerase activity * early detection of distant metastases * cancer reccurence Subject RIV: BB - Applied Statistics, Operational Research

  12. Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Chiodi, Ilaria; Mondello, Chiara, E-mail: mondello@igm.cnr.it [Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia (Italy)

    2012-09-28

    Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.

  13. Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Aparna Raval

    Full Text Available Telomere shortening is common in bone marrow failure syndromes such as dyskeratosis congenita (DC, aplastic anemia (AA and myelodysplastic syndromes (MDS. However, improved knowledge of the lineage-specific consequences of telomere erosion and restoration of telomere length in hematopoietic progenitors is required to advance therapeutic approaches. We have employed a reversible murine model of telomerase deficiency to compare the dependence of erythroid and myeloid lineage differentiation on telomerase activity. Fifth generation Tert-/- (G5 Tert-/- mice with shortened telomeres have significant anemia, decreased erythroblasts and reduced hematopoietic stem cell (HSC populations associated with neutrophilia and increased myelopoiesis. Intracellular multiparameter analysis by mass cytometry showed significantly reduced cell proliferation and increased sensitivity to activation of DNA damage checkpoints in erythroid progenitors and in erythroid-biased CD150hi HSC, but not in myeloid progenitors. Strikingly, Cre-inducible reactivation of telomerase activity restored hematopoietic stem and progenitor cell (HSPC proliferation, normalized the DNA damage response, and improved red cell production and hemoglobin levels. These data establish a direct link between the loss of TERT activity, telomere shortening and defective erythropoiesis and suggest that novel strategies to restore telomerase function may have an important role in the treatment of the resulting anemia.

  14. Quantitative Determination of Telomerase Activity in Breast Cancer and Benign Breast Diseases

    Czech Academy of Sciences Publication Activity Database

    Šimíčková, M.; Nekulová, M.; Pecen, Ladislav; Černoch, M.; Vagundová, M.; Pačovský, Z.

    2001-01-01

    Roč. 48, č. 4 (2001), s. 267-273 ISSN 0028-2685 R&D Projects: GA MZd NM17 Institutional research plan: AV0Z1030915 Keywords : telomerase activity * quantitative analysis * breast cancer * benign breast diseases * prognisis Subject RIV: BA - General Mathematics Impact factor: 0.637, year: 2001

  15. Telomere- and Telomerase-Associated Proteins and Their Functions in the Plant Cell

    Czech Academy of Sciences Publication Activity Database

    Schrumpfová, P.; Schorová, Š.; Fajkus, Jiří

    2016-01-01

    Roč. 7, č. 851 (2016) ISSN 1664-462X R&D Projects: GA ČR(CZ) GA13-06943S Institutional support: RVO:68081707 Keywords : telomere * telomerase * telomeric proteins Subject RIV: BO - Biophysics Impact factor: 4.298, year: 2016

  16. Tumorigenic Heterogeneity in Cancer Stem Cells Evolved from Long-term Cultures of Telomerase-Immortalized

    DEFF Research Database (Denmark)

    Burns, Jorge S; Abdallah, Basem M; Guldberg, Per

    2005-01-01

    Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if...

  17. Telomerase promoter reprogramming and interaction with general transcription factors in the human mesenchymal stem cell

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Hoare, Stacey F.; Kassem, Moustapha

    2006-01-01

    The human adult mesenchymal stem cell (hMSC) does not express telomerase and has been shown to be the target for neoplastic transformation after transduction with hTERT. These findings lend support to the stem cell hypothesis of cancer development but by supplying hTERT, the molecular events requ...

  18. HOT1 is a mammalian direct telomere repeat-binding protein contributing to telomerase recruitment

    NARCIS (Netherlands)

    Kappei, D.; Butter, F.; Benda, C.; Scheibe, M.; Draskovic, Irena; Stevense, M.; Novo, C.L.; Basquin, C.; Araki, M.; Araki, K.; Krastev, D.B.; Kittler, R.; Jessberger, R.; Londono-Vallejo, J.A.; Mann, M.; Buchholz, F.

    2013-01-01

    Telomeres are repetitive DNA structures that, together with the shelterin and the CST complex, protect the ends of chromosomes. Telomere shortening is mitigated in stem and cancer cells through the de novo addition of telomeric repeats by telomerase. Telomere elongation requires the delivery of the

  19. The Roles of Telomerase in the Generation of Polyploidy during Neoplastic Cell Growth

    Directory of Open Access Journals (Sweden)

    Agni Christodoulidou

    2013-02-01

    Full Text Available Polyploidy contributes to extensive intratumor genomic heterogeneity that characterizes advanced malignancies and is thought to limit the efficiency of current cancer therapies. It has been shown that telomere deprotection in p53-deficient mouse embryonic fibroblasts leads to high rates of polyploidization. We now show that tumor genome evolution through whole-genome duplication occurs in ∼15% of the karyotyped human neoplasms and correlates with disease progression. In a panel of human cancer and transformed cell lines representing the two known types of genomic instability (chromosomal and microsatellite, as well as the two known pathways of telomere maintenance in cancer (telomerase activity and alternative lengthening of telomeres, telomere dysfunction-driven polyploidization occurred independently of the mutational status of p53. Depending on the preexisting context of telomere maintenance, telomerase activity and its major components, human telomerase reverse transcriptase (hTERT and human telomerase RNA component (hTERC, exert both reverse transcriptase-related (canonical and noncanonical functions to affect tumor genome evolution through suppression or induction of polyploidization. These new findings provide a more complete mechanistic understanding of cancer progression that may, in the future, lead to novel therapeutic interventions.

  20. Does telomerase activity have an effect on infertility in patients with endometriosis?

    Science.gov (United States)

    Sofiyeva, Nigar; Ekizoglu, Seda; Gezer, Altay; Yilmaz, Handan; Kolomuc Gayretli, Tugba; Buyru, Nur; Oral, Engin

    2017-06-01

    This study aimed to investigate the role of telomerase activity in the development of endometriosis-related infertility by evaluation of the serum telomerase in eutopic and ectopic endometrial tissue. Eutopic endometrium, cystic wall/ovarian cortex, and venous blood were assessed in forty-seven patients. The following groups of patients were identified: females with endometriosis requiring surgical intervention and healthy control females. Patients with histopathologically confirmed endometriosis were further subdivided in the infertile (n=14) and fertile (n=17) groups. Patients who underwent hysterectomy and oophorectomy for benign gynecological conditions were enrolled in the healthy control group (n=16). Telomerase activity was evaluated with three-group, endometriosis-based and fertility-based designs. Analyses were performed regardless the menstrual cycle phase (Phase G), in proliferative (Phase P) (n=22) and secretory phases (Phase S) (n=25). Telomeric Repeat Amplification Protocol PCR was applied for telomerase activity assessment. All statistical analyses were performed with STATA 14.2, GraphPad Prisma 7.01. In analyses of the eutopic endometrium, with three-group design, a significant difference was not found in Phase G and P (p=0.58 and p=0.33, respectively). However, a statistical difference was shown in Phase S (p=0.008). A significant difference was not established in Phase G, P and S of endometriosis-based design (p=0.35, p=1.0, p=0.13, respectively). No difference was detected in Phase G and P of fertility-based design (p=0.66 and p=0.14, respectively), whereas in secretory phase difference was approved (p=0,049). Telomerase activity was not established in ectopic endometrium and in serum assessment. Telomerase activity is useless as a biomarker in peripheric blood analysis. The absence of activity in cystic wall approves the high differentiation of endometriosis tissue, what is the possible reason of low malignancy risk. The high rate of telomerase

  1. Search for infrared counterparts of gamma-ray bursters

    International Nuclear Information System (INIS)

    Schaefer, B.E.; Cline, T.L.

    1985-01-01

    The result of two searches for infrared counterparts of Gamma-ray Bursters (GRB's) is reported. The first search was made using data from the Infrared Astronomy Satellite and covered 23 positions. The second search was made with the Kitt Peak 1.5 m telescope and covered 3 positions. In neither of these two searches was any infrared candidate detected

  2. Continual Lie algebras and noncommutative counterparts of exactly solvable models

    Science.gov (United States)

    Zuevsky, A.

    2004-01-01

    Noncommutative counterparts of exactly solvable models are introduced on the basis of a generalization of Saveliev-Vershik continual Lie algebras. Examples of noncommutative Liouville and sin/h-Gordon equations are given. The simplest soliton solution to the noncommutative sine-Gordon equation is found.

  3. VARIABILITY OF OPTICAL COUNTERPARTS IN THE CHANDRA GALACTIC BULGE SURVEY

    Energy Technology Data Exchange (ETDEWEB)

    Britt, C. T.; Hynes, R. I.; Johnson, C. B.; Baldwin, A.; Collazzi, A.; Gossen, L. [Department of Physics and Astronomy, Louisiana State University, Baton Rouge, LA 70803-4001 (United States); Jonker, P. G.; Torres, M. A. P. [SRON, Netherlands Institute for Space Research, Sorbonnelaan 2, 3584 CA Utrecht (Netherlands); Nelemans, G. [Department of Astrophysics, IMAPP, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen (Netherlands); Maccarone, T. [Department of Physics, Texas Tech University, Box 41051, Science Building, Lubbock, TX 79409-1051 (United States); Steeghs, D.; Greiss, S. [Astronomy and Astrophysics, Department of Physics, University of Warwick, Coventry, CV4 7AL (United Kingdom); Heinke, C. [Department of Physics, University of Alberta, CCIS 4-183, Edmonton, AB T6G 2E1 (Canada); Bassa, C. G. [Jodrell Bank Centre for Astrophysics, School of Physics and Astronomy, University of Manchester, Manchester M13 9PL (United Kingdom); Villar, A. [Department of Physics, Massachussettes Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4307 (United States); Gabb, M. [Department of Physics, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991 (United States)

    2014-09-01

    We present optical light curves of variable stars consistent with the positions of X-ray sources identified with the Chandra X-ray Observatory for the Chandra Galactic Bulge Survey (GBS). Using data from the Mosaic-II instrument on the Blanco 4 m Telescope at CTIO, we gathered time-resolved photometric data on timescales from ∼2 hr to 8 days over the 3/4 of the X-ray survey containing sources from the initial GBS catalog. Among the light curve morphologies we identify are flickering in interacting binaries, eclipsing sources, dwarf nova outbursts, ellipsoidal variations, long period variables, spotted stars, and flare stars. Eighty-seven percent of X-ray sources have at least one potential optical counterpart. Twenty-seven percent of these candidate counterparts are detectably variable; a much greater fraction than expected for randomly selected field stars, which suggests that most of these variables are real counterparts. We discuss individual sources of interest, provide variability information on candidate counterparts, and discuss the characteristics of the variable population.

  4. 76 FR 61090 - Endangered and Threatened Species; Counterpart Regulations

    Science.gov (United States)

    2011-10-03

    ..., National Fire Plan Counterpart Regulation Alternative Consultation Agreements (ACAs). DATES: This is effective on October 1, 2011. ADDRESSES: The final decision of revocation is available on the internet at http://www.nmfs.noaa.gov/pr/laws/esa/policies.htm#consultation and http://www.fws.gov/endangered/esa...

  5. Antioxidant therapy attenuates myocardial telomerase activity reduction in superoxide dismutase-deficient mice.

    Science.gov (United States)

    Makino, Naoki; Maeda, Toyoki; Oyama, Jun-ichi; Sasaki, Makoto; Higuchi, Yoshihiro; Mimori, Koji; Shimizu, Takahiko

    2011-04-01

    Oxidative stress plays a pathological role in the development of heart failure. This study examined telomere biology in heart/muscle-specific manganese superoxide dismutase-deficient mice (H/M-SOD2(-/-)), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. EUK-8 (25mg/kg/day), a superoxide dismutase and catalase mimetic, was administered to H/M-SOD2(-/-) mice for four weeks beginning at 8 weeks of age. Telomere length, telomerase activity, telomere-associated proteins, and cell death signals were assessed in hearts from control wild-type mice (H/M-Sod2 (lox/ lox)) and H/M-SOD2(-/-) mice either treated or untreated with EUK-8. While cardiac function was unchanged in these experimental mice, the end-diastolic dimension in H/M-SOD2(-/-) mice was notably dilated and could be significantly reduced by EUK-8 treatment. At the end of the study, no shortening of telomere length was observed in heart tissues from all mice tested, but telomerase activity was decreased in heart tissue from H/M-SOD2(-/-) mice compared to control mice. Protein expression for telomerase reverse transcriptase and telomere repeat binding factor 2 was also downregulated in H/M-SOD2(-/-) heart tissue as was expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase. Expression levels of Sirt1, a lifespan modulator, were enhanced while FoxO3a was depressed in H/M-SOD2(-/-) hearts. All of the changes seen in H/M-SOD2(-/-) heart tissue could be inhibited by EUK-8 treatment. Taken together, the results suggest that oxidant stress might affect myocardial telomerase activity and telomere-associated proteins. Telomerase may therefore play a pivotal role in antioxidant defense mechanisms, and may be useful as a novel therapeutic tool for treating human heart failure. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Integration of intracellular telomerase monitoring by electrochemiluminescence technology and targeted cancer therapy by reactive oxygen species.

    Science.gov (United States)

    Zhang, Huairong; Li, Binxiao; Sun, Zhaomei; Zhou, Hong; Zhang, Shusheng

    2017-12-01

    Cancer therapies based on reactive oxygen species (ROS) have emerged as promising clinical treatments. Electrochemiluminescence (ECL) technology has also attracted considerable attention in the field of clinical diagnosis. However, studies about the integration of ECL diagnosis and ROS cancer therapy are very rare. Here we introduce a novel strategy that employs ECL technology and ROS to fill the above vacancy. Briefly, an ITO electrode was electrodeposited with polyluminol-Pt NPs composite films and modified with aptamer DNA to capture HL-60 cancer cells with high specificity. After that, mesoporous silica nanoparticles (MSNs) filled with phorbol 12-myristate 13-acetate (PMA) were closed by the telomerase primer DNA (T-primer DNA) and aptamer. After aptamer on MSN@PMA recognized and combined with the HL-60 cancer cells with high specificity, T-primer DNA on MSN@PMA could be moved away from the MSN@PMA surface after extension by telomerase in the HL-60 cancer cells and PMA was released to induce the production of ROS by the HL-60 cancer cells. After that, the polyluminol-Pt NPs composite films could react with hydrogen peroxide (a major ROS) and generate an ECL signal. Thus the intracellular telomerase activity of the HL-60 cancer cells could be detected in situ . Besides, ROS could induce apoptosis in the HL-60 cancer cells with high efficacy by causing oxidative damage to the lipids, protein, and DNA. Above all, the designed platform could not only detect intracellular telomerase activity instead of that of extracted telomerase, but could also kill targeted tumors by ECL technology and ROS.

  7. Dynamic telomerase gene suppression via network effects of GSK3 inhibition.

    Directory of Open Access Journals (Sweden)

    Alan E Bilsland

    2009-07-01

    Full Text Available Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression.In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3'-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFkappaB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc.Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting.

  8. Correlation between telomerase and mTOR pathway in cancer stem cells.

    Science.gov (United States)

    Dogan, Fatma; Biray Avci, Cigir

    2018-01-30

    Cancer stem cells (CSCs), which are defined as a subset of tumor cells, are able to self-renew, proliferate, differentiate similar to normal stem cells. Therefore, targeting CSCs has been considered as a new approach in cancer therapy. The mammalian target of rapamycin (mTOR) is a receptor tyrosine kinase which plays an important role in regulating cell proliferation, differentiation, cell growth, self-renewal in CSCs. On the other hand, hTERT overactivation provides replicative feature and immortality to CSCs, so the stemness and replicative properties of CSCs depend on telomerase activity. Therefore hTERT/telomerase activity may become a universal biomarker for anticancer therapy and it is an attractive therapeutic target for CSCs. It is known that mTOR regulates telomerase activity at the translational and post-translational level. Researchers show that mTOR inhibitor rapamycin reduces telomerase activity without changing hTERT mRNA activity. Correlation between mTOR and hTERT is important for survival and immortality of cancer cells. In addition, the PI3K/AKT/mTOR signaling pathway and hTERT up-regulation are related with cancer stemness features and drug resistance. mTOR inhibitor and TERT inhibitor combination may construct a novel strategy in cancer stem cells and it can make a double effect on telomerase enzyme. Consequently, inhibition of PI3K/AKT/mTOR signaling pathway components and hTERT activation may prohibit CSC self-renewal and surpass CSC-mediated resistance in order to develop new cancer therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Cell cycle-dependent transcription factors control the expression of yeast telomerase RNA.

    Science.gov (United States)

    Dionne, Isabelle; Larose, Stéphanie; Dandjinou, Alain T; Abou Elela, Sherif; Wellinger, Raymund J

    2013-07-01

    Telomerase is a specialized ribonucleoprotein that adds repeated DNA sequences to the ends of eukaryotic chromosomes to preserve genome integrity. Some secondary structure features of the telomerase RNA are very well conserved, and it serves as a central scaffold for the binding of associated proteins. The Saccharomyces cerevisiae telomerase RNA, TLC1, is found in very low copy number in the cell and is the limiting component of the known telomerase holoenzyme constituents. The reasons for this low abundance are unclear, but given that the RNA is very stable, transcriptional control mechanisms must be extremely important. Here we define the sequences forming the TLC1 promoter and identify the elements required for its low expression level, including enhancer and repressor elements. Within an enhancer element, we found consensus sites for Mbp1/Swi4 association, and chromatin immunoprecipitation (ChIP) assays confirmed the binding of Mbp1 and Swi4 to these sites of the TLC1 promoter. Furthermore, the enhancer element conferred cell cycle-dependent regulation to a reporter gene, and mutations in the Mbp1/Swi4 binding sites affected the levels of telomerase RNA and telomere length. Finally, ChIP experiments using a TLC1 RNA-binding protein as target showed cell cycle-dependent transcription of the TLC1 gene. These results indicate that the budding yeast TLC1 RNA is transcribed in a cell cycle-dependent fashion late in G1 and may be part of the S phase-regulated group of genes involved in DNA replication.

  10. Low LET radiation-induced telomerase catalytic subunit promoter activation is mediated by nuclear factor Kappa B

    International Nuclear Information System (INIS)

    Natarajan, M.; Hong, F.A.; Mohan, S.; Herman, T.S.

    2003-01-01

    Full text: The objective of this study is to understand whether low doses of low LET radiation induces survival advantage in normal cells. As an increase in telomerase activity is associated with longevity and cell proliferation, we examined the telomerase response following gamma-irradiation in normal aortic endothelial cells. Telomeric Repeat Amplification Protocol assay following low LET radiation showed an increase in telomerase enzyme activity as early as 8 h post irradiation and reaches its maximum at 24 h. Subsequent analysis revealed that the increased telomerse enzyme activity is due to increased synthesis resulting from an increased transcription. Examination of transcriptional activation of telomerase reverse transcriptase (TERT) promoter regulation showed an enhanced transcription of the telomerse gene following gamma-irradiation. In our previous reports we documented an increase in NF-kB DNA-binding property following low LET radiation (3). Therefore, to determine whether the activation of NF-kB-signaling is responsible for induced TERT promoter activation, cells transiently transfected with minimal promoter region of TERT containing wild type or mutant NF-kB binding site were examined following low LET radiation. TERT promoter activation was induced in wild type transfected cells whereas, in mutant kB binding site, the activation remained at the basal level similar to that of un-irradiated cells. More significantly, the gamma-ray mediated promoter activation of telomerase gene as well as induce telomerase enzyme activity was abrogated by ectopically expressing the IkBa mutant (IkBa (S32A/S36A)), which blocks NF-kB activation. The results thus suggest that exposure to low LET radiation could induce telomerase activity and the activation is at least, in part, mediated by the transcription factor NF-kB. Sustained activation of telomerase in these cells after low LET radiation may impart extended life span

  11. Search for Gravitational Wave Counterparts with Fermi GBM

    Science.gov (United States)

    Hui, C. M.

    2017-01-01

    The progenitor of short gamma-ray bursts (GRBs) is believed to be the merger of two compact objects. This type of events will also produce gravitational waves. Since the gravitational waves discovery by LIGO, the search for a joint detection with an electromagnetic counterpart has been ongoing. Fermi GBM detects approximately 40 short GRBs per year, and we have been expanding our search looking for faint events in the GBM data that did not trigger onboard.

  12. Nanocurcumin-Mediated Down-Regulation of Telomerase Via Stimulating TGFβ1 Signaling Pathway in Hepatocellular Carcinoma Cells

    Science.gov (United States)

    Shariati, Molood; Hajigholami, Samira; Veisi Malekshahi, Ziba; Entezari, Maliheh; Bodaghabadi, Narges; Sadeghizadeh, Majid

    2017-10-10

    Curcumin, extracted from turmeric, represents enormous potential to serve as an anticancer agent. Telomerase is viewed as a prominent molecular target of curcumin, and Transforming growth factor-β1 (TGFβ1) has proven to be a major inhibitory signaling pathway for telomerase activity. In the current study, we aimed to explore suppressive effects of nanocurcumin on telomerase expression through TGFβ1 pathway in a hepatocellular carcinoma cell line (Huh7). MTT assay was used to determine the effect of nonocurcumin on viability of Huh7 cells. RT-PCR was used to analyze the gene expression patterns. MTT assay revealed that nanocurcumin acts in a dose- and time-dependent manner to diminish the cell viability. RT-PCR analysis indicated that nanocurcumin results in augmentation of TGFβ1 72 hours post treatment and leads to the reduction of telomerase expression 48 and 72 hours post exposure. Also, up-regulation of Smad3 and E2F1 and down-regulation of Smad7 confirmed the effect of nanocurcumin on intermediate components of TGFβ1 pathway. Furthermore, transfection of the proximal promoter of telomerase triggered a significant reduction in luciferase activity. The data from the present study lead us to develop a deeper understanding of the mechanisms underlying nanocurcumin-mediated regulation of telomerase expression, thereby presenting a new perspective to the landscape of using nanocurcumin as a cancer-oriented therapeutic agent.

  13. Telomere Elongation and Naive Pluripotent Stem Cells Achieved from Telomerase Haplo-Insufficient Cells by Somatic Cell Nuclear Transfer

    Directory of Open Access Journals (Sweden)

    Li-Ying Sung

    2014-12-01

    Full Text Available Summary: Haplo-insufficiency of telomerase genes in humans leads to telomere syndromes such as dyskeratosis congenital and idiopathic pulmonary fibrosis. Generation of pluripotent stem cells from telomerase haplo-insufficient donor cells would provide unique opportunities toward the realization of patient-specific stem cell therapies. Recently, pluripotent human embryonic stem cells (ntESCs have been efficiently achieved by somatic cell nuclear transfer (SCNT. We tested the hypothesis that SCNT could effectively elongate shortening telomeres of telomerase haplo-insufficient cells in the ntESCs with relevant mouse models. Indeed, telomeres of telomerase haplo-insufficient (Terc+/− mouse cells are elongated in ntESCs. Moreover, ntESCs derived from Terc+/− cells exhibit naive pluripotency as evidenced by generation of Terc+/− ntESC clone pups by tetraploid embryo complementation, the most stringent test of naive pluripotency. These data suggest that SCNT could offer a powerful tool to reprogram telomeres and to discover the factors for robust restoration of telomeres and pluripotency of telomerase haplo-insufficient somatic cells. : Sung et al. demonstrate in a mouse model that telomeres of telomerase haplo-insufficient cells can be elongated by somatic cell nuclear transfer. Moreover, ntESCs derived from Terc+/− cells exhibit pluripotency evidenced by generation of Terc+/−ntESC clone pups by tetraploid embryo complementation, the most stringent test of naive pluripotency.

  14. Determination of the activity of telomerase in cancer cells by using BSA-protected gold nanoclusters as a fluorescent probe.

    Science.gov (United States)

    Xu, Yujuan; Zhang, Peng; Wang, Zhen; Lv, Shaoping; Ding, Caifeng

    2018-02-27

    Gold nanoclusters (AuNCs) protected with a bovine serum albumin (BSA) coating are known to emit red fluorescence (peaking at 650 nm) on photoexcitation with ultraviolet light (365 nm). On addition of Cu(II) ions, fluorescence is quenched because Cu(II) complexes certain amino acid units in the BSA chain. Fluorescence is, however, restored if pyrophosphate (PPi) is added because it will chelate Cu(II) and remove it from the BSA coating on the AuNCs. Because PPi is involved in the function of telomerase, the BSA@AuNCs loaded with Cu(II) can act as a fluorescent probe for determination of the activity of telomerase. A fluorescent assay was worked out for telomerase that is highly sensitive and has a wide linear range (10 nU to 10 fM per mL). The fluorescent probe was applied to the determination of telomerase activity in cervix carcinoma cells via imaging. It is shown that tumor cells can be well distinguished from normal cells by monitoring the differences in intracellular telomerase activity. Graphical abstract Gold nanoclusters (AuNCs) protected by bovine serum albumin (BSA) and displaying red photoluminescence were prepared as fluorescent probe for the determination of telomerase activity and used for imaging of cervix carcinoma (HeLa) cells.

  15. Formation of radiation induced chromosome aberrations: involvement of telomeric sequences and telomerase

    International Nuclear Information System (INIS)

    Pirzio, L.

    2004-07-01

    As telomeres are crucial for chromosome integrity; we investigated the role played by telomeric sequences in the formation and in the transmission of radio-induced chromosome rearrangements in human cells. Starting from interstitial telomeric sequences (ITS) as putative region of breakage, we showed that the radiation sensitivity is not equally distributed along chromosomes and. is not affected by ITS. On the contrary, plasmid integration sites are prone to radio-induced breaks, suggesting a possible integration at sites already characterized by fragility. However plasmids do not preferentially insert at radio-induced breaks in human cells immortalized by telomerase. These cells showed remarkable karyotype stability even after irradiation, suggesting a role of telomerase in the genome maintenance despite functional telomeres. Finally, we showed that the presence of more breaks in a cell favors the repair, leading to an increase of transmissible rearrangements. (author)

  16. Food supplement 20070721-GX may increase CD34+ stem cells and telomerase activity.

    Science.gov (United States)

    Lin, Po-Cheng; Chiou, Tzyy-Wen; Liu, Po-Yen; Chen, Shee-Ping; Wang, Hsin-I; Huang, Pi-Chun; Lin, Shinn-Zong; Harn, Horng-Jyh

    2012-01-01

    Few rejuvenation and antiaging markers are used to evaluate food supplements. We measured three markers in peripheral blood to evaluate the antiaging effects of a food supplement containing placental extract. Samples were evaluated for CD34(+) cells, insulin-like growth factor 1 (IGF1), and telomerase activity, which are all markers related to aging. To control the quality of this food supplement, five active components were monitored. In total, we examined 44 individuals who took the food supplement from 1.2 months to 23 months; the average number of CD34(+) cells was almost 6-fold higher in the experimental group compared with the control group. Food supplement intake did not change serum IGF1 levels significantly. Finally, the average telomerase activity was 30% higher in the subjects taking this food supplement. In summary, our results suggest that the placental extract in the food supplement might contribute to rejuvenation and antiaging.

  17. Food Supplement 20070721-GX May Increase CD34+ Stem Cells and Telomerase Activity

    Directory of Open Access Journals (Sweden)

    Po-Cheng Lin

    2012-01-01

    Full Text Available Few rejuvenation and antiaging markers are used to evaluate food supplements. We measured three markers in peripheral blood to evaluate the antiaging effects of a food supplement containing placental extract. Samples were evaluated for CD34+ cells, insulin-like growth factor 1 (IGF1, and telomerase activity, which are all markers related to aging. To control the quality of this food supplement, five active components were monitored. In total, we examined 44 individuals who took the food supplement from 1.2 months to 23 months; the average number of CD34+ cells was almost 6-fold higher in the experimental group compared with the control group. Food supplement intake did not change serum IGF1 levels significantly. Finally, the average telomerase activity was 30% higher in the subjects taking this food supplement. In summary, our results suggest that the placental extract in the food supplement might contribute to rejuvenation and antiaging.

  18. NBS1 plays a synergistic role with telomerase in the maintenance of telomeres in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Najdekrova Lucie

    2012-09-01

    Full Text Available Abstract Background Telomeres, as elaborate nucleo-protein complexes, ensure chromosomal stability. When impaired, the ends of linear chromosomes can be recognised by cellular repair mechanisms as double-strand DNA breaks and can be healed by non-homologous-end-joining activities to produce dicentric chromosomes. During cell divisions, particularly during anaphase, dicentrics can break, thus producing naked chromosome tips susceptible to additional unwanted chromosome fusion. Many telomere-building protein complexes are associated with telomeres to ensure their proper capping function. It has been found however, that a number of repair complexes also contribute to telomere stability. Results We used Arabidopsis thaliana to study the possible functions of the DNA repair subunit, NBS1, in telomere homeostasis using knockout nbs1 mutants. The results showed that although NBS1-deficient plants were viable, lacked any sign of developmental aberration and produced fertile seeds through many generations upon self-fertilisation, plants also missing the functional telomerase (double mutants, rapidly, within three generations, displayed severe developmental defects. Cytogenetic inspection of cycling somatic cells revealed a very early onset of massive genome instability. Molecular methods used for examining the length of telomeres in double homozygous mutants detected much faster telomere shortening than in plants deficient in telomerase gene alone. Conclusions Our findings suggest that NBS1 acts in concert with telomerase and plays a profound role in plant telomere renewal.

  19. NBS1 plays a synergistic role with telomerase in the maintenance of telomeres in Arabidopsis thaliana.

    Science.gov (United States)

    Najdekrova, Lucie; Siroky, Jiri

    2012-09-17

    Telomeres, as elaborate nucleo-protein complexes, ensure chromosomal stability. When impaired, the ends of linear chromosomes can be recognised by cellular repair mechanisms as double-strand DNA breaks and can be healed by non-homologous-end-joining activities to produce dicentric chromosomes. During cell divisions, particularly during anaphase, dicentrics can break, thus producing naked chromosome tips susceptible to additional unwanted chromosome fusion. Many telomere-building protein complexes are associated with telomeres to ensure their proper capping function. It has been found however, that a number of repair complexes also contribute to telomere stability. We used Arabidopsis thaliana to study the possible functions of the DNA repair subunit, NBS1, in telomere homeostasis using knockout nbs1 mutants. The results showed that although NBS1-deficient plants were viable, lacked any sign of developmental aberration and produced fertile seeds through many generations upon self-fertilisation, plants also missing the functional telomerase (double mutants), rapidly, within three generations, displayed severe developmental defects. Cytogenetic inspection of cycling somatic cells revealed a very early onset of massive genome instability. Molecular methods used for examining the length of telomeres in double homozygous mutants detected much faster telomere shortening than in plants deficient in telomerase gene alone. Our findings suggest that NBS1 acts in concert with telomerase and plays a profound role in plant telomere renewal.

  20. Mixed Integer Linear Programming based machine learning approach identifies regulators of telomerase in yeast.

    Science.gov (United States)

    Poos, Alexandra M; Maicher, André; Dieckmann, Anna K; Oswald, Marcus; Eils, Roland; Kupiec, Martin; Luke, Brian; König, Rainer

    2016-06-02

    Understanding telomere length maintenance mechanisms is central in cancer biology as their dysregulation is one of the hallmarks for immortalization of cancer cells. Important for this well-balanced control is the transcriptional regulation of the telomerase genes. We integrated Mixed Integer Linear Programming models into a comparative machine learning based approach to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in yeast mutants with deleted regulators showing aberrant telomere length, when compared to mutants with normal telomere length. We uncover novel regulators of telomerase expression, several of which affect histone levels or modifications. In particular, our results point to the transcription factors Sum1, Hst1 and Srb2 as being important for the regulation of EST1 transcription, and we validated the effect of Sum1 experimentally. We compiled our machine learning method leading to a user friendly package for R which can straightforwardly be applied to similar problems integrating gene regulator binding information and expression profiles of samples of e.g. different phenotypes, diseases or treatments. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging

    Directory of Open Access Journals (Sweden)

    Hoi-Hung Cheung

    2014-04-01

    Full Text Available Werner syndrome (WS patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem cells (MSCs and neural stem/progenitor cells (NPCs. We observed recurrence of premature senescence associated with accelerated telomere attrition and defective synthesis of the lagging strand telomeres in MSCs, but not in NPCs. We postulate this “aging” discrepancy is regulated by telomerase. Expression of hTERT or p53 knockdown ameliorated the accelerated aging phenotypein MSC, whereas inhibition of telomerase sensitized NPCs to DNA damage. Our findings unveil a role for telomerase in the protection of accelerated aging in a specific lineage of stem cells.

  2. Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Bu, Xinxin; Jia, Fengqi; Wang, Weifeng; Guo, Xianling; Wu, Mengchao; Wei, Lixin [Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Hospital, Second Military Medical Universisty, 225 Changhai Road, Shanghai 200438 (China)

    2007-11-12

    Hepatocellular carcinoma (HCC) is the most invasive and frequently diagnosed malignancy and the second leading cause of cancer death in many regions of Asia. The PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Up-regulation of telomerase activity is thought to be a critical step leading to cell transformation. This study investigated changes in mTOR pathway and telomerase activity in hepatocarcinoma cell line SMMC-7721 treated with chemotherapeutic agent 5-fluorouracil (5-Fu). We detected apoptosis of hepatocarcinoma cells by TUNEL assay. Telomerase activity, hTERT transcription level and p- p70 S6k was demonstrated by the telomeric repeat amplification protocol and silver staining assay, Dual-Luciferase Reporter Assay and Western blot analysis respectively. Treating SMMC-7721 cells with 5-Fu leads to apoptosis of the cells, and reduction in telomerase activity, as well as a dramatic reduction in the activated form of p70 S6 kinase, a mTOR substrate. The 5-Fu treatment nearly abolishes transcription of hTERT (the major component of telomerase) mRNA. Treating SMMC-7721 cells with Rapamycin, a specific mTOR inhibitor, significantly reduce hTERT protein level but did not affect hTERT transcription. 5-Fu and rapamycin were synergistic in regards to down-regulation of telomerase activity in hepatocarcinoma cells. These results suggest that chemotherapeutic agent 5-Fu may down-regulate telomerase activity at both transcriptional level and PI3K/Akt/mTOR pathway-dependent post-transcriptional level to facilitate hepatocellular carcinoma cell apoptosis.

  3. Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells

    International Nuclear Information System (INIS)

    Bu, Xinxin; Jia, Fengqi; Wang, Weifeng; Guo, Xianling; Wu, Mengchao; Wei, Lixin

    2007-01-01

    Hepatocellular carcinoma (HCC) is the most invasive and frequently diagnosed malignancy and the second leading cause of cancer death in many regions of Asia. The PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Up-regulation of telomerase activity is thought to be a critical step leading to cell transformation. This study investigated changes in mTOR pathway and telomerase activity in hepatocarcinoma cell line SMMC-7721 treated with chemotherapeutic agent 5-fluorouracil (5-Fu). We detected apoptosis of hepatocarcinoma cells by TUNEL assay. Telomerase activity, hTERT transcription level and p- p70 S6k was demonstrated by the telomeric repeat amplification protocol and silver staining assay, Dual-Luciferase Reporter Assay and Western blot analysis respectively. Treating SMMC-7721 cells with 5-Fu leads to apoptosis of the cells, and reduction in telomerase activity, as well as a dramatic reduction in the activated form of p70 S6 kinase, a mTOR substrate. The 5-Fu treatment nearly abolishes transcription of hTERT (the major component of telomerase) mRNA. Treating SMMC-7721 cells with Rapamycin, a specific mTOR inhibitor, significantly reduce hTERT protein level but did not affect hTERT transcription. 5-Fu and rapamycin were synergistic in regards to down-regulation of telomerase activity in hepatocarcinoma cells. These results suggest that chemotherapeutic agent 5-Fu may down-regulate telomerase activity at both transcriptional level and PI3K/Akt/mTOR pathway-dependent post-transcriptional level to facilitate hepatocellular carcinoma cell apoptosis

  4. Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Wu Mengchao

    2007-11-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is the most invasive and frequently diagnosed malignancy and the second leading cause of cancer death in many regions of Asia. The PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Up-regulation of telomerase activity is thought to be a critical step leading to cell transformation. Methods This study investigated changes in mTOR pathway and telomerase activity in hepatocarcinoma cell line SMMC-7721 treated with chemotherapeutic agent 5-fluorouracil (5-Fu. We detected apoptosis of hepatocarcinoma cells by TUNEL assay. Telomerase activity, hTERT transcription level and p- p70 S6k was demonstrated by the telomeric repeat amplification protocol and silver staining assay, Dual-Luciferase Reporter Assay and Western blot analysis respectively. Results Treating SMMC-7721 cells with 5-Fu leads to apoptosis of the cells, and reduction in telomerase activity, as well as a dramatic reduction in the activated form of p70 S6 kinase, a mTOR substrate. The 5-Fu treatment nearly abolishes transcription of hTERT (the major component of telomerase mRNA. Treating SMMC-7721 cells with Rapamycin, a specific mTOR inhibitor, significantly reduce hTERT protein level but did not affect hTERT transcription. 5-Fu and rapamycin were synergistic in regards to down-regulation of telomerase activity in hepatocarcinoma cells. Conclusion These results suggest that chemotherapeutic agent 5-Fu may down-regulate telomerase activity at both transcriptional level and PI3K/Akt/mTOR pathway-dependent post-transcriptional level to facilitate hepatocellular carcinoma cell apoptosis.

  5. Identification of a Likely Radio Counterpart to the Rapid Burster

    Science.gov (United States)

    Moore, Christopher B.; Rutledge, Robert E.; Fox, Derek W.; Guerriero, Robert A.; Lewin, Walter H. G.; Fender, Robert; van Paradijs, Jan

    2000-04-01

    We have identified a likely radio counterpart to the low-mass X-ray binary MXB 1730-335 (the Rapid Burster). The counterpart has shown 8.4 GHz radio on/off behavior correlated with the X-ray on/off behavior as observed by the RXTE/ASM during six VLA observations. The probability of an unrelated, randomly varying background source duplicating this behavior is 1%-3% depending on the correlation timescale. The location of the radio source is R.A. 17h33m24.61s, decl. -33 deg23'19.8" (J2000), +/-0.1". We do not detect 8.4 GHz radio emission coincident with type II (accretion-driven) X-ray bursts. The ratio of radio to X-ray emission during such bursts is constrained to be below the ratio observed during X-ray-persistent emission at the 2.9 σ level. Synchrotron bubble models of the radio emission can provide a reasonable fit to the full data set, collected over several outbursts, assuming that the radio evolution is the same from outburst to outburst but given the physical constraints the emission is more likely to be due to ~1 hr radio flares such as have been observed from the X-ray binary GRS 1915+105.

  6. Driving protocol for a Floquet topological phase without static counterpart

    Science.gov (United States)

    Quelle, A.; Weitenberg, C.; Sengstock, K.; Morais Smith, C.

    2017-11-01

    Periodically driven systems play a prominent role in optical lattices. In these ultracold atomic systems, driving is used to create a variety of interesting behaviours, of which an important example is provided by topological states of matter. Such Floquet topological phases have a richer classification than their equilibrium counterparts. Although there exist analogues of the equilibrium topological phases that are characterised by a Chern number, the corresponding Hall conductivity, and protected edge states, there is an additional possibility. This is a phase that has a vanishing Chern number and no Hall conductivity, but nevertheless hosts anomalous topological edge states (Rudner et al (2013 Phys. Rev. X 3 031005)). Due to experimental difficulties associated with the observation of such a phase, it has not been experimentally realised in optical lattices so far. In this paper, we show that optical lattices prove to be a good candidate for its realisation and observation, because they can be driven in a controlled manner. Specifically, we present a simple shaking protocol that serves to realise this special Floquet phase, discuss the specific properties that it has, and propose a method to experimentally detect this fascinating topological phase that has no counterpart in equilibrium systems.

  7. Herpesvirus telomerase RNA (vTR with a mutated template sequence abrogates herpesvirus-induced lymphomagenesis.

    Directory of Open Access Journals (Sweden)

    Benedikt B Kaufer

    2011-10-01

    Full Text Available Telomerase reverse transcriptase (TERT and telomerase RNA (TR represent the enzymatically active components of telomerase. In the complex, TR provides the template for the addition of telomeric repeats to telomeres, a protective structure at the end of linear chromosomes. Human TR with a mutation in the template region has been previously shown to inhibit proliferation of cancer cells in vitro. In this report, we examined the effects of a mutation in the template of a virus encoded TR (vTR on herpesvirus-induced tumorigenesis in vivo. For this purpose, we used the oncogenic avian herpesvirus Marek's disease virus (MDV as a natural virus-host model for lymphomagenesis. We generated recombinant MDV in which the vTR template sequence was mutated from AATCCCAATC to ATATATATAT (vAU5 by two-step Red-mediated mutagenesis. Recombinant viruses harboring the template mutation replicated with kinetics comparable to parental and revertant viruses in vitro. However, mutation of the vTR template sequence completely abrogated virus-induced tumor formation in vivo, although the virus was able to undergo low-level lytic replication. To confirm that the absence of tumors was dependent on the presence of mutant vTR in the telomerase complex, a second mutation was introduced in vAU5 that targeted the P6.1 stem loop, a conserved region essential for vTR-TERT interaction. Absence of vTR-AU5 from the telomerase complex restored virus-induced lymphoma formation. To test if the attenuated vAU5 could be used as an effective vaccine against MDV, we performed vaccination-challenge studies and determined that vaccination with vAU5 completely protected chickens from lethal challenge with highly virulent MDV. Taken together, our results demonstrate 1 that mutation of the vTR template sequence can completely abrogate virus-induced tumorigenesis, likely by the inhibition of cancer cell proliferation, and 2 that this strategy could be used to generate novel vaccine candidates

  8. Low-Dose Fluvastatin and Valsartan Rejuvenate the Arterial Wall Through Telomerase Activity Increase in Middle-Aged Men.

    Science.gov (United States)

    Janić, Miodrag; Lunder, Mojca; Cerkovnik, Petra; Prosenc Zmrzljak, Uršula; Novaković, Srdjan; Šabovič, Mišo

    2016-04-01

    Previously, we have shown that slightly to moderately aged arteries in middle-aged males can be rejuvenated functionally by sub-therapeutic, low-dose fluvastatin and valsartan treatment. Here, we explore whether this treatment could also increase telomerase activity. We hypothesized that telomerase activity might be associated with (1) an improvement of arterial wall properties and (2) a reduction of inflammatory/oxidative stress parameters (both observed in our previous studies). The stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin and valsartan combination (10 and 20 mg), respectively, and placebo (control), were analyzed. The samples were taken before and after treatment lasting 30 days, and 5 months after treatment discontinuation. Telomerase activity was measured in blood leukocytes by a TaqMan Gene Expression Assay. Low-dose fluvastatin or valsartan increased telomerase activity (106.9% and 59.5% respectively; both p valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress. These findings could lead to a new innovative approach to arterial rejuvenation.

  9. Dose-Dependent Cytotoxic Effects of Boldine in HepG-2 Cells—Telomerase Inhibition and Apoptosis Induction

    Directory of Open Access Journals (Sweden)

    Sakineh Kazemi Noureini

    2015-02-01

    Full Text Available Plant metabolites are valuable sources of novel therapeutic compounds. In an anti-telomerase screening study of plant secondary metabolites, the aporphine alkaloid boldine (1,10-dimethoxy-2,9-dihydroxyaporphine exhibited a dose and time dependent cytotoxicity against hepatocarcinoma HepG-2 cells. Here we focus on the modes and mechanisms of the growth-limiting effects of this compound. Telomerase activity and expression level of some related genes were estimated by real-time PCR. Modes of cell death also were examined by microscopic inspection, staining methods and by evaluating the expression level of some critically relevant genes. The growth inhibition was correlated with down-regulation of the catalytic subunit of telomerase (hTERT gene (p < 0.01 and the corresponding reduction of telomerase activity in sub-cytotoxic concentrations of boldine (p < 0.002. However, various modes of cell death were stimulated, depending on the concentration of boldine. Very low concentrations of boldine over a few passages resulted in an accumulation of senescent cells so that HepG-2 cells lost their immortality. Moreover, boldine induced apoptosis concomitantly with increasing the expression of bax/bcl2 (p < 0.02 and p21 (p < 0.01 genes. Boldine might thus be an interesting candidate as a potential natural compound that suppresses telomerase activity in non-toxic concentrations.

  10. X-ray Counterparts of Infrared Faint Radio Sources

    Science.gov (United States)

    Schartel, Norbert

    2011-10-01

    Infrared Faint Radio Sources (IFRS) are radio sources with extremely faint or even absent infrared emission in deep Spitzer Surveys. Models of their spectral energy distributions, the ratios of radio to infrared flux densities and their steep radio spectra strongly suggest that IFRS are AGN at high redshifts (2IFRS, but if confirmed, the increased AGN numbers at these redshifts will account for the unresolved part of the X-ray background. The identification of X-ray counterparts of IFRS is considered to be the smoking gun for this hypothesis. We propose to observe 8 IFRS using 30ks pointed observations. X-ray detections of IFRS with different ratios of radio-to-infrared fluxes, will constrain the class-specific SED.

  11. Gravitational Coleman–Weinberg potential and its finite temperature counterpart

    Energy Technology Data Exchange (ETDEWEB)

    Bhattacharjee, Srijit [Astroparticle Physics and Cosmology Division, Saha Institute of Nuclear Physics, Kolkata 700064 (India); Discipline of Physics, Indian Institute of Technology Gandhinagar, Ahmedabad, Gujarat 382424 (India); Majumdar, Parthasarathi [Department of Physics, Ramakrishna Mission Vivekananada University, Belur Math, Howrah 711202 (India)

    2014-08-15

    Coleman–Weinberg (CW) phenomena for the case of gravitons minimally coupled to massless scalar field is studied. The one-loop effect completely vanishes if there is no self-interaction term present in the matter sector. The one-loop effective potential is shown to develop an instability in the form of acquiring an imaginary part, which can be traced to the tachyonic pole in the graviton propagator. The finite temperature counterpart of this CW potential is computed to study the behaviour of the potential in the high and low temperature regimes with respect to the typical energy scale of the theory. Finite temperature contribution to the imaginary part of gravitational CW potential exhibits a damped oscillatory behaviour; all thermal effects are damped out as the temperature vanishes, consistent with the zero-temperature result.

  12. Effects of exogenous ATM gene on mRNA expression of human telomerase reverse transcriptase in AT cells induced by irradiation

    International Nuclear Information System (INIS)

    Sheng Fangjun; Cao Jianping; Luo Jialin; Zhu Wei; Liu Fenju; Feng Shuang; Song Jianyuan; Li Chong

    2005-01-01

    The study is to observe effects of exogenous ATM gene on mRNA expression of hTERT (human telomerase reverse transcriptase) in fibroblast cells (AT5BIVA cells) from skin of Ataxia-telangiectasia (AT) patients and to study the regulation of ATM to hTERT. Using reverse transcription polymerase chain reaction (RT-PCR), mRNA expression of hTERT in AT, PEBS7-AT, ATM + -AT and GM cells irradiated with 0 and 3 Gy of 60 Co γ-rays were examined respectively. The difference of the mRNA expression of hTERT among AT, PEBS7-AT, ATM + -AT and GM cells were analyzed. Difference of the mRNA expression of hTERT between 0 Gy and 3 Gy groups was analyzed, too. The results showed that the mRNA expression of hTERT in GM cells was negative, but positive mRNA expression of hTERT in AT cells. The mRNA expression of hTERT in ATM + -AT cells decreased significantly (p 60 Co γ-rays, the mRNA expression of hTERT in GM cells was positive, and that in AT, PEBS7-AT, ATM + -AT cells was increased (p + -AT cells was lower than that in AT and PEBS7-AT cells respectively (p<0.05). It is postulated that exogenous ATM is able to downregulate the mRNA expression of hTERT in AT cells, ionizing radiation can induce the mRNA expression of hTERT in cells and telomerase anticipates the repair of damaged DNA. (authors)

  13. Trend of telomerase activity change during human iPSC self-renewal and differentiation revealed by a quartz crystal microbalance based assay

    Science.gov (United States)

    Zhou, Yitian; Zhou, Ping; Xin, Yinqiang; Wang, Jie; Zhu, Zhiqiang; Hu, Ji; Wei, Shicheng; Ma, Hongwei

    2014-11-01

    Telomerase plays an important role in governing the life span of cells for its capacity to extend telomeres. As high activity of telomerase has been found in stem cells and cancer cells specifically, various methods have been developed for the evaluation of telomerase activity. To overcome the time-consuming procedures and complicated manipulations of existing methods, we developed a novel method named Telomeric Repeat Elongation Assay based on Quartz crystal microbalance (TREAQ) to monitor telomerase activity during the self-renewal and differentiation of human induced pluripotent stem cells (hiPSCs). TREAQ results indicated hiPSCs possess invariable telomerase activity for 11 passages on Matrigel and a steady decline of telomerase activity when differentiated for different periods, which is confirmed with existing golden standard method. The pluripotency of hiPSCs during differentiation could be estimated through monitoring telomerase activity and compared with the expression levels of markers of pluripotency gene via quantitative real time PCR. Regular assessment for factors associated with pluripotency or stemness was expensive and requires excessive sample consuming, thus TREAQ could be a promising alternative technology for routine monitoring of telomerase activity and estimate the pluripotency of stem cells.

  14. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells

    DEFF Research Database (Denmark)

    Simonsen, Janne Lytoft; Rosada, Cecilia; Serakinci, Nedime

    2002-01-01

    Human bone marrow stromal cells (hMSCs) were stably transduced by a retroviral vector containing the gene for the catalytic subunit of human telomerase (hTERT). Transduced cells (hMSC-TERTs) had telomerase activity, and the mean telomere length was increased as compared with that of control cells....... The transduced cells have now undergone more than 260 population doublings (PD) and continue to proliferate, whereas control cells underwent senescence-associated proliferation arrest after 26 PD. The cells maintained production of osteoblastic markers and differentiation potential during continuous subculturing......, did not form tumors, and had a normal karyotype. When implanted subcutaneously in immunodeficient mice, the transduced cells formed more bone than did normal cells. These results suggest that ectopic expression of telomerase in hMSCs prevents senescence-associated impairment of osteoblast functions....

  15. Reptin is required for the transcription of telomerase reverse transcriptase and over-expressed in gastric cancer

    Directory of Open Access Journals (Sweden)

    Liu Tiantian

    2010-05-01

    Full Text Available Abstract Background Telomerase is activated in oncogenesis, which confers an immortal phenotype to cancer cells. The AAA + ATPase Reptin is required for telomerase biogenesis by maintaining telomerase RNA (hTER stability and is aberrantly expressed in certain cancers. Given its role in chromatin remodeling and transcription regulation, we determined the effect of Reptin on the transcription of the telomerase reverse transcriptase (hTERT gene, a key component of the telomerase complex and its expression in gastric cancer. Results Knocking down Reptin or its partner Pontin using small interfering RNA in gastric and cervical cancer cells led to significant decreases in hTERT mRNA, but hTERT promoter activity was inhibited in only Reptin-depleted cells. Reptin interacted with the c-MYC oncoprotein and its stimulatory effect on the hTERTpromoter was significantly dependent on functional E-boxes in the promoter. Moreover, Reptin bound to the hTERT proximal promoter and the loss of the Reptin occupancy led to dissociation of c-MYC from the hTERT promoter in Reptin-depleted cells. Reptin inhibition dramatically impaired clonogenic potential of gastric cancer cells by inducing cell growtharrest and over-expression of Reptin was observed in primary gastric cancer specimens. Conclusions The hTERT gene is a direct target of Reptin, and hTERT transcription requires constitutive expression of Reptin and its cooperation with c-MYC. Thus, Reptin regulates telomerase at two different levels. This finding, together with the requirementof Reptin for the clonogenic potential of cancer cells and its over-expression in gastriccancer and other solid tumors, suggests that Reptin may be a putative therapeutic target.

  16. Evaluation of an oral telomerase activator for early age-related macular degeneration - a pilot study

    Directory of Open Access Journals (Sweden)

    Dow CT

    2016-01-01

    Full Text Available Coad Thomas Dow,1,2 Calvin B Harley3 1McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI, USA; 2Chippewa Valley Eye Clinic, Eau Claire, Wisconsin, WI, USA; 3Independent Telomere Biology Consultant, Murphys, CA, USA Purpose: Telomere attrition and corresponding cellular senescence of the retinal pigment epithelium contribute to the changes of age-related macular degeneration. Activation of the enzyme telomerase can add telomeric DNA to retinal pigment epithelium chromosomal ends and has been proposed as a treatment for age-related macular degeneration. We report the use of a small molecule, oral telomerase activator (TA-65 in early macular degeneration. This study, focusing on early macular degeneration, provides a model for the use of TAs in age-related disease.Method: Thirty-eight (38 patients were randomly assigned to a 1-year, double-blinded, placebo-controlled interventional study with arms for oral TA-65 or placebo. Macular functions via micro-perimetry were the primary measured outcomes.Results: The macular function in the arm receiving the TA-65 showed significant improvement relative to the placebo control. The improvement was manifest at 6 months and was maintained at 1 year: macular threshold sensitivity (measured as average dB [logarithmic decibel scale of light attenuation] improved 0.97 dB compared to placebo (P-value 0.02 and percent reduced thresholds lessened 8.2% compared to the placebo arm (P-value 0.04. Conclusion: The oral TA significantly improved the macular function of treatment subjects compared to controls. Although this study was a pilot and a larger study is being planned, it is noteworthy in that it is, to our knowledge, the first randomized placebo-controlled study of a TA supplement. Keywords: drusen, macular degeneration, micro-perimetry, senescence, telomerase activation, telomere

  17. MNS16A tandem repeats minisatellite of human telomerase gene: a risk factor for colorectal cancer.

    Science.gov (United States)

    Hofer, Philipp; Baierl, Andreas; Feik, Elisabeth; Führlinger, Gerhard; Leeb, Gernot; Mach, Karl; Holzmann, Klaus; Micksche, Michael; Gsur, Andrea

    2011-06-01

    Telomerase reactivation and expression of human telomerase gene [human telomerase reverse transcriptase (hTERT)] are hallmarks of unlimited proliferation potential of cancer cells. A polymorphic tandem repeats minisatellite of hTERT gene, termed MNS16A was reported to influence hTERT expression. To assess the role of MNS16A as potential biomarker for colorectal cancer (CRC), we investigated for the first time the association of MNS16A genotypes with risk of colorectal polyps and CRC. In the ongoing colorectal cancer study of Austria (CORSA), 3842 Caucasian participants were recruited within a large screening project in the province Burgenland including 90 CRC cases, 308 high-risk polyps, 1022 low-risk polyps and 1822 polyp free controls verified by colonoscopy. MNS16A genotypes were determined by polymerase chain reaction from genomic DNA. Associations of MNS16A genotypes with CRC risk were estimated by logistic regression analysis computing odds ratios (ORs) and 95% confidence intervals (CIs). We identified five different variable number of tandem repeats (VNTRs) of MNS16A including VNTR-364, a newly discovered rare variant. VNTR-274 allele was associated with a 2.7-fold significantly increased risk of CRC compared with the VNTR-302 wild-type (OR = 2.69; 95% CI = 1.11-6.50; P = 0.028). In our CORSA study, the medium length VNTR-274 was identified as risk factor for CRC. Although, this population-based study herewith reports the largest cohort size concerning MNS16A thus far, further large-scale studies in diverse populations are warranted to confirm hTERT MNS16A genotype as potential biomarker for assessment of CRC risk.

  18. Telomerase reverse transcriptase promoter mutations in glandular lesions of the urinary bladder.

    Science.gov (United States)

    Vail, Eric; Zheng, Xiaoyong; Zhou, Ming; Yang, Ximing; Fallon, John T; Epstein, Jonathan I; Zhong, Minghao

    2015-10-01

    Glandular lesions of the urinary bladder include a broad spectrum of entities ranging from completely benign to primary and secondary malignancies. The accurate diagnosis of these lesions is both important and challenging. Recently, studies suggest that telomerase reverse transcriptase (TERT) promoter mutations could be a biomarker for urothelial carcinoma (UC). We hypothesized that these mutations can distinguish UC with glandular differentiation from nephrogenic adenoma, primary adenocarcinoma of the urinary bladder (PAUB), or secondary malignancies. Twenty-five cases of benign glandular lesions (including nephrogenic adenoma); 29 cases of UC with glandular differentiation; 10 cases of PAUB; and 10 cases each of metastatic colon cancer, prostatic carcinoma, and carcinoma from Mullerian origin were collected. Slides were reviewed and selected to make sure the lesion was at least 10% to 20% of all tissue. Macrodissection was performed in some of cases, and genomic DNA was extracted from the tissue. Telomerase reverse transcriptase promoter mutations were determined by standard polymerase chain reaction sequencing. Twenty-one cases (72%) of UC with glandular differentiation were positive for TERT promoter mutations. However, none of the remaining cases (total 65 cases of benign lesions, PAUB, and metastatic carcinomas) was positive for TERT promoter mutation. Telomerase reverse transcriptase promoter mutations were highly associated with UC including UC with glandular differentiation but not other glandular lesions of bladder. Therefore, in conjunction with morphologic features, Immunohistochemistry stain profile, and clinical information, TERT promoter mutations could distinguish UC with glandular differentiation from other bladder glandular lesions. In addition, lack of TERT promoter mutations in primary adenocarcinoma of bladder suggests that this entity may have different origin or carcinogenesis from those of UC. Published by Elsevier Inc.

  19. Telomerase Activity, Cytokeratin 20 and Cytokeratin 19 in Urine Cells of Bladder Cancer Patients

    International Nuclear Information System (INIS)

    Morsi, M.I.; Youssef, A.I.; El-Sedafi, A.S.; Ghazal, A.A.; Zaher, E.R.; Hassouna, M.E.

    2006-01-01

    Aim of the Study: This work aims to search for markers suitable for the screening of bladder cancer, which should be specific, sensitive, reproducible, non-invasive and at acceptable cost. Patients and Methods: The study included 50 patients diagnosed as bladder cancer (35 TCC, 15 SCC) of different stages and grades, 30 patients with various urothelial diseases, besides 20 apparently healthy subjects of matched age and sex to the malignant group. A random midstream urine sample was collected in a sterile container for the determination of telomerase by RT-PCR, keratin 19 by ELSA CYFRA 21-1 IRMA kit, keratin 20 by RT-PCR and immunohistochemical staining, and urine cytology. Results: For all parameters (telomerase, K19, K20 and cytology) the malignant group was significantly different from both the benign and the control groups. None of the four studied parameters was correlated to the stage of the disease, and when it comes to grade, only KI9 showed a significant positive correlation with grade both in TCC and SCe. When ROC curves for all parameters were compared, K 19 had the largest area under the curve, and then comes K20 . o Conclusion: K 19 may be used as a biological marker for the diagnosis of bladder cancer. K 19 could not be used for differential diagnosis of different types of bladder cancer, meanwhile it could be a marker for differentiation that decreases in less differentiated tumors. As a tumor marker, K20 reflects inability to differentiate tumor type or grade in TCC, while in SCC of the bladder it is correlated with the grade. As a method, RT-PCR is superior to immunostaining for the detection of bladder cancer, meanwhile K20 immunohistochemistry ([HC) results were much better than urine cytology as a bladder cancer screening test. haematuria and inflammation reduced the specificity of telomerase assay, which reduced its validity as a tumor marker of bladder cancer. K 19 and K20 are the best candidates as screening tests for the diagnosis of bladder

  20. Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Larsen, Simon Asbjørn; Kassem, Moustapha; Rattan, Suresh

    2012-01-01

    ). Furthermore, the in vitro differentiation potential of hMSC-TERT to become functional osteoblasts was highly reduced in GO-treated stem cells, as determined by alkaline phosphatase (ALP) activity and mineralized matrix (MM) formation. Conclusions The results of our study imply that an imbalanced glucose...... physiological metabolite produced by the auto-oxidation of glucose, and can form covalent adducts known as advanced glycation endproducts (AGE). We have previously reported that GO accelerates ageing and causes premature senescence in normal human skin fibroblasts. Results Using a bone marrow-derived telomerase...

  1. ELECTROMAGNETIC COUNTERPARTS TO BLACK HOLE MERGERS DETECTED BY LIGO

    Energy Technology Data Exchange (ETDEWEB)

    Loeb, Abraham, E-mail: aloeb@cfa.harvard.edu [Department of Astronomy, Harvard University, 60 Garden St., Cambridge, MA 02138 (United States)

    2016-03-10

    Mergers of stellar-mass black holes (BHs), such as GW150914 observed by Laser Interferometer Gravitational Wave Observatory (LIGO), are not expected to have electromagnetic counterparts. However, the Fermi GBM detector identified a γ-ray transient 0.4 s after the gravitational wave (GW) signal GW150914 with consistent sky localization. I show that the two signals might be related if the BH binary detected by LIGO originated from two clumps in a dumbbell configuration that formed when the core of a rapidly rotating massive star collapsed. In that case, the BH binary merger was followed by a γ-ray burst (GRB) from a jet that originated in the accretion flow around the remnant BH. A future detection of a GRB afterglow could be used to determine the redshift and precise localization of the source. A population of standard GW sirens with GRB redshifts would provide a new approach for precise measurements of cosmological distances as a function of redshift.

  2. Unidentified EGRET sources and their possible Fermi counterparts

    International Nuclear Information System (INIS)

    Lyapin, A R; Arkhangelskaja, I V; Larin, D S

    2017-01-01

    Unidentified EGRET sources from 3EG catalog have been analyzed. Preliminary data analysis has shown at least 23 of these sources coincide with those in 3FGL Fermi catalogue within 1, 2 and 3 sigma error intervals of the coordinates and fluxes. Their properties are discussed in the presented work. Even 3-sigma difference allows supposing sources similarity because of more than 3-sigma distinctions in values of fluxes between identified EGRET sources and their Fermi counterparts. For instance, the coincidence between 3EG J1255-0549 and 3FGL J1256.1-0547 was reported in Fermi catalogues 1FGL, 2FGL, 3FGL. However, these sources fluxes (in units of 10 −8 photons × cm −2 × s −1 ) in the energy band E > 100 MeV were 179.7 ± 6.7 (3EG), 44.711 ± 0.724 (3FGL), 53.611 ± 0.997 (2FGL) and 67.939 ± 1.861 (1FGL). Such effect was observed for sufficient portion of identified EGRET sources. It could cause by troubles of particles identification by Fermi/LAT trigger system. Very often charged particles recognized as gamma-quanta because of wrong backsplash analysis. Nevertheless, gammas counts as charged particles due analogous reason and rejected during ground data processing. For example, it appears as geomagnetic modulation presence on gamma-quanta count rate latitudinal profiles in energy band E > 20 MeV. (paper)

  3. The Hunt for a Counterpart to GW150914

    Science.gov (United States)

    Kohler, Susanna

    2016-07-01

    On 14 September 2015, the Laser Interferometer Gravitational-wave Observatory (LIGO) in a pre-operative testing state at the time detected its first sign of gravitational-waves. The LIGO team sprang into action, performing data-quality checks on this unexpected signal. Within two days, they had sent a notification to 63 observing teams at observatories representing the entire electromagnetic spectrum, from radio to gamma-ray wavelengths.Illustration of a binary neutron star merger. The neutron stars 1) inspiral, 2) can produce a short gamma-ray burst, 3) can fling out hot, radioactive material in the form of a kilonova, and 4) form a massive neutron star or black hole with a possible remnant debris disk around it. [NASA/ESA/A. Feild (STScI)]Thus began the very first hunt for an electromagnetic counterpart to a detected gravitational wave signal.What were they looking for?As two compact objects in a binary system merge, the system is expected to emit energy in the form of gravitational waves. If both of the compact objects are black holes, were unlikely to see any electromagnetic radiation in the process, unless the merger is occurring in an (improbable) environment filled with gas and dust.But if one or both of the two compact objects is a neutron star, then there are a number of electromagnetic signatures that could occur due to energetic outflows. If a relativistic jet forms, we could see a short gamma-ray burst and X-ray, optical, and radio afterglows. Sub-relativistic outflows could produce optical and near-infrared signals, or a radio blast wave.Timeline of observations of GW150914, separated by wavelength band, and relative to the time of the gravitational-wave trigger. The top row shows LIGO information releases. The bottom four rows show high-energy, optical, near-infrared, and radio observations, respectively. Click for a closer look! [Abbott et al. 2016]Surprise SignalSince LIGO and Virgo (LIGOs European counterpart), wereprimarily expecting to detect

  4. A dynamic counterpart of Lamb vector in viscous compressible aerodynamics

    International Nuclear Information System (INIS)

    Liu, L Q; Wu, J Z; Shi, Y P; Zhu, J Y

    2014-01-01

    The Lamb vector is known to play a key role in incompressible fluid dynamics and vortex dynamics. In particular, in low-speed steady aerodynamics it is solely responsible for the total force acting on a moving body, known as the vortex force, with the classic two-dimensional (exact) Kutta–Joukowski theorem and three-dimensional (linearized) lifting-line theory as the most famous special applications. In this paper we identify an innovative dynamic counterpart of the Lamb vector in viscous compressible aerodynamics, which we call the compressible Lamb vector. Mathematically, we present a theorem on the dynamic far-field decay law of the vorticity and dilatation fields, and thereby prove that the generalized Lamb vector enjoys exactly the same integral properties as the Lamb vector does in incompressible flow, and hence the vortex-force theory can be generalized to compressible flow with exactly the same general formulation. Moreover, for steady flow of polytropic gas, we show that physically the force exerted on a moving body by the gas consists of a transverse force produced by the original Lamb vector and a new longitudinal force that reflects the effects of compression and irreversible thermodynamics. (paper)

  5. Analysis of SCTF/CCTF counterpart test results

    International Nuclear Information System (INIS)

    Okubo, Tsutomu; Sobajima, Makoto; Iwamura, Takamichi; Ohnuki, Akira; Abe, Yutaka; Adachi, Hiromichi; Murao, Yoshio

    1990-06-01

    Slab Core Test Facility (SCTF) and Cylindrical Core Test Facility (CCTF) are large scale experimental facilities of Japan Atomic Energy Research Institute (JAERI) for the investigation of reflooding behavior during a postulated loss-of-coolant accident (LOCA) in PWRs. Although the flow area scaling ratios of both facilities to a 1,000 MWe class PWR are the same and 1/21.4, the SCTF has the same core width as the radius of the reference PWR while the CCTF has a 1/4.5 times shorter core radius. Therefore, a few SCTF/CCTF counterpart tests were conducted in order to investigate the difference in core reflooding behavior between in the SCTF and CCTF tests as well as the effect of core radial length on core two-dimensional thermo-hydrodynamic behavior. This report present the test results and an analysis on them. Major results obtained are: (1) Taking account of the differences in test conditions and facility design, core reflooding behavior is considered to be similar between the SCTF and the CCTF test. Main difference of the facility design is in the effective core flow area and this is considered to result in the difference in core water accumulation behavior. (2) The effect of core radial length on core two-dimensional thermo-hydrodynamic behavior has been observed to be significant and heat transfer enhancement or degradation in radial direction is more significant for the longer radius core. (3) In addition, where the core power varies significantly in the radial direction, significant heat transfer enhancement has been observed in the higher power bundle during the LPCI period. Also, in the peripheral region, heat transfer degradation has been observed more significantly in the outer bundle even they have the same bundle power. (4) Magnitude of these heat transfer enhancement or degradation was larger at the higher elevation than the midplane level in the SCTF test, whereas smaller in the CCTF test. (author)

  6. Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study.

    Science.gov (United States)

    Daubenmier, Jennifer; Lin, Jue; Blackburn, Elizabeth; Hecht, Frederick M; Kristeller, Jean; Maninger, Nicole; Kuwata, Margaret; Bacchetti, Peter; Havel, Peter J; Epel, Elissa

    2012-07-01

    Psychological distress and metabolic dysregulation are associated with markers of accelerated cellular aging, including reduced telomerase activity and shortened telomere length. We examined whether participation in a mindfulness-based intervention, and, secondarily, improvements in psychological distress, eating behavior, and metabolic factors are associated with increases in telomerase activity in peripheral blood mononuclear cells (PBMCs). We enrolled 47 overweight/obese women in a randomized waitlist-controlled pilot trial (n=47) of a mindfulness-based intervention for stress eating and examined changes in telomerase activity from pre- to post-intervention. In secondary analyses, changes in telomerase activity across the sample were examined in relation to pre- to post-intervention changes in psychological distress, eating behavior, and metabolic factors (weight, serum cortisol, fasting glucose and insulin, and insulin resistance). Both groups increased in mean telomerase activity over 4 months in intent-to-treat and treatment efficacy analyses (peating behavior, and metabolic health and increases in telomerase activity. These findings suggest that telomerase activity may be in part regulated by levels of both psychological and metabolic stress. Published by Elsevier Ltd.

  7. Label-free electrochemiluminescence biosensor for ultrasensitive detection of telomerase activity in HeLa cells based on extension reaction and intercalation of Ru(phen)3 (2.).

    Science.gov (United States)

    Lin, Yue; Yang, Linlin; Yue, Guiyin; Chen, Lifen; Qiu, Bin; Guo, Longhua; Lin, Zhenyu; Chen, Guonan

    2016-10-01

    Telomerase is one of the most common markers of human malignant tumors, such as uterine, stomach, esophageal, breast, colorectal, laryngeal squamous cell, thyroid, bladder, and so on. It is necessary to develop some sensitive but convenient detection methods for telomerase activity determination. In this study, a label-free and ultrasensitive electrochemiluminescence (ECL) biosensor has been fabricated to detect the activity of telomerase extracted from HeLa cells. Thiolated telomerase substrate (TS) primer was immobilized on the gold electrode surface through gold-sulfur (Au-S) interaction and then elongated by telomerase specifically. Then, it was hybridized with complementary DNA to form double-stranded DNA (dsDNA) fragments on the electrode surface, and Ru(phen)3 (2+) has been intercalated into the dsDNA grooves to act as the ECL probe. The enhanced ECL intensity has a linear relationship with the number of HeLa cells in the range of 5∼5000 and with a detection limit of 2 HeLa cells. The proposed ECL biosensor has high specificity to telomerase in the presence of common interferents. The relative standard deviations (RSDs) were HeLa cells. The proposed method provides a convenient approach for telomerase-related cancer screening or diagnosis.

  8. The TROVE module: A common element in Telomerase, Ro and Vault ribonucleoproteins

    Directory of Open Access Journals (Sweden)

    Bateman Alex

    2003-10-01

    Full Text Available Abstract Background Ribonucleoproteins carry out a variety of important tasks in the cell. In this study we show that a number of these contain a novel module, that we speculate mediates RNA-binding. Results The TROVE module – Telomerase, Ro and Vault module – is found in TEP1 and Ro60 the protein components of three ribonucleoprotein particles. This novel module, consisting of one or more domains, may be involved in binding the RNA components of the three RNPs, which are telomerase RNA, Y RNA and vault RNA. A second conserved region in these proteins is shown to be a member of the vWA domain family. The vWA domain in TEP1 is closely related to the previously recognised vWA domain in VPARP a second component of the vault particle. This vWA domain may mediate interactions between these vault components or bind as yet unidentified components of the RNPs. Conclusions This work suggests that a number of ribonucleoprotein components use a common RNA-binding module. The TROVE module is also found in bacterial ribonucleoproteins suggesting an ancient origin for these ribonucleoproteins.

  9. Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors.

    Science.gov (United States)

    Zheng, Dong-Shu; Chen, Liang-Shu

    2017-10-01

    Nasopharyngeal carcinoma (NPC) is a malignant disease that threatens the health of humans. To find effective agents for the inhibition of Epstein-Barr virus (EBV) infection, which is associated with NPC, a phytochemical investigation of Ganoderma lucidum was carried out in the present study. Five triterpenoids were identified, including ganoderic acid A (compound 1), ganoderic acid B (compound 2), ganoderol B (compound 3), ganodermanontriol (compound 4), and ganodermanondiol (compound 5), on the basis of spectroscopic analysis. An inhibition of EBV antigens activation assay was implemented to elucidate the triterpenoids from G. lucidum and potentially prevent NPC. All the triterpenoids showed significant inhibitory effects on both EBV EA and CA activation at 16 nmol. At 3.2 nmol, all the compounds moderately inhibited the activation of the two antigens. The activity of telomerase was inhibited by these triterpenoids at 10 µM. Molecular docking demonstrated that compound 1 was able to inhibit telomerase as a ligand. In addition, the physicochemical properties of these compounds were calculated to elucidate their drug-like properties. These results provided evidence for the application of these triterpenoids and whole G. lucidum in the treatment of NPC.

  10. The TROVE module: a common element in Telomerase, Ro and Vault ribonucleoproteins.

    Science.gov (United States)

    Bateman, Alex; Kickhoefer, Valerie

    2003-10-16

    Ribonucleoproteins carry out a variety of important tasks in the cell. In this study we show that a number of these contain a novel module, that we speculate mediates RNA-binding. The TROVE module--Telomerase, Ro and Vault module--is found in TEP1 and Ro60 the protein components of three ribonucleoprotein particles. This novel module, consisting of one or more domains, may be involved in binding the RNA components of the three RNPs, which are telomerase RNA, Y RNA and vault RNA. A second conserved region in these proteins is shown to be a member of the vWA domain family. The vWA domain in TEP1 is closely related to the previously recognised vWA domain in VPARP a second component of the vault particle. This vWA domain may mediate interactions between these vault components or bind as yet unidentified components of the RNPs. This work suggests that a number of ribonucleoprotein components use a common RNA-binding module. The TROVE module is also found in bacterial ribonucleoproteins suggesting an ancient origin for these ribonucleoproteins.

  11. Rapid blockade of telomerase activity and tumor cell growth by the DPL lipofection of ribbon antisense to hTR.

    Science.gov (United States)

    Bajpai, Arun K; Park, Jeong-Hoh; Moon, Ik-Jae; Kang, Hyungu; Lee, Yun-Han; Doh, Kyung-Oh; Suh, Seong-Il; Chang, Byeong-Churl; Park, Jong-Gu

    2005-09-29

    Ribbon antisense (RiAS) to the hTR RNA, a component of the telomerase complex, was employed to inhibit telomerase activity and cancer cell growth. The antisense molecule, hTR-RiAS, combined with enhanced cellular uptake was shown to effectively inhibit telomerase activity and cause rapid cell death in various cancer cell lines. When cancer cells were treated with hTR-RiAS, the level of hTR RNA was reduced by more than 90% accompanied with reduction in telomerase activity. When checked for cancer cell viability, cancer cell lines treated with hTR-RiAS using DNA+Peptide+Lipid complex showed 70-80% growth inhibition in 3 days. The reduced cell viability was due to apoptosis as the percentage of cells exhibiting the sub-G0 arrest and DNA fragmentation increased after antisense treatment. Further, when subcutaneous tumors of a colon cancer cell line (SW480) were treated intratumorally with hTR-RiAS, tumor growth was markedly suppressed with almost total ablation of hTR RNA in the tumor tissue. Cells in the tumor tissue were also found to undergo apoptosis after hTR-RiAS treatment. These results suggest that hTR-RiAS is an effective anticancer reagent, with a potential for broad efficacy to diverse malignant tumors.

  12. Comparison of Inhibitory Effect of Curcumin Nanoparticles and Free Curcumin in Human Telomerase Reverse Transcriptase Gene Expression in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nosratollah Zarghami

    2013-02-01

    Full Text Available Purpose: Telomerase is expressed in most cancers, including breast cancer. Curcumin, a polyphenolic compound that obtained from the herb of Curcuma longa, has many anticancer effects. But, its effect is low due to poor water solubility. In order to improve its solubility and drug delivery, we have utilized a β-cyclodextrin-curcumin inclusion complex. Methods: To evaluate cytotoxic effects of cyclodextrin-curcumin and free curcumin, MTT assay was done. Cells were treated with equal concentration of cyclodextrin-curcumin and free curcumin. Telomerase gene expression level in two groups was compared by Real-time PCR. Results: MTT assay demonstrated that β-cyclodextrin-curcumin enhanced curcumin delivery in T47D breast cancer cells. The level of telomerase gene expression in cells treated with cyclodextrin-curcumin was lower than that of cells treated with free curcumin (P=0.001. Conclusion: Results are suggesting that cyclodextrin-curcumin complex can be more effective than free curcumin in inhibition of telomerase expression.

  13. Telomerase: a target for therapeutic effects of curcumin and a curcumin derivative in Aβ1-42 insult in vitro.

    Directory of Open Access Journals (Sweden)

    Zijian Xiao

    Full Text Available This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aβ1-42 (10 µg/ml to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aβ1-42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aβ1-42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1.

  14. Telomerase: A Target for Therapeutic Effects of Curcumin and a Curcumin Derivative in Aβ1-42 Insult In Vitro

    Science.gov (United States)

    Lin, Jianwen; Zheng, Zhenyang; Shi, Xiaolei; Di, Wei; Qi, Weiwei; Zhu, Yingting; Zhou, Guijuan; Fang, Yannan

    2014-01-01

    This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aβ1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aβ1–42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aβ1–42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1. PMID:24983737

  15. When negation is not negation

    OpenAIRE

    Milicevic, Nataša

    2008-01-01

    In this paper I will discuss the formation of different types of yes/no questions in Serbian (examples in (1)), focusing on the syntactically and semantically puzzling example (1d), which involves the negative auxiliary inversion. Although there is a negative marker on the fronted auxiliary, the construction does not involve sentential negation. This coincides with the fact that the negative quantifying NPIs cannot be licensed. The question formation and sentential negation have similar synta...

  16. Superatom spectroscopy and the electronic state correlation between elements and isoelectronic molecular counterparts.

    Science.gov (United States)

    Peppernick, Samuel J; Gunaratne, K D Dasitha; Castleman, A W

    2010-01-19

    Detailed in the present investigation are results pertaining to the photoelectron spectroscopy of negatively charged atomic ions and their isoelectronic molecular counterparts. Experiments utilizing the photoelectron imaging technique are performed on the negative ions of the group 10 noble metal block (i.e. Ni-, Pd-, and Pt-) of the periodic table at a photon energy of 2.33 eV (532 nm). The accessible electronic transitions, term energies, and orbital angular momentum components of the bound electronic states in the atom are then compared with photoelectron images collected for isoelectronic early transition metal heterogeneous diatomic molecules, M-X- (M = Ti,Zr,W; X = O or C). A superposition principle connecting the spectroscopy between the atomic and molecular species is observed, wherein the electronic structure of the diatomic is observed to mimic that present in the isoelectronic atom. The molecular ions studied in this work, TiO-, ZrO-, and WC- can then be interpreted as possessing superatomic electronic structures reminiscent of the isoelectronic elements appearing on the periodic table, thereby quantifying the superatom concept.

  17. Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia

    International Nuclear Information System (INIS)

    Parra, E.R.; Pincelli, M.S.; Teodoro, W.R.; Velosa, A.P.P.; Martins, V.; Rangel, M.P.; Barbas-Filho, J.V.; Capelozzi, V.L.

    2014-01-01

    Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis

  18. Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia

    Energy Technology Data Exchange (ETDEWEB)

    Parra, E.R.; Pincelli, M.S. [Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Teodoro, W.R.; Velosa, A.P.P. [Disciplina de Reumatologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Martins, V.; Rangel, M.P.; Barbas-Filho, J.V.; Capelozzi, V.L. [Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-06-04

    Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis.

  19. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

    International Nuclear Information System (INIS)

    Verma, Vikas; Sharma, Vikas; Singh, Vishal; Sharma, Siddharth; Bishnoi, Ajay Kumar; Chandra, Vishal; Maikhuri, J.P.; Dwivedi, Anila; Kumar, Atul; Gupta, Gopal

    2014-01-01

    The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3′diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ∼ 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P < 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP

  20. [The role of telomerase activity in non-invasive diagnostics of bladder cancer].

    Science.gov (United States)

    Glybochko, P V; Alyaev, J G; Potoldykova, N V; Polyakovsky, K A; Vinarov, A Z; Glukhov, A I; Gordeev, S A

    2016-08-01

    To evaluate the potentials of determining the telomerase activity (TA) in the cellular material of the urine for noninvasive diagnosis of bladder cancer (BC). Evaluation of TA was performed in the urine of 48 patients with bladder cancer (study group) before and after transurethral resection of the bladder wall (n=38), an open resection of the bladder (n=4), and cystectomy (n=6). TA was also evaluated in 48 tumor tissue samples obtained from these patients during removal of the bladder tumor. Each sample of the tumor tissue was separated into two parts, one of which was subjected to histological examination, and the latter was used to determine the telomerase activity. In all cases, the diagnosis of bladder cancer was confirmed morphologically. Determination of TA in the samples was performed by the modified TRAP-method (telomerase repeat amplification protocol), RT-PCR, PCR, and electrophoresis. As a control, cell material of the urine and tissue in 12 patients with chronic cystitis was investigated. TA before surgery was found in 45 (93.75%) of 48 samples of cellular material of the urine from patients with suspected bladder cancer. BC was histologically verified in all patients in this group. In the postoperative period, TA was not observed in the 48 samples of cellular material of the urine from patients with BC. In the control group of patients with histologically verified cystitis, weak TA was determined only in one sample of cellular material of the urine. The analysis indicates statistically significant predominance of patients with bladder cancer in case of TA in the urine (P=0.001). TA was detected in all samples of tumor tissue. We also analyzed the dependence of TA levels in urine and tissue on the degree of BC differentiation. In patients with highly differentiated BC, mean AT in the cellular materials of the urine was 0,61% (n=15), in patients with moderately differentiated BC - 0.95% (n=23), in patients with low-grade bladder cancer - 1.33% (n=10

  1. Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Verma, Vikas; Sharma, Vikas; Singh, Vishal [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Sharma, Siddharth; Bishnoi, Ajay Kumar [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Chandra, Vishal; Maikhuri, J.P.; Dwivedi, Anila [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Kumar, Atul [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031 (India); Gupta, Gopal, E-mail: g_gupta@cdri.res.in [Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031 (India)

    2014-10-15

    The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3′diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ∼ 5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P < 0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

  2. Analysis of telomerase target gene expression effects from murine models in patient cohorts by homology translation and random survival forest modeling

    Directory of Open Access Journals (Sweden)

    Frederik Otzen Bagger

    2016-03-01

    Full Text Available Acute myeloid leukemia (AML is an aggressive and rapidly fatal blood cancer that affects patients of any age group. Despite an initial response to standard chemotherapy, most patients relapse and this relapse is mediated by leukemia stem cell (LSC populations. We identified a functional requirement for telomerase in sustaining LSC populations in murine models of AML and validated this requirement using an inhibitor of telomerase in human AML. Here, we describe in detail the contents, quality control and methods of the gene expression analysis used in the published study (Gene Expression Omnibus GSE63242. Additionally, we provide annotated gene lists of telomerase regulated genes in AML and R code snippets to access and analyze the data used in the original manuscript. Keywords: AML, Leukemia, Stem cells, Telomere, Telomerase

  3. Cyclic Fatigue Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts.

    Science.gov (United States)

    2018-04-26

    Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts. 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sd...Endodontics 14. ABSTRACT Cyclic Fatigue Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts. David J. Weyh DDS...Resistance of 3 Proprietary Rotary File Brands and their Analogous EdgeEndo Counterparts. David J. Weyh DDS Jarom J. Ray DDS Introduction: The aim of this

  4. Zinc sulfate contributes to promote telomere length extension via increasing telomerase gene expression, telomerase activity and change in the TERT gene promoter CpG island methylation status of human adipose-derived mesenchymal stem cells.

    Directory of Open Access Journals (Sweden)

    Raheleh Farahzadi

    Full Text Available The use of mesenchymal stem cells (MSCs for cell therapy and regenerative medicine has received widespread attention over the past few years, but their application can be complicated by factors such as reduction in proliferation potential, the senescent tendency of the MSCs upon expansion and their age-dependent decline in number and function. It was shown that all the mentioned features were accompanied by a reduction in telomerase activity and telomere shortening. Furthermore, the role of epigenetic changes in aging, especially changes in promoter methylation, was reported. In this study, MSCs were isolated from the adipose tissue with enzymatic digestion. In addition, immunocytochemistry staining and flow cytometric analysis were performed to investigate the cell-surface markers. In addition, alizarin red-S, sudan III, toluidine blue, and cresyl violet staining were performed to evaluate the multi-lineage differentiation of hADSCs. In order to improve the effective application of MSCs, these cells were treated with 1.5 × 10-8 and 2.99 × 10-10 M of ZnSO4 for 48 hours. The length of the absolute telomere, human telomerase reverse transcriptase (hTERT gene expression, telomerase activity, the investigation of methylation status of the hTERT gene promoter and the percentage of senescent cells were analyzed with quantitative real-time PCR, PCR-ELISA TRAP assay, methylation specific PCR (MSP, and beta-galactosidase (SA-β-gal staining, respectively. The results showed that the telomere length, the hTERT gene expression, and the telomerase activity had significantly increased. In addition, the percentage of senescent cells had significantly decreased and changes in the methylation status of the CpG islands in the hTERT promoter region under treatment with ZnSO4 were seen. In conclusion, it seems that ZnSO4 as a proper antioxidant could improve the aging-related features due to lengthening of the telomeres, increasing the telomerase gene expression

  5. PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK)

    International Nuclear Information System (INIS)

    Senthilkumar, P.K.; Robertson, L.W.; Ludewig, G.

    2012-01-01

    Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24 days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism. -- Highlights: ► Human immortal (HaCaT) and primary (NFK) keratinocytes were exposed to PCB153. ► PCB153 significantly reduced telomerase activity and telomere length in HaCaT. ► No effect on telomere length and

  6. Elucidation of the TMab-6 Monoclonal Antibody Epitope Against Telomerase Reverse Transcriptase.

    Science.gov (United States)

    Kaneko, Mika K; Yamada, Shinji; Itai, Shunsuke; Chang, Yao-Wen; Nakamura, Takuro; Yanaka, Miyuki; Harada, Hiroyuki; Suzuki, Hiroyoshi; Kato, Yukinari

    2018-05-03

    Telomerase reverse transcriptase (TERT) and mutations of the TERT promoter are significant in the pathogenesis of 1p/19q-codeleted oligodendrogliomas and isocitrate dehydrogenase gene wild-type glioblastomas, as well as melanomas and squamous cell carcinomas. We previously developed an antihuman TERT monoclonal antibody (mAb), TMab-6, which is applicable in immunohistochemistry for human tissues. However, the binding epitope of TMab-6 against TERT is yet to be elucidated. In this study, enzyme-linked immunosorbent assay and immunohistochemistry were utilized for investigating the epitope of TMab-6. The findings revealed that the critical epitope of TMab-6 is the TERT sequence PSTSRPPRPWD; Thr310 and Ser311 of TERT are especially significant amino acids for TMab-6 recognition.

  7. Effects of water extract of Curcuma longa (L.) roots on immunity and telomerase function.

    Science.gov (United States)

    Pan, Min-Hsiung; Wu, Jia-Ching; Ho, Chi-Tang; Badmaev, Vladimir

    2017-05-12

    Background Immunity and Longevity Methods A water extract of Curcuma longa (L.) [vern. Turmeric] roots (TurmericImmune™) standardized for a minimum 20 % of turmeric polysaccharides ukonan A, B, C and D was evaluated for its biological properties in in vitro tissue culture studies. Results The water extract of turmeric (TurP) exhibited induced-nitric oxide (NO) production in RAW264.7 macrophages. These results suggested the immunomodulatory effects of TurP. In addition, the polysaccharides up-regulated function of telomerase reverse transcriptase (TERT) equally to the phenolic compound from turmeric, curcumin. Conclusions The ukonan family of polysaccharides may assist in promoting cellular immune responses, tissue repair and lifespan by enhancing immune response and telomere function.

  8. Negative mass

    International Nuclear Information System (INIS)

    Hammond, Richard T

    2015-01-01

    Some physical aspects of negative mass are examined. Several unusual properties, such as the ability of negative mass to penetrate any armor, are analysed. Other surprising effects include the bizarre system of negative mass chasing positive mass, naked singularities and the violation of cosmic censorship, wormholes, and quantum mechanical results as well. In addition, a brief look into the implications for strings is given. (paper)

  9. Telomerase activity and cellular aging might be positively modified by a yoga-based lifestyle intervention.

    Science.gov (United States)

    Kumar, Shiv Basant; Yadav, Rashmi; Yadav, Raj Kumar; Tolahunase, Madhuri; Dada, Rima

    2015-06-01

    Recent studies showed that a brief yoga-based lifestyle intervention was efficacious in reducing levels of oxidative stress and cellular aging in obese men. The objective of this case report was to assess the efficacy of this intervention in reducing the levels of biochemical markers of cellular ageing, oxidative stress, and inflammation at baseline (day 0), at the end of active intervention (day 10), and follow-up at day 90. Single case report from a prospective ongoing study with pre-post design assessing the level of various markers of cellular aging. Integral Health Clinic, an outpatient facility conducting meditation and yoga-based lifestyle intervention programs for management of chronic diseases. A 31-year-old man with class I obesity (body-mass index, 29.5 kg/m(2)) who presented to the medicine outpatient department at All India Institute of Medical Sciences, New Delhi, India, with a history of fatigue, difficulty losing weight, and lack of motivation. He noted a marked decrease in his energy level, particularly in the afternoon. A pretested intervention program included asanas (postures), pranayama (breathing exercises), stress management, group discussions, lectures, and individualized advice. From baseline (day 0) to day 90, the activity of telomerase and levels of β-endorphins, plasma cortisol, and interleukin-6 increased, and a sustained reduction in oxidative stress markers, such as reactive oxygen species and 8-hydroxy-2-deoxy-guanosine levels. Adopting yoga/meditation-based lifestyle modification causes reversal of markers of aging, mainly oxidative stress, telomerase activity, and oxidative DNA damage. This may not only delay aging and prolong a youthful healthy life but also delay or prevent onset of several lifestyle-related diseases, of which oxidative stress and inflammation are the chief cause. This report suggests this simple lifestyle intervention may be therapeutic for oxidative DNA damage and oxidative stress.

  10. Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines.

    Science.gov (United States)

    Abbas, Ata; Hall, J Adam; Patterson, William L; Ho, Emily; Hsu, Anna; Al-Mulla, Fahd; Georgel, Philippe T

    2016-02-01

    Epidemiologic studies have revealed that diets rich in sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in prostate cancer incidence. The chemo-preventive role of SFN is associated with its histone de-acetylase inhibitor activity. However, the effect of SFN on chromatin composition and dynamic folding, especially in relation to HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 2 prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in chromatin structure and composition. The SFN-mediated changes in levels of histone post-translational modifications, more specifically acetylation of histone H3 lysine 18 and di-methylation of histone H3 lysine 4, 2 modifications linked with high risk of prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region. Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known chromatin compactor, were altered in SFN treated prostate cancer cells. Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in prostate cancer cells. This ability of SFN to modify chromatin composition and structure associated with target gene expression provides a new model by which dietary phytochemicals may exert their chemoprevention activity.

  11. siRNA inhibition of telomerase enhances the anti-cancer effect of doxorubicin in breast cancer cells

    International Nuclear Information System (INIS)

    Dong, Xuejun; Liu, Anding; Zer, Cindy; Feng, Jianguo; Zhen, Zhuan; Yang, Mingfeng; Zhong, Li

    2009-01-01

    Doxorubicin is an effective breast cancer drug but is hampered by a severe, dose-dependent toxicity. Concomitant administration of doxorubicin and another cancer drug may be able to sensitize tumor cells to the cytotoxicity of doxorubicin and lowers the therapeutic dosage. In this study, we examined the combined effect of low-dose doxorubicin and siRNA inhibition of telomerase on breast cancer cells. We found that when used individually, both treatments were rapid and potent apoptosis inducers; and when the two treatments were combined, we observed an enhanced and sustained apoptosis induction in breast cancer cells. siRNA targeting the mRNA of the protein component of telomerase, the telomerase reverse transcriptase (hTERT), was transfected into two breast cancer cell lines. The siRNA inhibition was confirmed by RT-PCR and western blot on hTERT mRNA and protein levels, respectively, and by measuring the activity level of telomerase using the TRAP assay. The effect of the hTERT siRNA on the tumorigenicity of the breast cancer cells was also studied in vivo by injection of the siRNA-transfected breast cancer cells into nude mice. The effects on cell viability, apoptosis and senescence of cells treated with hTERT siRNA, doxorubicin, and the combined treatment of doxorubicin and hTERT siRNA, were examined in vitro by MTT assay, FACS and SA-β-galactosidase staining. The hTERT siRNA effectively knocked down the mRNA and protein levels of hTERT, and reduced the telomerase activity to 30% of the untreated control. In vivo, the tumors induced by the hTERT siRNA-transfected cells were of reduced sizes, indicating that the hTERT siRNA also reduced the tumorigenic potential of the breast cancer cells. The siRNA treatment reduced cell viability by 50% in breast cancer cells within two days after transfection, while 0.5 μM doxorubicin treatment had a comparable effect but with a slower kinetics. The combination of hTERT siRNA and 0.5 μM doxorubicin killed twice as many

  12. Evaluation of Energy Balance on Human Telomerase Reverse Transcriptase (hTERT) Alternative Splicing by Semi-quantitative RT-PCR in Human Umbilical Vein Endothelial Cells.

    Science.gov (United States)

    Behjati, Mohaddeseh; Hashemi, Mohammad; Kazemi, Mohammad; Salehi, Mansoor; Javanmard, Shaghayegh Haghjooy

    2017-01-01

    Decreased high-energy phosphate level is involved in endothelial cell injury and dysfunction. Reduced telomerase activity in endothelial cells in parallel with reduced energy levels might be due to altered direction of alternative splicing machine as a complication of depleted energy during the process of atherosclerosis. Isolated human umbilical vein endothelial cells (HUVECs) were treated for 24 hours by oligomycine (OM) and 2-deoxy glucose (2-DG). After 24 hours, the effect of energy depletion on telomerase splicing pattern was evaluated using RT-PCR. Indeed, in both treated and untargeted cells, nitric oxide (NO) and von Willebrand factor (vWF) were measured. ATP was depleted in treated cells by 43.9% compared with control group. We observed a slight decrease in NO levels ( P = 0.09) and vWF ( P = 0.395) in the setting of 49.36% ATP depletion. In both groups, no telomerase gene expression was seen. Telomerase and housekeeping gene expression were found in positive control group (colon cancer tissue) and sample tissue. The absence of telomerase gene expression in HUVECs might be due to the mortality of these cells or the low level of telomerase gene expression in these cells under normal circumstances.

  13. No counterpart of visual perceptual echoes in the auditory system.

    Directory of Open Access Journals (Sweden)

    Barkın İlhan

    Full Text Available It has been previously demonstrated by our group that a visual stimulus made of dynamically changing luminance evokes an echo or reverberation at ~10 Hz, lasting up to a second. In this study we aimed to reveal whether similar echoes also exist in the auditory modality. A dynamically changing auditory stimulus equivalent to the visual stimulus was designed and employed in two separate series of experiments, and the presence of reverberations was analyzed based on reverse correlations between stimulus sequences and EEG epochs. The first experiment directly compared visual and auditory stimuli: while previous findings of ~10 Hz visual echoes were verified, no similar echo was found in the auditory modality regardless of frequency. In the second experiment, we tested if auditory sequences would influence the visual echoes when they were congruent or incongruent with the visual sequences. However, the results in that case similarly did not reveal any auditory echoes, nor any change in the characteristics of visual echoes as a function of audio-visual congruence. The negative findings from these experiments suggest that brain oscillations do not equivalently affect early sensory processes in the visual and auditory modalities, and that alpha (8-13 Hz oscillations play a special role in vision.

  14. Metaphors are Embodied, and so are Their Literal Counterparts.

    Science.gov (United States)

    Santana, Eduardo; de Vega, Manuel

    2011-01-01

    This study investigates whether understanding up/down metaphors as well as semantically homologous literal sentences activates embodied representations online. Participants read orientational literal sentences (e.g., she climbed up the hill), metaphors (e.g., she climbed up in the company), and abstract sentences with similar meaning to the metaphors (e.g., she succeeded in the company). In Experiments 1 and 2, participants were asked to perform a speeded upward or downward hand motion while they were reading the sentence verb. The hand motion either matched or mismatched the direction connoted by the sentence. The results showed a meaning-action effect for metaphors and literals, that is, faster hand motion responses in the matching conditions. Notably, the matching advantage was also found for homologous abstract sentences, indicating that some abstract ideas are conceptually organized in the vertical dimension, even when they are expressed by means of literal sentences. In Experiment 3, participants responded to an upward or downward visual motion associated with the sentence verb by pressing a single key. In this case, the facilitation effect for matching visual motion-sentence meaning faded, indicating that the visual motion component is less important than the action component in conceptual metaphors. Most up and down metaphors convey emotionally positive and negative information, respectively. We suggest that metaphorical meaning elicits upward/downward movements because they are grounded on the bodily expression of the corresponding emotions.

  15. Metaphors are embodied, and so are their literal counterparts

    Directory of Open Access Journals (Sweden)

    Eduardo eSantana

    2011-05-01

    Full Text Available This study investigates whether understanding up/down metaphors as well as semantically homologous literal sentences activates embodied representations online. Participants read orientational literal sentences (e.g. she climbed up the hill, metaphors (e.g. she climbed up in the company, and abstract sentences with similar meaning to the metaphors (e.g. she succeeded in the company. In Experiments 1 and 2, participants were asked to perform a speeded upward or downward hand motion while they were reading the sentence verb. The hand motion either matched or mismatched the direction connoted by the sentence. The results showed a meaning-action effect for metaphors and literals, that is faster hand motion responses in the matching conditions. Notably, the matching advantage was also found for homologous abstract sentences, indicating that some abstract ideas are conceptually organized in the vertical dimension, even when they are expressed by means of literal sentences. In Experiment 3, participants responded to an upward or downward visual motion associated with the sentence verb by pressing a single key. In this case, the facilitation effect for matching visual motion-sentence meaning faded, indicating that the visual motion component is less important than the action component in conceptual metaphors. Most up and down metaphors convey emotionally positive and negative information, respectively. We suggest that metaphorical meaning elicits upward/downward movements because they are grounded on the bodily expression of the corresponding emotions.

  16. Negative Leadership

    Science.gov (United States)

    2013-03-01

    Negative Leadership by Colonel David M. Oberlander United States Army United States Army War...SUBTITLE Negative Leadership 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Colonel David M...Dr. Richard C. Bullis Department of Command Leadership , and Management 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING

  17. Negative liability

    NARCIS (Netherlands)

    Dari-Mattiacci, G.

    2009-01-01

    Negative and positive externalities pose symmetrical problems to social welfare. The law internalizes negative externalities by providing general tort liability rules. According to such rules, those who cause harm to others should pay compensation. In theory, in the presence of positive

  18. Negative ... concord?

    NARCIS (Netherlands)

    Giannakidou, A

    The main claim of this paper is that a general theory of negative concord (NC) should allow for the possibility of NC involving scoping of a universal quantifier above negation. I propose that Greek NC instantiates this option. Greek n-words will be analyzed as polarity sensitive universal

  19. Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b

    Directory of Open Access Journals (Sweden)

    Brosens Jan J

    2009-07-01

    Full Text Available Abstract Background Coordinated differentiation of the endometrial compartments in the second half of the menstrual cycle is a prerequisite for the establishment of pregnancy. Endometrial stromal cells (ESC decidualize under the influence of ovarian progesterone to accommodate implantation of the blastocyst and support establishment of the placenta. Studies into the mechanisms of decidualization are often hampered by the lack of primary ESC. Here we describe a novel immortalized human ESC line. Methods Primary ESC were immortalized by the transduction of telomerase. The resultant cell line, termed St-T1b, was characterized for its morphological and biochemical properties by immunocytochemistry, RT-PCR and immunoblotting. Its progestational response was tested using progesterone and medroxyprogesterone acetate with and without 8-Br-cAMP, an established inducer of decidualization in vitro. Results St-T1b were positive for the fibroblast markers vimentin and CD90 and negative for the epithelial marker cytokeratin-7. They acquired a decidual phenotype indistinguishable from primary ESC in response to cAMP stimulation. The decidual response was characterized by transcriptional activation of marker genes, such as PRL, IGFBP1, and FOXO1, and enhanced protein levels of the tumor suppressor p53 and the metastasis suppressor KAI1 (CD82. Progestins alone had no effect on St-T1b cells, but medroxyprogesterone acetate greatly enhanced the cAMP-stimulated expression of IGFBP-1 after 3 and 7 days. Progesterone, albeit more weakly, also augmented the cAMP-induced IGFBP-1 production but only after 7 days of treatment. The cell line remained stable in continuous culture for more than 150 passages. Conclusion St-T1b express the appropriate phenotypic ESC markers and their decidual response closely mimics that of primary cultures. Decidualization is efficiently induced by cAMP analog and enhanced by medroxyprogesterone acetate, and, to a lesser extent, by natural

  20. Telomerase activity is spontaneously increased in lymphocytes from patients with atopic dermatitis and correlates with cellular proliferation

    DEFF Research Database (Denmark)

    Wu, Kehuai; Volke, Anne Rehné; Lund, Marianne

    1999-01-01

    blood mononuclear cells (PBMC) were isolated from 15 patients with AD and 13 healthy donors. Cells were stimulated with purified protein derivative (PPD) of tuberculin (10 microg/ml), interleukin 2 (IL-2) (100 U/ml), anti-CD3 monoclonal antibody (anti-CD3) (1 microg/ml), anti-CD3 plus IL-2......-thymidine incorporation. We found that telomerase activity in non-stimulated PBMC from patients with AD was significantly up-regulated without any stimulation during the 72 h of in vitro incubation. The most potent stimulator of telomerase activity was SEA, followed by anti-CD3 plus IL-2, anti-CD3 alone, and PPD. IL-2...

  1. Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells

    Science.gov (United States)

    Jia, Pingping; Chastain, Megan; Zou, Ying; Her, Chengtao

    2017-01-01

    Abstract Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI. Moreover, TSI requires telomerase activity but is independent of the functional status of p53 and Rb. Lastly, we show that TSI is associated with chromosome instabilities including chromosome loss, micronuclei formation and chromosome breakage that are further elevated by replication stress. Our studies uncover a novel link between MLH1, telomerase, telomere and genome stability. PMID:28180301

  2. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Christian Bär

    2016-01-01

    Full Text Available Telomeres, the protective ends of linear chromosomes, shorten throughout an individual’s lifetime. Telomere shortening is a hallmark of molecular aging and is associated with premature appearance of diseases associated with aging. Here, we discuss the role of telomere shortening as a direct cause for aging and age-related diseases. In particular, we draw attention to the fact that telomere length influences longevity. Furthermore, we discuss intrinsic and environmental factors that can impact on human telomere erosion. Finally, we highlight recent advances in telomerase-based therapeutic strategies for the treatment of diseases associated with extremely short telomeres owing to mutations in telomerase, as well as age-related diseases, and ultimately aging itself.

  3. Telomerase-Deficient Mice Exhibit Bone Loss Owing to Defects in Osteoblasts and Increased Osteoclastogenesis by Inflammatory Microenvironment

    DEFF Research Database (Denmark)

    Saeed, H.; Abdallah, B. M.; Ditzel, N.

    2011-01-01

    Telomere shortening owing to telomerase deficiency leads to accelerated senescence of human skeletal (mesenchymal) stem cells (MSCs) in vitro, whereas overexpression leads to telomere elongation, extended life span, and enhanced bone formation. To study the role of telomere shortening in vivo, we...... studied the phenotype of telomerase-deficient mice (Terc(-/-)).Terc(-/-) mice exhibited accelerated age-related bone loss starting at 3 months of age and during 12 months of follow-up revealed by dual-energy X-ray absorptiometric (DXA) scanning and by micro-computed tomography (mu CT). Bone...... histomorphometry revealed decreased mineralized surface and bone-formation rate as well as increased osteoclast number and size in Terc(-/-) mice. Also, serum total deoxypyridinoline (tDPD) was increased in Terc(-/-) mice. MSCs and osteoprogenitors isolated from Terc(-l-) mice exhibited intrinsic defects...

  4. cDNA Library Screening Identifies Protein Interactors Potentially Involved in Non-Telomeric Roles of Arabidopsis Telomerase

    Czech Academy of Sciences Publication Activity Database

    Dokládal, Ladislav; Honys, David; Rana, Rajiv; Lee, L.-Y.; Gelvin, S.B.; Sýkorová, Eva

    2015-01-01

    Roč. 6, NOV2015 (2015) ISSN 1664-462X R&D Projects: GA ČR GA13-06943S; GA MŠk(CZ) ED1.1.00/02.0068 Grant - others:GA MŠk(CZ) LH10352 Institutional support: RVO:68081707 ; RVO:61389030 Keywords : telomerase * nuclear poly(A)-binding protein * telobox Subject RIV: BO - Biophysics; EF - Botanics (UEB-Q) Impact factor: 4.495, year: 2015

  5. Comparison of Inhibitory Effect of Curcumin Nanoparticles and Free Curcumin in Human Telomerase Reverse Transcriptase Gene Expression in Breast Cancer

    OpenAIRE

    Nosratollah Zarghami; Abbas Rami; Fatemeh Kazemi-Lomedasht

    2013-01-01

    Purpose: Telomerase is expressed in most cancers, including breast cancer. Curcumin, a polyphenolic compound that obtained from the herb of Curcuma longa, has many anticancer effects. But, its effect is low due to poor water solubility. In order to improve its solubility and drug delivery, we have utilized a β-cyclodextrin-curcumin inclusion complex. Methods: To evaluate cytotoxic effects of cyclodextrin-curcumin and free curcumin, MTT assay was done. Cells were treated with equal concentrati...

  6. Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer

    Directory of Open Access Journals (Sweden)

    Iniesta Pilar

    2011-08-01

    Full Text Available Abstract Background Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. Results The aldehyde dehydrogenase (ALDH positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect and through decrease in telomere length (long-term effect. Administration of this telomerase inhibitor (40 mg/kg in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls. Combination therapy consisting of irradiation (10Gy plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. Conclusions We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer.

  7. Telomerase-mediated life-span extension of human primary fibroblasts by human artificial chromosome (HAC) vector

    International Nuclear Information System (INIS)

    Shitara, Shingo; Kakeda, Minoru; Nagata, Keiko; Hiratsuka, Masaharu; Sano, Akiko; Osawa, Kanako; Okazaki, Akiyo; Katoh, Motonobu; Kazuki, Yasuhiro; Oshimura, Mitsuo; Tomizuka, Kazuma

    2008-01-01

    Telomerase-mediated life-span extension enables the expansion of normal cells without malignant transformation, and thus has been thought to be useful in cell therapies. Currently, integrating vectors including the retrovirus are used for human telomerase reverse transcriptase (hTERT)-mediated expansion of normal cells; however, the use of these vectors potentially causes unexpected insertional mutagenesis and/or activation of oncogenes. Here, we established normal human fibroblast (hPF) clones retaining non-integrating human artificial chromosome (HAC) vectors harboring the hTERT expression cassette. In hTERT-HAC/hPF clones, we observed the telomerase activity and the suppression of senescent-associated SA-β-galactosidase activity. Furthermore, the hTERT-HAC/hPF clones continued growing beyond 120 days after cloning, whereas the hPF clones retaining the silent hTERT-HAC senesced within 70 days. Thus, hTERT-HAC-mediated episomal expression of hTERT allows the extension of the life-span of human primary cells, implying that gene delivery by non-integrating HAC vectors can be used to control cellular proliferative capacity of primary cultured cells

  8. cDNA Library Screening Identifies Protein Interactors Potentially Involved in Non-telomeric Roles of Arabidopsis Telomerase

    Directory of Open Access Journals (Sweden)

    Ladislav eDokládal

    2015-11-01

    Full Text Available Telomerase-reverse transcriptase (TERT plays an essential catalytic role in maintaining telomeres. However, in animal systems telomerase plays additional non-telomeric functional roles. We previously screened an Arabidopsis cDNA library for proteins that interact with the C-terminal extension (CTE TERT domain and identified a nuclear-localized protein that contains a RNA recognition motif (RRM. This RRM-protein forms homodimers in both plants and yeast. Mutation of the gene encoding the RRM-protein had no detectable effect on plant growth and development, nor did it affect telomerase activity or telomere length in vivo, suggesting a non-telomeric role for TERT/RRM-protein complexes. The gene encoding the RRM-protein is highly expressed in leaf and reproductive tissues. We further screened an Arabidopsis cDNA library for proteins that interact with the RRM-protein and identified five interactors. These proteins are involved in numerous non-telomere-associated cellular activities. In plants, the RRM-protein, both alone and in a complex with its interactors, localizes to nuclear speckles. Transcriptional analyses in wild-type and rrm mutant plants, as well as transcriptional co-analyses, suggest that TERT, the RRM-protein, and the RRM-protein interactors may play important roles in non-telomeric cellular functions.

  9. The putative Leishmania telomerase RNA (LeishTER undergoes trans-splicing and contains a conserved template sequence.

    Directory of Open Access Journals (Sweden)

    Elton J R Vasconcelos

    Full Text Available Telomerase RNAs (TERs are highly divergent between species, varying in size and sequence composition. Here, we identify a candidate for the telomerase RNA component of Leishmania genus, which includes species that cause leishmaniasis, a neglected tropical disease. Merging a thorough computational screening combined with RNA-seq evidence, we mapped a non-coding RNA gene localized in a syntenic locus on chromosome 25 of five Leishmania species that shares partial synteny with both Trypanosoma brucei TER locus and a putative TER candidate-containing locus of Crithidia fasciculata. Using target-driven molecular biology approaches, we detected a ∼2,100 nt transcript (LeishTER that contains a 5' spliced leader (SL cap, a putative 3' polyA tail and a predicted C/D box snoRNA domain. LeishTER is expressed at similar levels in the logarithmic and stationary growth phases of promastigote forms. A 5'SL capped LeishTER co-immunoprecipitated and co-localized with the telomerase protein component (TERT in a cell cycle-dependent manner. Prediction of its secondary structure strongly suggests the existence of a bona fide single-stranded template sequence and a conserved C[U/C]GUCA motif-containing helix II, representing the template boundary element. This study paves the way for further investigations on the biogenesis of parasite TERT ribonucleoproteins (RNPs and its role in parasite telomere biology.

  10. Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy.

    Science.gov (United States)

    Sandri, Sara; De Sanctis, Francesco; Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T; Nishimura, Michael I; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

    2017-10-20

    Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

  11. Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes.

    Science.gov (United States)

    Endorf, Elizabeth B; Qing, Hua; Aono, Jun; Terami, Naoto; Doyon, Geneviève; Hyzny, Eric; Jones, Karrie L; Findeisen, Hannes M; Bruemmer, Dennis

    2017-02-01

    Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. These data indicate a previously unrecognized role for TERT in neointima formation through epigenetic regulation of proliferative gene expression in SMC. © 2016 American Heart Association, Inc.

  12. Long telomeres produced by telomerase-resistant recombination are established from a single source and are subject to extreme sequence scrambling.

    Directory of Open Access Journals (Sweden)

    Jianing Xu

    Full Text Available Considerable evidence now supports the idea that the moderate telomere lengthening produced by recombinational telomere elongation (RTE in a Kluyveromyces lactis telomerase deletion mutant occurs through a roll-and-spread mechanism. However, it is unclear whether this mechanism can account for other forms of RTE that produce much longer telomeres such as are seen in human alternative lengthening of telomere (ALT cells or in the telomerase-resistant type IIR "runaway" RTE such as occurs in the K. lactis stn1-M1 mutant. In this study we have used mutationally tagged telomeres to examine the mechanism of RTE in an stn1-M1 mutant both with and without telomerase. Our results suggest that the establishment stage of the mutant state in newly generated stn1-M1 ter1-Δ mutants surprisingly involves a first stage of sudden telomere shortening. Our data also show that, as predicted by the roll-and-spread mechanism, all lengthened telomeres in a newly established mutant cell commonly emerge from a single telomere source. However, in sharp contrast to the RTE of telomerase deletion survivors, we show that the RTE of stn1-M1 ter1-Δ cells produces telomeres whose sequences undergo continuous intense scrambling via recombination. While telomerase was not necessary for the long telomeres in stn1-M1 cells, its presence during their establishment was seen to interfere with the amplification of repeats via recombination, a result consistent with telomerase retaining its ability to add repeats during active RTE. Finally, we observed that the presence of active mismatch repair or telomerase had important influences on telomeric amplification and/or instability.

  13. An integrable counterpart of the D-AKNS soliton hierarchy from so(3,R)

    International Nuclear Information System (INIS)

    Ma, Wen-Xiu

    2014-01-01

    An integrable counterpart of the D-AKNS soliton hierarchy is generated from a matrix spectral problem associated with so(3,R). Hamiltonian structures of the resulting counterpart soliton hierarchy are furnished by using the trace identity, which yields its Liouville integrability. -- Highlights: •Use the Lie algebra so(3,R) to generate a counterpart of the D-AKNS soliton hierarchy. •Generate Hamiltonian structures depending potentials by the trace identity. •Obtain hierarchies of independent commuting symmetries and conserved densities.

  14. Negative CO

    NARCIS (Netherlands)

    Meysman, F.J.R.; Montserrat, F.

    2017-01-01

    Negative emission technologies (NETs) target the removal of carbon dioxide (CO2) from the atmosphere, and are being actively investigated as a strategy to limit global warming to within the 1.5–2°C targets of the 2015 UN climate agreement. Enhanced silicate weathering (ESW) proposes to

  15. Negative Certainty

    Science.gov (United States)

    Ariso, José María

    2017-01-01

    The definitions of "negative knowledge" and the studies in this regard published to date have not considered the categorial distinction Wittgenstein established between knowledge and certainty. Hence, the important role that certainty, despite its omission, should have in these definitions and studies has not yet been shown. In this…

  16. X(3872) and the search for its bottomonium counterpart at the LHC

    CERN Document Server

    Toms, Konstantin; The ATLAS collaboration

    2016-01-01

    X(3872) history and theoretical status overview. ATLAS study of the ψ(2S) and X(3872) production. Search for X(3872) bottomonium counterpart by ATLAS. Search for Xb at CMS. Determination of X(3872) quantum numbers at LHCb.

  17. Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK dependent pathway in human endometrial cancer cells.

    Directory of Open Access Journals (Sweden)

    Chunxiao Zhou

    Full Text Available Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2 induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs, and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.

  18. Induced apoptosis by mild hyperthermia occurs via telomerase inhibition on the three human myeloid leukemia cell lines: TF-1, K562, and HL-60.

    Science.gov (United States)

    Deezagi, Abdolkhaleg; Manteghi, Sanaz; Khosravani, Pardis; Vaseli-Hagh, Neda; Soheili, Zahra-Soheila

    2009-09-01

    The purpose of this research was to understand the effect of hyperthermia on the telomerase activity in human leukemic cell lines (HL-60, K562, and TF-1). The cells were treated by hyperthermia at the range of 41-44 degrees C for 120 min and incubated for 96 h. Then telomerase activity, cell proliferation, and apoptosis were assessed. The results indicated that hyperthermia significantly induced apoptosis on the cells. The cells exhibited pre-apoptotic pattern at 41 and 42 degrees C at 60-120 min and apoptotic pattern at 43 and 44 degrees C over 30 min after hyperthermia. Telomerase activity (that was assayed immediately after hyperthermia) was stable at 41-42 degrees C for 60 min but decreased to 35-40% at 120 min. However, at severe hyperthermia (43-44 degrees C) telomerase activity was decreased in a time- and dose-dependent manner. Following hyperthermia (41-44 degrees C up to 120 min), the cells were incubated for 96 h. In these conditions, the telomerase activity was decreased by about 60-80% in comparison with that untreated control cells.

  19. In Situ Synthesized Silver Nanoclusters for Tracking the Role of Telomerase Activity in the Differentiation of Mesenchymal Stem Cells to Neural Stem Cells.

    Science.gov (United States)

    Dong, Fangyuan; Feng, Enduo; Zheng, Tingting; Tian, Yang

    2018-01-17

    Human mesenchymal stem cells (hMSCs) have potential use in cell replacement therapy for central nervous system disorders. However, the factors that impacted the differentiation process are unclear at the present stage because the powerful analytical method is the bottleneck. Herein, a novel strategy was developed for self-imaging and biosensing of telomerase activity in stem cells, using in situ biosynthesized silver nanoclusters (AgNCs) full of C bases. The present AgNCs possess synthetic convenience, long-time stability, and cytocompatibility. The weak fluorescence of these AgNCs is quickly turned on when approaching telomerase because of the strong interaction between C bases on AgNCs and G bases in telomerase, resulting in telomerase-dependent fluorescent signals. The developed method demonstrated high sensitivity and selectivity and broad dynamic linear range with a low detection limit. Using this powerful tool, it was first discovered that telomerase activity plays important roles in the proliferation of hMSCs and neural stem cells (NSCs) as well as during the differentiation processes from hMSCs to NSCs.

  20. Comparison of nutrition composition of transgenic maize (chitinase gene) with its non-transgenic counterpart

    OpenAIRE

    Ping-mei, Yan; Yu-kui, Rui; Xiao-yan, Yan; Zheng, Chai; Qing, Wang; Jian-zhong, Du; Yi, Sun

    2011-01-01

    In order to compare the nutrition components of transgenic maize seeds (chitinase gene), achieved by the pollen-mediated approach, with its non-transgenic counterpart, Vitamin B1, vitamin B2, fatty acids and essential amino acids of transgenic maize seeds and their counterparts were analyzed by the Chinese national standard methods or AOAC methods. The results showed that the contents of all the six kinds of fatty acids detected in transgenic maize seeds were significantly higher than those i...

  1. Telomerase reverse transcriptase mediated immortalization of human bone marrow stromal cells

    Directory of Open Access Journals (Sweden)

    Yong Teng

    2014-02-01

    Full Text Available Primary human bone marrow stromal cells (hMSCs were transfected with human telomerase reverse transcriptase (hTERT gene with lipofection method. The hTERT transfected hMSCs of passage 100 underwent chondrogenesis induction with dexamethasone, transforming the growth factor β and vitamin C, osteogenesis induction with dexamethasone, β glycerophosphoric acid and vitamin C, and cardiomyocyte induction with 5-azacytidine. After 7, 14, 21 and 28 days of induction, immunocytochemistry was performed to detect the expressions of type I and II collagen and osteocalcin, and alizarin red staining was performed to detect the bone nodule formation in osteogenesis induction. Immunocytochemistry was carried out to detect the striated muscle actin expression in cardiomyocytes. The hMSCs undergoing successful transfection were positive for the hTERT. The hTERT transfected cells were grown in vitro successfully and passaged for 136 generations. Results showed that these cells could be induced to differentiate into chondrocytes, bone and myocardial cells. Introduction of exogenous hTERT into hMSCs could achieve immortalized hMSCs with the potential of multi-directional differentiation. Thus, these cells could be applied as seed cells in tissue engineering.

  2. Similarities between long interspersed element-1 (LINE-1) reverse transcriptase and telomerase.

    Science.gov (United States)

    Kopera, Huira C; Moldovan, John B; Morrish, Tammy A; Garcia-Perez, Jose Luis; Moran, John V

    2011-12-20

    Long interspersed element-1 (LINE-1 or L1) retrotransposons encode two proteins (ORF1p and ORF2p) that contain activities required for conventional retrotransposition by a mechanism termed target-site primed reverse transcription. Previous experiments in XRCC4 or DNA protein kinase catalytic subunit-deficient CHO cell lines, which are defective for the nonhomologous end-joining DNA repair pathway, revealed an alternative endonuclease-independent (ENi) pathway for L1 retrotransposition. Interestingly, some ENi retrotransposition events in DNA protein kinase catalytic subunit-deficient cells are targeted to dysfunctional telomeres. Here we used an in vitro assay to detect L1 reverse transcriptase activity to demonstrate that wild-type or endonuclease-defective L1 ribonucleoprotein particles can use oligonucleotide adapters that mimic telomeric ends as primers to initiate the reverse transcription of L1 mRNA. Importantly, these ribonucleoprotein particles also contain a nuclease activity that can process the oligonucleotide adapters before the initiation of reverse transcription. Finally, we demonstrate that ORF1p is not strictly required for ENi retrotransposition at dysfunctional telomeres. Thus, these data further highlight similarities between the mechanism of ENi L1 retrotransposition and telomerase.

  3. p53 and telomerase control rat myocardial tissue response to hypoxia and ageing

    Directory of Open Access Journals (Sweden)

    A. Cataldi

    2009-12-01

    Full Text Available Cellular senescence implies loss of proliferative and tissue regenerative capability. Also hypoxia, producing Reactive Oxygen Species (ROS, can damage cellular components through the oxidation of DNA, proteins and lipids, thus influencing the shortening of telomeres. Since ribonucleoprotein Telomerase (TERT, catalyzing the replication of the ends of eukaryotic chromosomes, promotes cardiac muscle cell proliferation, hypertrophy and survival, here we investigated its role in the events regulating apoptosis occurrence and life span in hearts deriving from young and old rats exposed to hypoxia. TUNEL (terminal-deoxinucleotidyl -transferase- mediated dUTP nick end-labeling analysis reveals an increased apoptotic cell number in both samples after hypoxia exposure, mainly in the young with respect to the old. TERT expression lowers either in the hypoxic young, either in the old in both experimental conditions, with respect to the normoxic young. These events are paralleled by p53 and HIF-1 ? expression dramatic increase and by p53/ HIF-1 ? co-immunoprecipitation in the hypoxic young, evidencing the young subject as the most stressed by such challenge. These effects could be explained by induction of damage to genomic DNA by ROS that accelerates cell senescence through p53 activation. Moreover, by preventing TERT enzyme down-regulation, cell cycle exit and apoptosis occurrence could be delayed and new possibilities for intervention against cell ageing and hypoxia could be opened.

  4. Transcriptional activity of telomerase complex in CD34- stem cells of cord blood in dependence of preparation time.

    Directory of Open Access Journals (Sweden)

    M Bojdys-Szyndlar

    2009-12-01

    Full Text Available The aim of the study was to determine whether the expression of telomerase subunits encoding genes changes during the process of cord blood preparation. It should establish if the commonly accepted 24 hours time interval in stem cells kriopreservation procedure significantly influences their immortalization and so decreases the "quality" of cord blood stem cells. Investigation includes 69 women. Spontaneous labour was the inclusion condition. The material was collected at birth after clamping of umbilical cord by direct vasopuncture. CD34- cells were extracted from cord blood (MACS, Miltenyi Biotec; Bisley, Surrey, UK. The expression profile of telomerase activators and inhibitors encoding genes was determined using HG_U133A oligonucleotide microarray (Affymetrix. We used a real-time quantitative RT-PCR assay to quantify the telomerase TERT, hTR and TP1 subunits mRNA copy numbers in CD34- cells in 0, 6, 12 and 24 hours after cord blood collection. We observed significant decrease of numbers of copies of TERTA+B mRNA within the successive hours of observation. Significant decrease of numbers of TERTA mRNA copies was confirmed after 24 hours. However, we observed significant increase of numbers of copies of TERTB mRNA after 6 hours of observation. Similar level was maintained during another 6h. The significantly lower number of copies of TERTB mRNA was observed after 24h. We also observed significant increase of number of copies of TERT mRNA after 6 hours. Number of copies of TERT mRNA significantly decreased after another 6h, remaining, however, on a higher then initial one. The significant lower number of copies of TERT mRNA was observed 24h after delivery. The possible explanation of those results is discussed in the paper.

  5. Massive scalar counterpart of gravitational waves in scalarized neutron star binaries

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing [Sun Yat-sen University, School of Physics and Astronomy, Guangzhou (China)

    2017-09-15

    In analogy with spontaneous magnetization of ferromagnets below the Curie temperature, a neutron star (NS), with a compactness above a certain critical value, may undergo spontaneous scalarization and exhibit an interior nontrivial scalar configuration. Consequently, the exterior spacetime is changed, and an external scalar field appears, which subsequently triggers a scalarization of its companion. The dynamical interplay produces a gravitational scalar counterpart of tensor gravitational waves. In this paper, we resort to scalar-tensor theory and demonstrate that the gravitational scalar counterpart from a double neutron star (DNS) and a neutron star-white dwarf (NS-WD) system become massive. We report that (1) a gravitational scalar background field, arising from convergence of external scalar fields, plays the role of gravitational scalar counterpart in scalarized DNS binary, and the appearance of a mass-dimensional constant in a Higgs-like gravitational scalar potential is responsible for a massive gravitational scalar counterpart with a mass of the order of the Planck scale; (2) a dipolar gravitational scalar radiated field, resulting from differing binding energies of NS and WD, plays the role of a gravitational scalar counterpart in scalarized orbital shrinking NS-WDs, which oscillates around a local and scalar-energy-density-dependent minimum of the gravitational scalar potential and obtains a mass of the order of about 10{sup -21} eV/c{sup 2}. (orig.)

  6. EFEK EKSTRAK SAMBILOTO (ANDROGRAPHIS PANICULATA NEES PADA EKSPRESI TELOMERASE DARI KANKER PAYUDARA TIKUS YANG DIINDUKSI DENGAN DMBA

    Directory of Open Access Journals (Sweden)

    Yurika Sastyarina

    2010-12-01

    Full Text Available ABSTRACT   It has been well documented that chemical carcinogen, 7.12 dimethylbenz(aanthracene (DMBA,  plays a role in the incidence and growth of mammary cancer. Present study was designed to investigate the influence of Andrographis paniculata extract on telomerase activities on DMBA induced breast cancer in the female rat Sprague Dawley strain. DMBA-induced mammary cancer is a useful model to investigate the changes of epithelial cells that occur during mammary cancer progression. Mammary cancer model was induced 10 times twice a week by oral DMBA 20 mg/kg body weight. Mammary cancer occurred in 75 % animals nine weeks after oral administration of DMBA, it was represented with nodule on the mammary gland and the increasing of mammary gland volume compare with normal control F(1.8 = 731.711; p < 0.001. This study was also designed to investigate the effect of Andrographis paniculata extract mammary carcinoma induced by DMBA. Administration of three different dose of Andrographis paniculata (100 mg/kg, 300 mg/kg and 1000 mg/kg had statistically different with mammary gland volume of DMBA treated rat F (4.17 = 92.777; p<0.05. So, Andrographis paniculata has significant effect on the treatment of DMBA-induced mammary carcinoma. The Epithelial cells were harvested on day 90 and stained with routine histology staining, hematoxylineosin, for morphological qualitative analysis, immunohistochemical examination. The lesions observed from the removed samples ranged widely from benign to malignant. The results showed that DMBA induce cell proliferation, nuclear irregularities, and numerous mitoses and induced cell necrosis. The effect of Andrographis paniculata inhibits cell proliferation and induces apoptosis in cancer cells. On immunohistochemical examination, it shows that Andrographis paniculata can stimulate of telomerase enzyme.   Key word: Andrographis paniculata, DMBA, mammary cancer, cell proliferation     ABSTRAK   Telah dilakukan

  7. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

    Directory of Open Access Journals (Sweden)

    Stefanou Nikolaos

    2010-08-01

    Full Text Available Abstract Background Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC. The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT, a known mediator of cellular immortalization. Methods We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3 and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. Results We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC. Conclusions We propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

  8. The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

    Science.gov (United States)

    Rampazzo, Enrica; Del Bianco, Paola; Bertorelle, Roberta; Boso, Caterina; Perin, Alessandro; Spiro, Giovanna; Bergamo, Francesca; Belluco, Claudio; Buonadonna, Angela; Palazzari, Elisa; Leonardi, Sara; De Paoli, Antonino; Pucciarelli, Salvatore; De Rossi, Anita

    2018-01-01

    Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT=T0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4–8 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (P<0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73–0.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10–4.11)-fold and 4.55 (95% CI 1.48–13.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy. PMID:29449673

  9. Rice (Oryza sativa L.) containing the bar gene is compositionally equivalent to the nontransgenic counterpart.

    Science.gov (United States)

    Oberdoerfer, Regina B; Shillito, Raymond D; de Beuckeleer, Marc; Mitten, Donna H

    2005-03-09

    This publication presents an approach to assessing compositional equivalence between grain derived from glufosinate-tolerant rice grain, genetic event LLRICE62, and its nontransgenic counterpart. Rice was grown in the same manner as is common for commercial production, using either conventional weed control practices or glufosinate-ammonium herbicide. A two-season multisite trial design provided a robust data set to evaluate environmental effects between the sites. Statistical comparisons to test for equivalence were made between glufosinate-tolerant rice and a conventional counterpart variety. The key nutrients, carbohydrates, protein, iron, calcium, thiamin, riboflavin, and niacin, for which rice can be the principal dietary source, were investigated. The data demonstrate that rice containing the genetic locus LLRICE62 has the same nutritional value as its nontransgenic counterpart, and most results for nutritional components fall within the range of values reported for rice commodities in commerce.

  10. Observations of the First Electromagnetic Counterpart to a Gravitational-wave Source by the TOROS Collaboration

    Science.gov (United States)

    Díaz, M. C.; Macri, L. M.; Garcia Lambas, D.; Mendes de Oliveira, C.; Nilo Castellón, J. L.; Ribeiro, T.; Sánchez, B.; Schoenell, W.; Abramo, L. R.; Akras, S.; Alcaniz, J. S.; Artola, R.; Beroiz, M.; Bonoli, S.; Cabral, J.; Camuccio, R.; Castillo, M.; Chavushyan, V.; Coelho, P.; Colazo, C.; Costa-Duarte, M. V.; Cuevas Larenas, H.; DePoy, D. L.; Domínguez Romero, M.; Dultzin, D.; Fernández, D.; García, J.; Girardini, C.; Gonçalves, D. R.; Gonçalves, T. S.; Gurovich, S.; Jiménez-Teja, Y.; Kanaan, A.; Lares, M.; Lopes de Oliveira, R.; López-Cruz, O.; Marshall, J. L.; Melia, R.; Molino, A.; Padilla, N.; Peñuela, T.; Placco, V. M.; Quiñones, C.; Ramírez Rivera, A.; Renzi, V.; Riguccini, L.; Ríos-López, E.; Rodriguez, H.; Sampedro, L.; Schneiter, M.; Sodré, L.; Starck, M.; Torres-Flores, S.; Tornatore, M.; Zadrożny, A.

    2017-10-01

    We present the results of prompt optical follow-up of the electromagnetic counterpart of the gravitational-wave event GW170817 by the Transient Optical Robotic Observatory of the South Collaboration. We detected highly significant dimming in the light curves of the counterpart ({{Δ }}g=0.17+/- 0.03 mag, {{Δ }}r=0.14+/- 0.02 mag, {{Δ }}I=0.10+/- 0.03 mag) over the course of only 80 minutes of observations obtained ˜35 hr after the trigger with the T80-South telescope. A second epoch of observations, obtained ˜59 hr after the event with the EABA 1.5 m telescope, confirms the fast fading nature of the transient. The observed colors of the counterpart suggest that this event was a “blue kilonova” relatively free of lanthanides.

  11. Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective.

    Science.gov (United States)

    Darwiche, Walaa; Gubler, Brigitte; Marolleau, Jean-Pierre; Ghamlouch, Hussein

    2018-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells.

  12. Discovery of the optical counterpart and early optical observations of GRB 990712

    DEFF Research Database (Denmark)

    Sahu, K.C.; Vreesvijk, P.; Bakos, G.

    2000-01-01

    We present the discovery observations of the optical counterpart of the gamma-ray burst GRB 990712 taken 4.16 hr after the outburst and discuss its light curve observed in the V, R, and I bands during the first similar to 35 days after the outburst. The observed light curves were fitted with a po......We present the discovery observations of the optical counterpart of the gamma-ray burst GRB 990712 taken 4.16 hr after the outburst and discuss its light curve observed in the V, R, and I bands during the first similar to 35 days after the outburst. The observed light curves were fitted...

  13. Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.

    Science.gov (United States)

    Findeisen, Hannes M; Gizard, Florence; Zhao, Yue; Cohn, Dianne; Heywood, Elizabeth B; Jones, Karrie L; Lovett, David H; Howatt, Deborah A; Daugherty, Alan; Bruemmer, Dennis

    2011-02-01

    Abdominal aortic aneurysms (AAA) are an age-related vascular disease and an important cause of morbidity and mortality. In this study, we sought to determine whether the catalytic component of telomerase, telomerase reverse transcriptase (TERT), modulates angiotensin (Ang) II-induced AAA formation. Low-density lipoprotein receptor-deficient (LDLr-/-) mice were lethally irradiated and reconstituted with bone marrow-derived cells from TERT-deficient (TERT-/-) mice or littermate wild-type mice. Mice were placed on a diet enriched in cholesterol, and AAA formation was quantified after 4 weeks of Ang II infusion. Repopulation of LDLr-/- mice with TERT-/- bone marrow-derived cells attenuated Ang II-induced AAA formation. TERT-deficient recipient mice revealed modest telomere attrition in circulating leukocytes at the study end point without any overt effect of the donor genotype on white blood cell counts. In mice repopulated with TERT-/- bone marrow, aortic matrix metalloproteinase-2 (MMP-2) activity was reduced, and TERT-/- macrophages exhibited decreased expression and activity of MMP-2 in response to stimulation with Ang II. Finally, we demonstrated in transient transfection studies that TERT overexpression activates the MMP-2 promoter in macrophages. TERT deficiency in bone marrow-derived macrophages attenuates Ang II-induced AAA formation in LDLr-/- mice and decreases MMP-2 expression. These results point to a previously unrecognized role of TERT in the pathogenesis of AAA.

  14. Expression of human telomerase reverse transcriptase protein in oral epithelial dysplasia and oral squamous cell carcinoma: An immunohistochemical study

    Science.gov (United States)

    Raghunandan, Bangalore Nagarajachar; Sanjai, Karpagaselvi; Kumaraswamy, Jayalakshmi; Papaiah, Lokesh; Pandey, Bhavna; Jyothi, Bellur MadhavaRao

    2016-01-01

    Background: Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA sequences and almost universally provides the molecular basis for unlimited proliferative potential. The telomeres become shorter with each cycle of replication and reach a critical limit; most cells die or enter stage of replicative senescence. Telomere length maintenance by telomerase is required for all the cells that exhibit limitless replicative potential. It has been postulated that reactivation of telomerase expression is necessary for the continuous proliferation of neoplastic cells to attain immortality. Use of immunohistochemistry (IHC) is a useful, reliable method of localizing the human telomerase reverse transcriptase (hTERT) protein in tissue sections which permits cellular localization. Although there exists a lot of information on telomerase in oral cancer, little is known about their expression in oral epithelial dysplasia and their progression to oral squamous cell carcinoma (OSCC) compared to normal oral mucosa. This study addresses this lacuna. Aims: To compare the expression of hTERT protein in oral epithelial dysplasia and OSCC with normal oral mucosa by Immunohistochemical method. Subjects and Methods: In this preliminary study, IHC was used to detect the expression of hTERT protein in OSCC (n = 20), oral epithelial dysplasia (n = 21) and normal oral mucosa (n = 10). The tissue localization of immunostain, cellular localization of immunostain, nature of stain, intensity of stain, percentage of cells stained with hTERT protein were studied. A total number of 100 cells were counted in each slide. Statistical Analysis: All the data were analyzed using SPSS software version 16.0. The tissue localization, cellular localization of cytoplasmic/nuclear/both of hTERT stain, staining intensity was compared across the groups using Pearson's Chi-square test. The mean percentage of cells stained for oral epithelial dysplasia, OSCC and normal oral mucosa were

  15. Activation of Telomerase by Ionizing Radiation: Differential Response to the Inhibition of DNA Double-Strand Break Repair by Abrogation of Poly(ADP-ribosyl)ation, by LY294002, or by Wortmannin

    International Nuclear Information System (INIS)

    Neuhof, Dirk; Zwicker, Felix; Kuepper, Jan-Heiner; Debus, Juergen; Weber, Klaus-Josef

    2007-01-01

    Purpose: Telomerase activity represents a radiation-inducible function, which may be targeted by a double-strand break (DSB)-activated signal transduction pathway. Therefore, the effects of DNA-PK inhibitors (Wortmannin and LY294002) on telomerase upregulation after irradiation were studied. In addition, the role of trans-dominant inhibition of poly(ADP-ribosyl)ation, which strongly reduces DSB rejoining, was assessed in comparison with 3-aminobenzamide. Methods and Materials: COM3 rodent cells carry a construct for the dexamethasone-inducible overexpression of the DNA-binding domain of PARP1 and exhibit greatly impaired DSB rejoining after irradiation. Telomerase activity was measured using polymerase chain reaction ELISA 1 h after irradiation with doses up to 10 Gy. Phosphorylation status of PKB/Akt and of PKCα/β II was assessed by western blotting. Results: No telomerase upregulation was detectable for irradiated cells with undisturbed DSB rejoining. In contrast, incubation with LY294002 or dexamethasone yielded pronounced radiation induction of telomerase activity that could be suppressed by Wortmannin. 3-Aminobenzamide not only was unable to induce telomerase activity but also suppressed telomerase upregulation upon incubation with LY294002 or dexamethasone. Phospho-PKB was detectable independent of irradiation or dexamethasone pretreatment, but was undetectable upon incubations with LY294002 or Wortmannin, whereas phospho-PKC rested detectable. Conclusions: Telomerase activation postirradiation was triggered by different treatments that interfere with DNA DSB processing. This telomerase upregulation, however, was not reflected by the phosporylation status of the putative mediators of TERT activation, PKB and PKC. Although an involvement of PKB in TERT activation is not supported by the present findings, a respective role of PKC isoforms other than α/β II cannot be ruled out

  16. Stability patterns for a size-structured population model and its stage-structured counterpart

    DEFF Research Database (Denmark)

    Zhang, Lai; Pedersen, Michael; Lin, Zhigui

    2015-01-01

    In this paper we compare a general size-structured population model, where a size-structured consumer feeds upon an unstructured resource, to its simplified stage-structured counterpart in terms of equilibrium stability. Stability of the size-structured model is understood in terms of an equivale...... to the population level....

  17. Counterpart experimental study of ISP-42 PANDA tests on PUMA facility

    International Nuclear Information System (INIS)

    Yang, Jun; Choi, Sung-Won; Lim, Jaehyok; Lee, Doo-Yong; Rassame, Somboon; Hibiki, Takashi; Ishii, Mamoru

    2013-01-01

    Highlights: ► Counterpart tests were performed on two large-scale BWR integral facilities. ► Similarity of post-LOCA system behaviors observed between two tests. ► Passive core and containment cooling systems work as design in both tests. -- Abstract: A counterpart test to the Passive Nachwärmeabfuhr und Druckabbau Test Anlage (Passive Decay Heat Removal and Depressurization Test Facility, PANDA) International Standard Problem (ISP)-42 test was conducted at the Purdue University Multi-Dimensional Integral Test Assembly (PUMA) facility. Aimed to support code validation on a range of light water reactor (LWR) containment issues, the ISP-42 test consists of six sequential phases (Phases A–F) with separately defined initial and boundary conditions, addressing different stages of anticipated accident scenario and system responses. The counterpart test was performed from Phases A to D, which are within the scope of the normal integral tests performed on the PUMA facility. A scaling methodology was developed by using the PANDA facility as prototype and PUMA facility as test model, and an engineering scaling has been applied to the PUMA facility. The counterpart test results indicated that functions of passive safety systems, such as passive containment cooling system (PCCS) start-up, gravity-driven cooling system (GDCS) discharge, PCCS normal operation and overload function were confirmed in both the PANDA and PUMA facilities with qualitative similarities

  18. Telomerase RNA Component (TERC) genetic variants interact with the mediterranean diet modifying the inflammatory status and its relationship with aging: CORDIOPREV study

    Science.gov (United States)

    Background: Leukocyte telomere length (LTL) attrition has been associated with age-related diseases. Telomerase RNA Component (TERC) genetic variants have been associated with LTL; whereas fatty acids (FAs) can interact with genetic factors and influence in aging. We explore whether variability at t...

  19. Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection—The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

    Science.gov (United States)

    Quryshi, Nabeel; Norwood Toro, Laura E.; Ait-Aissa, Karima; Kong, Amanda; Beyer, Andreas M.

    2018-01-01

    Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (mtDNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating mtDNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of mtDNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage. PMID:29534446

  20. Infrared Counterparts to Chandra X-Ray Sources in the Antennae

    Science.gov (United States)

    Clark, D. M.; Eikenberry, S. S.; Brandl, B. R.; Wilson, J. C.; Carson, J. C.; Henderson, C. P.; Hayward, T. L.; Barry, D. J.; Ptak, A. F.; Colbert, E. J. M.

    2007-03-01

    We use deep J (1.25 μm) and Ks (2.15 μm) images of the Antennae (NGC 4038/4039) obtained with the Wide-field InfraRed Camera on the Palomar 200 inch (5 m) telescope, together with the Chandra X-ray source list of Zezas and coworkers to search for infrared counterparts to X-ray point sources. We establish an X-ray/IR astrometric frame tie with ~0.5" rms residuals over a ~4.3' field. We find 13 ``strong'' IR counterparts brighter than Ks=17.8 mag and 99.9% confidence level that IR counterparts to X-ray sources are ΔMKs~1.2 mag more luminous than average non-X-ray clusters. We also note that the X-ray/IR matches are concentrated in the spiral arms and ``overlap'' regions of the Antennae. This implies that these X-ray sources lie in the most ``super'' of the Antennae's super star clusters, and thus trace the recent massive star formation history here. Based on the NH inferred from the X-ray sources without IR counterparts, we determine that the absence of most of the ``missing'' IR counterparts is not due to extinction, but that these sources are intrinsically less luminous in the IR, implying that they trace a different (possibly older) stellar population. We find no clear correlation between X-ray luminosity classes and IR properties of the sources, although small-number statistics hamper this analysis.

  1. Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis.

    Science.gov (United States)

    Mocellin, Simone; Verdi, Daunia; Pooley, Karen A; Landi, Maria T; Egan, Kathleen M; Baird, Duncan M; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

    2012-06-06

    Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic

  2. IDENTIFYING ELUSIVE ELECTROMAGNETIC COUNTERPARTS TO GRAVITATIONAL WAVE MERGERS: AN END-TO-END SIMULATION

    International Nuclear Information System (INIS)

    Nissanke, Samaya; Georgieva, Alexandra; Kasliwal, Mansi

    2013-01-01

    Combined gravitational wave (GW) and electromagnetic (EM) observations of compact binary mergers should enable detailed studies of astrophysical processes in the strong-field gravity regime. This decade, ground-based GW interferometers promise to routinely detect compact binary mergers. Unfortunately, networks of GW interferometers have poor angular resolution on the sky and their EM signatures are predicted to be faint. Therefore, a challenging goal will be to unambiguously pinpoint the EM counterparts of GW mergers. We perform the first comprehensive end-to-end simulation that focuses on: (1) GW sky localization, distance measures, and volume errors with two compact binary populations and four different GW networks; (2) subsequent EM detectability by a slew of multiwavelength telescopes; and (3) final identification of the merger counterpart amidst a sea of possible astrophysical false positives. First, we find that double neutron star binary mergers can be detected out to a maximum distance of 400 Mpc (or 750 Mpc) by three (or five) detector GW networks, respectively. Neutron-star-black-hole binary mergers can be detected a factor of 1.5 further out; their median to maximum sky localizations are 50-170 deg 2 (or 6-65 deg 2 ) for a three (or five) detector GW network. Second, by optimizing depth, cadence, and sky area, we quantify relative fractions of optical counterparts that are detectable by a suite of different aperture-size telescopes across the globe. Third, we present five case studies to illustrate the diversity of scenarios in secure identification of the EM counterpart. We discuss the case of a typical binary, neither beamed nor nearby, and the challenges associated with identifying an EM counterpart at both low and high Galactic latitudes. For the first time, we demonstrate how construction of low-latency GW volumes in conjunction with local universe galaxy catalogs can help solve the problem of false positives. We conclude with strategies that would

  3. [The efficacy of autocatalytic casapse-3 driven by human telomerase reverse transcriptase promoter on human ovarian carcinoma].

    Science.gov (United States)

    Song, Yue; Shen, Keng; Yu, Jing-rong

    2007-11-06

    To construct recombinant adenoviral vector expressing autocatalysis caspase-3 driven by human telomerase reverse transcriptase promoter (hTERTp), and investigate its antitumor effect on ovarian cancer in vitro and in vivo. Recombinant adenovirus expressing autocatalytic caspase-3 (rev-csapase-3) driven by hTERTp, AdHT-rev-casp3, was constructed. Ad-rev-casp3 expressing rev-caspase-3 driven by cytomegalovirus promoter (CMVp) was used as a positive control. hTERT positive human ovarian cancer cells of the line AO and hTERT-negative human umbilical venous endothelial cells (HUVECs) were cultured and transfected with AdHT-rev-casp3, Ad-rev-casp3, or Ad-EGFG expressing enhanced green fluorescent protein as control group. Western blotting, Cell Counting Kit (CCK-8), flow cytometry, and TUNEL were used to detect the expression of p17, active subunit of caspase-3, and p85, a poly ADP-ribose polymerase (PARP) cleavage fragment, and they were also used to measure the cell survival rate and apoptotic rate. Western blotting was used to detect the expression of active caspase-3 and its substrate PARP in the AO cells and HUVECs. Twenty nude BALB/c mice were inoculated subcutaneously with AO cells to establish subcutaneous tumor models, when the tumor grew to the volume of 150 mm3 the rats were divided into 4 equal groups to undergo intra-tumor injection of AdHT-rev-casp3, Ad-rev-casp3, Ad-EGFG, and phosphate-buffered saline (PBS) respectively, the survival rate tumor inhibition rate was observed, 72 days later the mice were killed with their livers and tumors taken out, and Western blotting was used to detect the expression of active caspase-3. Another 40 mice underwent intraperitoneal injection of AO cells to establish intraperitoneal transplanted tumor models, 21 days later the rats were divided into 4 equal groups to be injected intraperitoneally with AdHT-rev-casp3, Ad-rev-casp3, Ad-EGFG, or PBS, the survival rate was observed, and the blood levels of alanine transaminase

  4. Do Foreign-Owned Firms Provide Better Working Conditions Than Their Domestic Counterparts? A Comparative Analysis

    OpenAIRE

    Hijzen, Alexander; Martins, Pedro S.; Schank, Thorsten; Upward, Richard

    2010-01-01

    This paper analyses to what extent working conditions in foreign-owned firms differ from those in their domestic counterparts. It makes three main contributions. First, we replicate the consensus in the empirical literature by applying a standardised methodology to firm-level data for three developed (Germany, Portugal, UK) and two emerging economies (Brazil, Indonesia). We show that, consistent with previous evidence, foreign-owned firms offer substantially higher average wages than domestic...

  5. HST/ACS Imaging of Omega Centauri: Optical Counterparts of Chandra X-Ray Sources

    Science.gov (United States)

    Cool, Adrienne M.; Haggard, Daryl; Arias, Tersi; Brochmann, Michelle; Dorfman, Jason; Gafford, April; White, Vivian; Anderson, Jay

    2013-02-01

    We present results of a search for optical counterparts of X-ray sources in and toward the globular cluster Omega Centauri (NGC 5139) using the Advanced Camera for Surveys (ACS) on the Hubble Space Telescope. The ACS data consist of a mosaic of Wide Field Channel images obtained using F625W, F435W, and F658N filters; with nine pointings we cover the central ~10' × 10' of the cluster and encompass 109 known Chandra sources. We find promising optical counterparts for 59 of the sources, ~40 of which are likely to be associated with the cluster. These include 27 candidate cataclysmic variables (CVs), 24 of which are reported here for the first time. Fourteen of the CV candidates are very faint, with absolute magnitudes in the range M 625 =10.4-12.6, making them comparable in brightness to field CVs near the period minimum discovered in the Sloan Digital Sky Survey. Additional optical counterparts include three BY Dra candidates, a possible blue straggler, and a previously reported quiescent low-mass X-ray binary. We also identify 3 foreground stars and 11 probable active galactic nuclei. Finally, we report the discovery of a group of seven stars whose X-ray properties are suggestive of magnetically active binaries, and whose optical counterparts lie on or very near the metal-rich anomalous giant and subgiant branches in ω Cen. If the apparent association between these seven stars and the RGB/SGB-a stars is real, then the frequency of X-ray sources in this metal-rich population is enhanced by a factor of at least five relative to the other giant and subgiant populations in the cluster. If these stars are not members of the metal-rich population, then they bring the total number of red stragglers (also known as sub-subgiants) that have been identified in ω to Cen 20, the largest number yet known in any globular cluster.

  6. The credit counterparts of broad money : a structural base for macroeconomic policy

    OpenAIRE

    Steele, Gerald

    2014-01-01

    Tautological structures bring clarity to arguments in macroeconomics: familiar structures relate to the circulation of money, the circular flow of real income, and the balance of international payments. Less familiar is a structure incorporating all aspects of macroeconomic policy interventions. The origins and use of the credit counterparts of broad money are examined in the context of the application of UK monetary policy in the period since 1945.

  7. Finding X-ray counterparts for unidentified sources in the 105 months BAT survey - 1

    Science.gov (United States)

    Stephen, J. B.; Bassani, L.; Malizia, A.; Masetti, N.; Ubertini, P.

    2018-02-01

    We provide X-ray counterparts for the unidentified Swift/BAT sources listed in the 105 month catalogue (Oh et al. 2018, ApJS in press). These associations were found by cross-correlating the list of U1,U2 and U3 sources with the ROSAT Bright (RASSBSC, Voges et al. 1999, A & A, 349, 389) and the XMM-Newton Slew (XMMSlew, Saxton et al. 2008, A & A, 480, 611) catalogues.

  8. Finding X-ray counterparts for unidentified sources in the 105 months BAT survey - 2

    Science.gov (United States)

    Stephen, J. B.; Bassani, L.; Malizia, A.; Masetti, N.; Ubertini, P.

    2018-02-01

    We provide X-ray counterparts for unidentified Swift/BAT sources in the 105 month catalogue (Oh et al. 2018, ApJS in press). They were found by cross-correlating the list of U1,U2 and U3 sources with the ROSAT Bright (RASSBSC, Voges et al. 1999, A & A, 349, 389) and XMM-Newton Slew (XMMSlew, Saxton et al. 2008, A & A, 480, 611) catalogues and optically identified as reported in Atel #11340.

  9. The optical counterpart of IGR J00291+5934 in quiescence

    Science.gov (United States)

    D'Avanzo, P.; Campana, S.; Covino, S.; Israel, G. L.; Stella, L.; Andreuzzi, G.

    2007-09-01

    Aims:The recent (December 2004) discovery of the sixth accretion-powered millisecond X-ray pulsar IGR J00291+5934 provides a very good chance to deepen our knowledge of such systems. Although these systems are well studied at high energies, poor informations are available for their optical/NIR counterparts during quiescence. Up to now, only for SAX J1808.4-3658, the first discovered system of this type, we have a secure multiband detection of its optical counterpart in quiescence. Among the seven known system IGR J00291+5934 is the one that resembles SAX J1808.4-3658 more closely. Methods: With the Italian 3.6 m TNG telescope, we have performed deep optical and NIR photometry of the field of IGR J00291+5934 during quiescence in order to look for the presence of a variable counterpart. Results: We present here the first multiband (VRIJH) detection of the optical and NIR counterpart of IGR J00291+5934 in quiescence as well as a deep upper limit in the K-band. We obtain an optical light curve that shows variability consistent with a sinusoidal modulation at the known 2.46 h orbital period and present evidence for a strongly irradiated companion. Based on observations made with the Italian Telescopio Nazionale Galileo (TNG) operated on the island of La Palma by the Fundación Galileo Galilei of the INAF (Istituto Nazionale di Astrofisica) at the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias.

  10. INVESTIGATING THE OPTICAL COUNTERPART CANDIDATES OF FOUR INTEGRAL SOURCES LOCALIZED WITH CHANDRA

    International Nuclear Information System (INIS)

    Özbey Arabacı, Mehtap; Kalemci, Emrah; Tomsick, John A.; Bodaghee, Arash; Halpern, Jules; Chaty, Sylvain; Rodriguez, Jerome; Rahoui, Farid

    2012-01-01

    We report on the optical spectroscopic follow-up observations of the candidate counterparts to four INTEGRAL sources: IGR J04069+5042, IGR J06552–1146, IGR J21188+4901, and IGR J22014+6034. The candidate counterparts were determined with Chandra, and the optical observations were performed with 1.5 m RTT-150 telescope (TÜBİTAK National Observatory, Antalya, Turkey) and 2.4 m Hiltner Telescope (MDM Observatory, Kitt Peak, Arizona). Our spectroscopic results show that one of the two candidates of IGR J04069+5042 and the one observed for IGR J06552–1146 could be active late-type stars in RS CVn systems. However, according to the likelihood analysis based on Chandra and INTEGRAL, two optically weaker sources in the INTEGRAL error circle of IGR J06552–1146 have higher probabilities to be the actual counterpart. The candidate counterparts of IGR J21188+4901 are classified as an active M-type star and a late-type star. Among the optical spectra of four candidates of IGR J22014+6034, two show Hα emission lines, one is a late-type star, and the other is an M type. The likelihood analysis favors a candidate with no distinguishing features in the optical spectrum. Two of the candidates classified as M-type dwarfs, are similar to some IGR candidates claimed to be symbiotic stars. However, some of the prominent features of symbiotic systems are missing in our spectra, and their NIR colors are not consistent with those expected for giants. We consider the IR colors of all IGR candidates claimed to be symbiotic systems and find that low-resolution optical spectrum may not be enough for conclusive identification.

  11. The optical counterpart of the bright X-ray transient Swift J1745-26

    NARCIS (Netherlands)

    Muñoz-Darias, T.; de Ugarte Postigo, A.; Russell, D.M.; Guziy, S.; Gorosabel, J.; Casares, J.; Armas Padilla, M.; Charles, P.A.; Fender, R.P.; Belloni, T.M.; Lewis, F.; Motta, S.; Castro-Tirado, A.; Mundell, C.G.; Sánchez-Ramirez, R.; Thöne, C.C.

    2013-01-01

    We present a 30-day monitoring campaign of the optical counterpart of the bright X-ray transient Swift J1745−26, starting only 19 min after the discovery of the source. We observe the system peaking at i′ ∼ 17.6 on day six (MJD 561 92) to then decay at a rate of ∼0.04 mag d−1. We show that the

  12. Strategic Wholesale Pricing for an Incumbent Supplier Facing with a Competitive Counterpart

    OpenAIRE

    Sun, Jianwu

    2014-01-01

    We introduce a wholesale pricing strategy for an incumbent supplier facing with a competitive counterpart. We propose a profit function which considers both the present loss and future loss from a wholesale price and then study the optimal wholesale prices for different objectives about this profit function for the incumbent supplier. First, we achieve an optimal wholesale price for the incumbent supplier to maximize his expected profit. Then, to reduce the risk originating from the fluctuati...

  13. A comparative study between South African serial killers and their American counterparts

    OpenAIRE

    2009-01-01

    M.A. This dissertation explores the similarities and differences between South African serial killers and their American counterparts. Seven male candidates, each having committed their reign of terror within the relevant time period, have been included. The candidates compared well in home environments, number of friendships, emotional maturity, abuse undergone, temperament, and anti-social behaviour. Differences were found in comparing family bonding, wealth and education. This dissertat...

  14. Counterpart synchronization of duplex networks with delayed nodes and noise perturbation

    International Nuclear Information System (INIS)

    Wei, Xiang; Wu, Xiaoqun; Lu, Jun-an; Zhao, Junchan

    2015-01-01

    In the real world, many complex systems are represented not by single networks but rather by sets of interdependent ones. In these specific networks, nodes in one network mutually interact with nodes in other networks. This paper focuses on a simple representative case of two-layer networks (the so-called duplex networks) with unidirectional inter-layer couplings. That is, each node in one network depends on a counterpart in the other network. Accordingly, the former network is called the response layer and the latter network is the drive layer. Specifically, synchronization between each node in the drive layer and its counterpart in the response layer (counterpart synchronization (CS)) in these kinds of duplex networks with delayed nodes and noise perturbation is investigated. Based on the LaSalle-type invariance principle, a control technique is proposed and a sufficient condition is developed for realizing CS of duplex networks. Furthermore, two corollaries are derived as special cases. In addition, node dynamics within each layer can be varied and topologies of the two layers are not necessarily identical. Therefore, the proposed synchronization method can be applied to a wide range of multiplex networks. Numerical examples are provided to illustrate the feasibility and effectiveness of the results. (paper)

  15. Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus.

    Science.gov (United States)

    Takehara, Kiyoto; Yano, Shuya; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Narii, Nobuhiro; Mizuguchi, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M

    2017-08-18

    Melanoma is a highly recalcitrant cancer and transformative therapy is necessary for the cure of this disease. We recently developed a telomerase-dependent adenovirus containing the fluorescent protein Killer-Red. In the present report, we first determined the efficacy of Killer-Red adenovirus combined with laser irradiation on human melanoma cell lines in vitro. Cell viability of human melanoma cells was reduced in a dose-dependent and irradiation-time-dependent manner. We used an intradermal xenografted melanoma model in nude mice to determine efficacy of the Killer-Red adenovirus. Intratumoral injection of Killer-Red adenovirus, combined with laser irradiation, eradicated the melanoma indicating the potential of a new paradigm of cancer therapy.

  16. A telomerase immortalized human proximal tubule cell line with a truncation mutation (Q4004X in polycystin-1.

    Directory of Open Access Journals (Sweden)

    Brittney-Shea Herbert

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is associated with a variety of cellular phenotypes in renal epithelial cells. Cystic epithelia are secretory as opposed to absorptive, have higher proliferation rates in cell culture and have some characteristics of epithelial to mesenchymal transitions. In this communication we describe a telomerase immortalized cell line that expresses proximal tubule markers and is derived from renal cysts of an ADPKD kidney. These cells have a single detectable truncating mutation (Q4004X in polycystin-1. These cells make normal appearing but shorter cilia and fail to assemble polycystin-1 in the cilia, and less uncleaved polycystin-1 in membrane fractions. This cell line has been maintained in continuous passage for over 35 passages without going into senescence. Nephron segment specific markers suggest a proximal tubule origin for these cells and the cell line will be useful to study mechanistic details of cyst formation in proximal tubule cells.

  17. Telomerase activity and telomere length in the colorectal polyp-carcinoma sequence Actividad de la telomerasa y longitud del telómero en la secuencia pólipo-carcinoma colorrectal

    OpenAIRE

    C. Valls Bautista; C. Piñol Felis; J. M. Reñe Espinet; J. Buenestado García; J. Viñas Salas

    2009-01-01

    Objective: the role of telomerase activity and telomere length in the adenoma-carcinoma sequence of colon carcinogenesis has not been well established. The objective of this study was to determine telomerase activity and telomere length patterns in patients with adenomatous polyps either associated or not with colorectal cancer, as well as the role of telomeric instability in the adenoma-carcinoma sequence. Patients and methods: we included in the study 14 patients who underwent surgery for c...

  18. Effects of Lifestyle Modification on Telomerase Gene Expression in Hypertensive Patients: A Pilot Trial of Stress Reduction and Health Education Programs in African Americans.

    Directory of Open Access Journals (Sweden)

    Shanthi Duraimani

    Full Text Available African Americans suffer from disproportionately high rates of hypertension and cardiovascular disease. Psychosocial stress, lifestyle and telomere dysfunction contribute to the pathogenesis of hypertension and cardiovascular disease. This study evaluated effects of stress reduction and lifestyle modification on blood pressure, telomerase gene expression and lifestyle factors in African Americans.Forty-eight African American men and women with stage I hypertension who participated in a larger randomized controlled trial volunteered for this substudy. These subjects participated in either stress reduction with the Transcendental Meditation technique and a basic health education course (SR or an extensive health education program (EHE for 16 weeks. Primary outcomes were telomerase gene expression (hTERT and hTR and clinic blood pressure. Secondary outcomes included lifestyle-related factors. Data were analyzed for within-group and between-group changes.Both groups showed increases in the two measures of telomerase gene expression, hTR mRNA levels (SR: p< 0.001; EHE: p< 0.001 and hTERT mRNA levels (SR: p = 0.055; EHE: p< 0.002. However, no statistically significant between-group changes were observed. Both groups showed reductions in systolic BP. Adjusted changes were SR = -5.7 mm Hg, p< 0.01; EHE = -9.0 mm Hg, p < 0.001 with no statistically significant difference between group difference. There was a significant reduction in diastolic BP in the EHE group (-5.3 mm Hg, p< 0.001 but not in SR (-1.2 mm Hg, p = 0.42; the between-group difference was significant (p = 0.04. The EHE group showed a greater number of changes in lifestyle behaviors.In this pilot trial, both stress reduction (Transcendental Meditation technique plus health education and extensive health education groups demonstrated increased telomerase gene expression and reduced BP. The association between increased telomerase gene expression and reduced BP observed in this high

  19. Selective suppression of autocatalytic caspase-3 driven by two-step transcriptional amplified human telomerase reverse transcriptase promoter on ovarian carcinoma growth in vitro and in mice.

    Science.gov (United States)

    Song, Yue; Xin, Xing; Xia, Zhijun; Zhai, Xingyue; Shen, Keng

    2014-07-01

    The objective of our study was to construct recombinant adenovirus (rAd) AdHTVP2G5-rev-casp3, which expresses autocatalytic caspase-3 driven by human telomerase reverse transcriptase promoter (hTERTp) with a two-step transcription amplification (TSTA) system and investigate its antitumor effects on ovarian cancer in vitro and in vivo. Fluorescent detection was used to detect EGFP expression in various cells. Cell viabilities were determined using the Cell Counting Kit-8 and flow cytometry. RT-PCR and immunoblotting assays were used to detect cellular apoptotic activities. Tumor growth and survival of tumor-bearing mice were studied. The hTERTp-TSTA system showed the strongest activity in hTERT-positive cancer cells when compared with hTERTp and cytomeglovirus promoter (CMVp). In contrast, it showed no activity in hTERT‑negative HUVECs. AdHTVP2G5‑rev-casp3 markedly suppressed the survival of AO cells in a dose-dependent modality with a viability rate of 17.8 ± 3.5% at an MOI of 70, which was significantly lower than that by AdHT-rev-casp3 and Ad-rev-casp3 (rAds which express rev-caspase-3 driven by hTERTp and CMVp, respectively). In contrast, AdHTVP2G5‑rev-casp3 induced little HUVEC death with a viability rate of 92.7 ± 5.2% at the same MOI. Additionally, AdHTVP2G5-rev-casp3 (MOI=70) caused significant apoptosis in AO cells with an apoptotic rate of 42%. The tumor growth suppression rate of AdHTVP2G5-rev-casp3 was 81.52%, significantly higher than that of AdHT-rev-casp3 (54.94%) or Ad-rev-casp3 (21.35%). AdHTVP2G5-rev-casp3 significantly improved the survival of tumor-bearing mice with little liver damage, with a mean survival of 258 ± 28 days. These results showed that AdHTVP2G5-rev-casp3 caused effective apoptosis with significant tumor selectivity, strongly suppressed tumor growth and improved mouse survival with little liver toxicity. It can be a potent therapeutic agent for tumor targeted treatment of ovarian cancer.

  20. DISCOVERY OF A TRANSIENT GAMMA-RAY COUNTERPART TO FRB 131104

    International Nuclear Information System (INIS)

    DeLaunay, J. J.; Murase, K.; Mészáros, P.; Keivani, A.; Messick, C.; Mostafá, M. A.; Oikonomou, F.; Tešić, G.; Turley, C. F.; Fox, D. B.

    2016-01-01

    We report our discovery in Swift satellite data of a transient gamma-ray counterpart (3.2 σ confidence) to the fast radio burst (FRB) FRB 131104, the first such counterpart to any FRB. The transient has a duration T _9_0 ≳ 100 s and a fluence S_γ ≈ 4 × 10"−"6 erg cm"−"2, increasing the energy budget for this event by more than a billion times; at the nominal z ≈ 0.55 redshift implied by its dispersion measure, the burst’s gamma-ray energy output is E_γ ≈ 5 × 10"5"1 erg. The observed radio to gamma-ray fluence ratio for FRB 131104 is consistent with a lower limit we derive from Swift observations of another FRB, which is not detected in gamma-rays, and with an upper limit previously derived for the brightest gamma-ray flare from SGR 1806−20, which was not detected in the radio. X-ray, ultraviolet, and optical observations beginning two days after the FRB do not reveal any associated afterglow, supernova, or transient; Swift observations exclude association with the brightest 65% of Swift gamma-ray burst (GRB) X-ray afterglows, while leaving the possibility of an associated supernova at much more than 10% the FRB’s nominal distance, D ≳ 320 Mpc, largely unconstrained. Transient high-luminosity gamma-ray emission arises most naturally in a relativistic outflow or shock breakout, such as, for example, from magnetar flares, GRBs, relativistic supernovae, and some types of galactic nuclear activity. Our discovery thus bolsters the case for an extragalactic origin for some FRBs and suggests that future rapid-response observations might identify long-lived counterparts, resolving the nature of these mysterious phenomena and realizing their promise as probes of cosmology and fundamental physics.

  1. INTERSTELLAR SCINTILLATION AND THE RADIO COUNTERPART OF THE FAST RADIO BURST FRB 150418

    Energy Technology Data Exchange (ETDEWEB)

    Akiyama, Kazunori [Massachusetts Institute of Technology, Haystack Observatory, Route 40, Westford, MA 01886 (United States); Johnson, Michael D., E-mail: kazu@haystack.mit.edu [Harvard Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States)

    2016-06-10

    Keane et al. have recently reported the discovery of a new fast radio burst (FRB), FRB 150418, with a promising radio counterpart at 5.5 and 7.5 GHz—a rapidly decaying source, falling from 200–300 μ Jy to 100 μ Jy on timescales of ∼6 days. This transient source may be associated with an elliptical galaxy at redshift z = 0.492, providing the first firm spectroscopic redshift for an FRB and the ability to estimate the density of baryons in the intergalactic medium via the combination of known redshift and radio dispersion of the FRB. An alternative explanation, first suggested by Williams and Berger, is that the identified counterpart may instead be a compact active galactic nucleus (AGN). The putative counterpart’s variation may then instead be extrinsic, caused by refractive scintillation in the ionized interstellar medium of the Milky Way, which would invalidate the association with FRB 150418. We examine this latter explanation in detail and show that the reported observations are consistent with scintillating radio emission from the core of a radio-loud AGN having a brightness temperature T {sub b} ≳ 10{sup 9} K. Using numerical simulations of the expected scattering for the line of sight to FRB 150418, we provide example images and light curves of such an AGN at 5.5 and 7.5 GHz. These results can be compared with continued radio monitoring to conclusively determine the importance of scintillation for the observed radio variability, and they show that scintillation is a critical consideration for continued searches for FRB counterparts at radio wavelengths.

  2. DISCOVERY OF A TRANSIENT GAMMA-RAY COUNTERPART TO FRB 131104

    Energy Technology Data Exchange (ETDEWEB)

    DeLaunay, J. J.; Murase, K.; Mészáros, P.; Keivani, A.; Messick, C.; Mostafá, M. A.; Oikonomou, F.; Tešić, G.; Turley, C. F. [Department of Physics, Pennsylvania State University, University Park, PA 16802 (United States); Fox, D. B., E-mail: jjd330@psu.edu [Department of Astronomy and Astrophysics, Pennsylvania State University, University Park, PA 16802 (United States)

    2016-11-20

    We report our discovery in Swift satellite data of a transient gamma-ray counterpart (3.2 σ confidence) to the fast radio burst (FRB) FRB 131104, the first such counterpart to any FRB. The transient has a duration T {sub 90} ≳ 100 s and a fluence S{sub γ} ≈ 4 × 10{sup −6} erg cm{sup −2}, increasing the energy budget for this event by more than a billion times; at the nominal z ≈ 0.55 redshift implied by its dispersion measure, the burst’s gamma-ray energy output is E{sub γ} ≈ 5 × 10{sup 51} erg. The observed radio to gamma-ray fluence ratio for FRB 131104 is consistent with a lower limit we derive from Swift observations of another FRB, which is not detected in gamma-rays, and with an upper limit previously derived for the brightest gamma-ray flare from SGR 1806−20, which was not detected in the radio. X-ray, ultraviolet, and optical observations beginning two days after the FRB do not reveal any associated afterglow, supernova, or transient; Swift observations exclude association with the brightest 65% of Swift gamma-ray burst (GRB) X-ray afterglows, while leaving the possibility of an associated supernova at much more than 10% the FRB’s nominal distance, D ≳ 320 Mpc, largely unconstrained. Transient high-luminosity gamma-ray emission arises most naturally in a relativistic outflow or shock breakout, such as, for example, from magnetar flares, GRBs, relativistic supernovae, and some types of galactic nuclear activity. Our discovery thus bolsters the case for an extragalactic origin for some FRBs and suggests that future rapid-response observations might identify long-lived counterparts, resolving the nature of these mysterious phenomena and realizing their promise as probes of cosmology and fundamental physics.

  3. INTERSTELLAR SCINTILLATION AND THE RADIO COUNTERPART OF THE FAST RADIO BURST FRB 150418

    International Nuclear Information System (INIS)

    Akiyama, Kazunori; Johnson, Michael D.

    2016-01-01

    Keane et al. have recently reported the discovery of a new fast radio burst (FRB), FRB 150418, with a promising radio counterpart at 5.5 and 7.5 GHz—a rapidly decaying source, falling from 200–300 μ Jy to 100 μ Jy on timescales of ∼6 days. This transient source may be associated with an elliptical galaxy at redshift z = 0.492, providing the first firm spectroscopic redshift for an FRB and the ability to estimate the density of baryons in the intergalactic medium via the combination of known redshift and radio dispersion of the FRB. An alternative explanation, first suggested by Williams and Berger, is that the identified counterpart may instead be a compact active galactic nucleus (AGN). The putative counterpart’s variation may then instead be extrinsic, caused by refractive scintillation in the ionized interstellar medium of the Milky Way, which would invalidate the association with FRB 150418. We examine this latter explanation in detail and show that the reported observations are consistent with scintillating radio emission from the core of a radio-loud AGN having a brightness temperature T _b ≳ 10"9 K. Using numerical simulations of the expected scattering for the line of sight to FRB 150418, we provide example images and light curves of such an AGN at 5.5 and 7.5 GHz. These results can be compared with continued radio monitoring to conclusively determine the importance of scintillation for the observed radio variability, and they show that scintillation is a critical consideration for continued searches for FRB counterparts at radio wavelengths.

  4. Bright optical synchrotron counterpart of the western hot spot in Pictor A

    International Nuclear Information System (INIS)

    Roeser, H.J.; Meisenheimer, K.; Royal Observatory, Edinburgh, Scotland)

    1987-01-01

    A B = 19.5 mag bright, highly polarized object was detected close to the western hot spot in Pictor A during an optical polarization survey of radio hot spots in classical double radio sources. The unresolved source exhibits a featureless continuum between 400 and 800 nm and is identified as the optical counterpart of the radio hot spot. It is surrounded by optical filaments aligned roughly perpendicular to the source axis. The hot spot is also marginally detected in an Einstein IPC frame. 17 references

  5. The radio and optical counterpart of the new Fermi LAT flaring source J0109+6134

    Science.gov (United States)

    Paredes, J. M.; Martí, J.; Peracaula, M.

    2010-02-01

    Following the recent ATELs #2414, #2416 and #2420 concerning the Fermi-LAT, AGILE and Swift/XRT consistent detections of the new gamma-ray flaring source J0109+6134, we wish to remind that the proposed radio counterpart (VCS2 J0109+6133/GT 0106+613) was extensively observed nearly two decades ago by different authors in the context of the GT catalogue of Galactic Plane radio sources (Taylor and Gregory 1983, AJ, 88, 1784; Gregory and Taylor 1986, AJ 92, 371).

  6. Understanding possible electromagnetic counterparts to loud gravitational wave events: Binary black hole effects on electromagnetic fields

    International Nuclear Information System (INIS)

    Palenzuela, Carlos; Lehner, Luis; Yoshida, Shin

    2010-01-01

    In addition to producing loud gravitational waves, the dynamics of a binary black hole system could induce emission of electromagnetic radiation by affecting the behavior of plasmas and electromagnetic fields in their vicinity. We study how the electromagnetic fields are affected by a pair of orbiting black holes through the merger. In particular, we show how the binary's dynamics induce a variability in possible electromagnetically induced emissions as well as an enhancement of electromagnetic fields during the late-merge and merger epochs. These time dependent features will likely leave their imprint in processes generating detectable emissions and can be exploited in the detection of electromagnetic counterparts of gravitational waves.

  7. HST/ACS IMAGING OF OMEGA CENTAURI: OPTICAL COUNTERPARTS OF CHANDRA X-RAY SOURCES

    International Nuclear Information System (INIS)

    Cool, Adrienne M.; Arias, Tersi; Brochmann, Michelle; Dorfman, Jason; Gafford, April; White, Vivian; Haggard, Daryl; Anderson, Jay

    2013-01-01

    We present results of a search for optical counterparts of X-ray sources in and toward the globular cluster Omega Centauri (NGC 5139) using the Advanced Camera for Surveys (ACS) on the Hubble Space Telescope. The ACS data consist of a mosaic of Wide Field Channel images obtained using F625W, F435W, and F658N filters; with nine pointings we cover the central ∼10' × 10' of the cluster and encompass 109 known Chandra sources. We find promising optical counterparts for 59 of the sources, ∼40 of which are likely to be associated with the cluster. These include 27 candidate cataclysmic variables (CVs), 24 of which are reported here for the first time. Fourteen of the CV candidates are very faint, with absolute magnitudes in the range M 625 =10.4-12.6, making them comparable in brightness to field CVs near the period minimum discovered in the Sloan Digital Sky Survey. Additional optical counterparts include three BY Dra candidates, a possible blue straggler, and a previously reported quiescent low-mass X-ray binary. We also identify 3 foreground stars and 11 probable active galactic nuclei. Finally, we report the discovery of a group of seven stars whose X-ray properties are suggestive of magnetically active binaries, and whose optical counterparts lie on or very near the metal-rich anomalous giant and subgiant branches in ω Cen. If the apparent association between these seven stars and the RGB/SGB-a stars is real, then the frequency of X-ray sources in this metal-rich population is enhanced by a factor of at least five relative to the other giant and subgiant populations in the cluster. If these stars are not members of the metal-rich population, then they bring the total number of red stragglers (also known as sub-subgiants) that have been identified in ω to Cen 20, the largest number yet known in any globular cluster.

  8. PSB-VVER counterpart experiment simulating a small cold leg break LOCA

    International Nuclear Information System (INIS)

    Blinkov, V.N.; Melikhov, O.I.; Kapustin, A.V.; Lipatov, I.A.; Dremin, G.I.; Nikonov, S.M.; Rovnov, A.A.; Elkin, I.V.; Pylev, S.S.

    2005-01-01

    Full text of publication follows: An experiment simulating a small break LOCA has been performed in PSB-VVER facility, under PSB-VVER OECD Project. The test is intended to be a counterpart one to an experiment performed in the LOBI integral test facility. The objectives of the PSB-VVER small cold leg break test are: to study VVER-1000 thermal hydraulic response following a small break in the cold leg, to provide data for code assessment regarding phenomena indicated in the VVER-1000 code validation matrix and to study the scaling effect. The scenario for the PSB-VVER experiment has been designed taking the LOBI BL-34 test as reference. The ratio of primary system volumes (without volume of the pressurizer and the surge line) has been chosen to scale the reference experiment conditions and to generate the conditions of PSB-VVER cold leg break experiment. The resulting conditions are compared with the LOBI cold leg break test conditions by means of different counterpart test criteria. Comparing the two experiments in terms of the criteria shows that basic requirements to the counterpart test are fulfilled. A pretest analysis with RELAP5/MOD3.2 code has shown that the PSBVVER small break experiment is expected to show the same relevant phenomena and main events as the LOBI BL-34 test. The predicted PSB-VVER primary pressure is very close to that measured in the LOBI facility. The measured pressure in the PSB-VVER primary system has turned out to be very close to that registered in LOBI BL-34 test. This verifies the approach used for developing the conditions of the PSB-VVER counterpart test. The experiment results and the RELAP5/MOD3.2 pretest calculation are in good agreement. A posttest calculation of the experiment with RELAP5/MOD3.2 code has been performed in order to assess the codes capability to simulate the phenomena relevant to the test. The code has shown a reasonable prediction of the phenomena measured in the experiment. (authors)

  9. PSB-VVER counterpart experiment simulating a small cold leg break LOCA

    Energy Technology Data Exchange (ETDEWEB)

    Blinkov, V.N.; Melikhov, O.I.; Kapustin, A.V.; Lipatov, I.A.; Dremin, G.I.; Nikonov, S.M.; Rovnov, A.A. [Elektrogorsk Research and Engineering Center, EREC, Bezymiannaja Street, 6, Elektrogorsk, Moscow Region, 142530 (Russian Federation); Elkin, I.V.; Pylev, S.S. [NSI RRC ' Kurchatov Institute' , Kurchatov Sq., 1, Moscow, 123182 (Russian Federation)

    2005-07-01

    Full text of publication follows: An experiment simulating a small break LOCA has been performed in PSB-VVER facility, under PSB-VVER OECD Project. The test is intended to be a counterpart one to an experiment performed in the LOBI integral test facility. The objectives of the PSB-VVER small cold leg break test are: to study VVER-1000 thermal hydraulic response following a small break in the cold leg, to provide data for code assessment regarding phenomena indicated in the VVER-1000 code validation matrix and to study the scaling effect. The scenario for the PSB-VVER experiment has been designed taking the LOBI BL-34 test as reference. The ratio of primary system volumes (without volume of the pressurizer and the surge line) has been chosen to scale the reference experiment conditions and to generate the conditions of PSB-VVER cold leg break experiment. The resulting conditions are compared with the LOBI cold leg break test conditions by means of different counterpart test criteria. Comparing the two experiments in terms of the criteria shows that basic requirements to the counterpart test are fulfilled. A pretest analysis with RELAP5/MOD3.2 code has shown that the PSBVVER small break experiment is expected to show the same relevant phenomena and main events as the LOBI BL-34 test. The predicted PSB-VVER primary pressure is very close to that measured in the LOBI facility. The measured pressure in the PSB-VVER primary system has turned out to be very close to that registered in LOBI BL-34 test. This verifies the approach used for developing the conditions of the PSB-VVER counterpart test. The experiment results and the RELAP5/MOD3.2 pretest calculation are in good agreement. A posttest calculation of the experiment with RELAP5/MOD3.2 code has been performed in order to assess the codes capability to simulate the phenomena relevant to the test. The code has shown a reasonable prediction of the phenomena measured in the experiment. (authors)

  10. Optical and radio counterpart of Circinus X-1 (3U 1516-56)

    Energy Technology Data Exchange (ETDEWEB)

    Whelan, J A.J.; Murdin, P G; Peterson, B A [Anglo-Australian Observatory, Epping (Australia); and others

    1977-11-01

    Circinus X-1 (3U 1516-56) has a radio counterpart which, at high frequencies, show flares with the same 16.6 day periodicity as the X-ray intensity. In each cycle the radio flare occurs shortly after the intensity drop-off which defines the X-ray modulation. The radio source is positionally coincident with a faint red star having very strong H..cap alpha.. and weak He I emission lines which are probably variable. The object may be an early-type emission-line star or a symbiotic star, at a distance of 10 kpc.

  11. A randomized controlled trial of qigong exercise on fatigue symptoms, functioning, and telomerase activity in persons with chronic fatigue or chronic fatigue syndrome.

    Science.gov (United States)

    Ho, Rainbow T H; Chan, Jessie S M; Wang, Chong-Wen; Lau, Benson W M; So, Kwok Fai; Yuen, Li Ping; Sham, Jonathan S T; Chan, Cecilia L W

    2012-10-01

    Chronic fatigue is common in the general population. Complementary therapies are often used by patients with chronic fatigue or chronic fatigue syndrome to manage their symptoms. This study aimed to assess the effect of a 4-month qigong intervention program among patients with chronic fatigue or chronic fatigue syndrome. Sixty-four participants were randomly assigned to either an intervention group or a wait list control group. Outcome measures included fatigue symptoms, physical functioning, mental functioning, and telomerase activity. Fatigue symptoms and mental functioning were significantly improved in the qigong group compared to controls. Telomerase activity increased in the qigong group from 0.102 to 0.178 arbitrary units (p chronic fatigue and chronic fatigue syndrome.

  12. Telomerase activity, telomere length and hTERT DNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits.

    Science.gov (United States)

    Marcon, Francesca; Siniscalchi, Ester; Andreoli, Cristina; Allione, Alessandra; Fiorito, Giovanni; Medda, Emanuela; Guarrera, Simonetta; Matullo, Giuseppe; Crebelli, Riccardo

    2017-10-01

    Increased telomerase expression has been implicated in the pathogenesis of lung cancer and, since the primary cause of lung cancer is smoking, an association between telomerase reactivation and tobacco smoke has been proposed. In this work an investigation has been performed to assess the relationship between tobacco smoke exposure and telomerase activity (TA) in peripheral blood mononuclear cells of healthy smokers. The methylation status of the catalytic subunit of telomerase hTERT was concurrently investigated to assess the possible association between epigenetic modifications of hTERT and TA. Besides, the association between smoke and telomere length (TL) has been evaluated. Healthy monozygotic twins with discordant smoking habits were selected as study population to minimize inter-individual differences because of demographic characteristics and genetic heterogeneity. Statistically significant higher values of TA and TL were observed in smokers compared to nonsmoker co-twins. The multivariate analysis of data showed, besides smoking habits (P = 0.02), an influence of gender (P = 0.006) and BMI (P = 0.001) on TA and a borderline effect of gender (P = 0.05) on TL. DNA methylation analysis, focused on 100 CpG sites mapping in hTERT, highlighted nine CpG sites differentially methylated in smokers. When co-twins were contrasted, selecting as variables the intra-twin difference in TA and hTERT DNA methylation, a statistically significant inverse correlation (P = 0.003) was observed between TA and DNA methylation at the cg05521538 site. In conclusion, these results indicate an association of tobacco smoke with TA and TL and suggest a possible association between smoke-induced epigenetic effects and TA in healthy smokers. Environ. Mol. Mutagen. 58:551-559, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Insights into the evolution of mammalian telomerase: Platypus TERT shares similarities with genes of birds and other reptiles and localizes on sex chromosomes

    Directory of Open Access Journals (Sweden)

    Hrdličková Radmila

    2012-06-01

    Full Text Available Abstract Background The TERT gene encodes the catalytic subunit of the telomerase complex and is responsible for maintaining telomere length. Vertebrate telomerase has been studied in eutherian mammals, fish, and the chicken, but less attention has been paid to other vertebrates. The platypus occupies an important evolutionary position, providing unique insight into the evolution of mammalian genes. We report the cloning of a platypus TERT (OanTERT ortholog, and provide a comparison with genes of other vertebrates. Results The OanTERT encodes a protein with a high sequence similarity to marsupial TERT and avian TERT. Like the TERT of sauropsids and marsupials, as well as that of sharks and echinoderms, OanTERT contains extended variable linkers in the N-terminal region suggesting that they were present already in basal vertebrates and lost independently in ray-finned fish and eutherian mammals. Several alternatively spliced OanTERT variants structurally similar to avian TERT variants were identified. Telomerase activity is expressed in all platypus tissues like that of cold-blooded animals and murine rodents. OanTERT was localized on pseudoautosomal regions of sex chromosomes X3/Y2, expanding the homology between human chromosome 5 and platypus sex chromosomes. Synteny analysis suggests that TERT co-localized with sex-linked genes in the last common mammalian ancestor. Interestingly, female platypuses express higher levels of telomerase in heart and liver tissues than do males. Conclusions OanTERT shares many features with TERT of the reptilian outgroup, suggesting that OanTERT represents the ancestral mammalian TERT. Features specific to TERT of eutherian mammals have, therefore, evolved more recently after the divergence of monotremes.

  14. Reactive oxygen species-dependent HSP90 protein cleavage participates in arsenical As+3- and MMA+3-induced apoptosis through inhibition of telomerase activity via JNK activation

    International Nuclear Information System (INIS)

    Shen, S.-C.; Yang, L.-Y.; Lin, H.-Y.; Wu, C.-Y.; Su, T.-H.; Chen, Y.-C.

    2008-01-01

    The effects of six arsenic compounds including As +3 , MMA +3 , DMA +3 , As +5 , MMA +5 , and DMA +5 on the viability of NIH3T3 cells were examined. As +3 and MMA +3 , but not the others, exhibited significant cytotoxic effects in NIH3T3 cells through apoptosis induction. The apoptotic events such as DNA fragmentation and chromosome condensation induced by As +3 and MMA +3 were prevented by the addition of NAC and CAT, and induction of HO-1 gene expression in accordance with cleavage of the HSP90 protein, and suppression of telomerase activity were observed in NIH3T3 cells under As +3 and MMA +3 treatments. An increase in the intracellular peroxide level was examined in As +3 - and MMA +3 -treated NIH3T3 cells, and As +3 - and MMA +3 -induced apoptotic events were blocked by NAC, CAT, and DPI addition. HSP90 inhibitors, GA and RD, significantly attenuated the telomerase activity in NIH3T3 cells with an enhancement of As +3 - and MMA +3 -induced cytotoxicity. Suppression of JNKs significantly inhibited As +3 - and MMA +3 -induced apoptosis by blocking HSP90 protein cleavage and telomerase reduction in NIH3T3 cells. Furthermore, Hb, SnPP, and dexferosamine showed no effect against As +3 - and MMA +3 -induced apoptosis, and overexpression of HO-1 protein or inhibition of HO-1 protein expression did not affect the apoptosis induced by As +3 or MMA +3 . These data provide the first evidence to indicate that apoptosis induced by As +3 and MMA +3 is mediated by an ROS-dependent degradation of HSP90 protein and reduction of telomerase via JNK activation, and HO-1 induction might not be involved

  15. Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation†

    Science.gov (United States)

    Selvam, Shanmugam P.; De Palma, Ryan M.; Oaks, Joshua J.; Oleinik, Natalia; Peterson, Yuri K.; Stahelin, Robert V.; Skordalakes, Emmanuel; Ponnusamy, Suriyan; Garrett-Mayer, Elizabeth; Smith, Charles D.; Ogretmen, Besim

    2015-01-01

    During DNA replication, the enzyme telomerase maintains the ends of chromosomes, called telomeres. Shortened telomeres trigger cell senescence, and cancer cells often have increased telomerase activity to promote their ability to proliferate indefinitely. The catalytic subunit, human telomerase reverse transcriptase (hTERT), is stabilized by phosphorylation. Here, we found that the lysophospholipid sphingosine 1-phosphate (S1P), generated by sphingosine kinase 2 (SK2), bound hTERT at the nuclear periphery in human and mouse fibroblasts. Docking predictions and mutational analyses revealed that binding occurred between a hydroxyl group (C′3-OH) in S1P and Asp684 in hTERT. Inhibiting or depleting SK2 or mutating the S1P binding site decreased the stability of hTERT in cultured cells and promoted senescence and loss of telomere integrity. S1P binding inhibited the interaction of hTERT with MKRN1, an E3 ubiquitin ligase that tags hTERT for degradation. Murine Lewis lung carcinoma (LLC) cells formed smaller tumors in mice lacking SK2 than in wild-type mice, and knocking down SK2 in LLC cells before implantation into mice suppressed their growth. Pharmacologically inhibiting SK2 decreased the growth of subcutaneous A549 lung cancer cell-derived xenografts in mice, and expression of wild-type hTERT, but not an S1P-binding mutant, restored tumor growth. Thus, our data suggest that S1P binding to hTERT allosterically mimicks phosphorylation, promoting telomerase stability and hence telomere maintenance, cell proliferation, and tumor growth PMID:26082434

  16. A gene expression signature classifying telomerase and ALT immortalization reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT

    DEFF Research Database (Denmark)

    Lafferty-Whyte, K; Cairney, C J; Will, M B

    2009-01-01

    Telomere length is maintained by two known mechanisms, the activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular le......TERT in different tumour types and normal tissues. We also show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalization in cell lines and mesenchymal tissues....

  17. Amarogentin Induces Apoptosis of Liver Cancer Cells via Upregulation of p53 and Downregulation of Human Telomerase Reverse Transcriptase in Mice

    Science.gov (United States)

    Li, Runqin; Zhang, Yinglin

    2016-01-01

    Background and Objective: Amarogentin has been reported to have a preventive effect on liver cancer via inducing cancer cell apoptosis. We attempted to elucidate the roles of p53-associated apoptosis pathways in the chemopreventive mechanism of amarogentin. The findings of this study will facilitate the development of a novel supplementary strategy for the treatment of liver cancer. Materials and Methods: The purity of amarogentin was assessed by high-performance liquid chromatography. The inhibitory ratios of the liver cell lines were determined using a Cell Counting Kit-8 following treatment with a gradient concentration of amarogentin. Cell apoptosis was detected by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide kits. The gene and protein expression of p53-associated molecules, such as Akt, human telomerase reverse transcriptase, RelA, and p38, was detected by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical staining in liver cancer cells and mouse tumor tissues after treatment with amarogentin. Results: The inhibitory effect of amarogentin on cell proliferation was more obvious in liver cancer cells, and amarogentin was more likely to induce the apoptosis of liver cancer cells than that of normal liver cells. The gene and protein expression levels of Akt, RelA, and human telomerase reverse transcriptase were markedly higher in the control group than in the preventive group and treatment groups. Only the expression of human telomerase reverse transcriptase was downregulated, accompanied by the upregulation of p53. Conclusion: The results of our study suggest that amarogentin promotes apoptosis of liver cancer cells by the upregulation of p53 and downregulation of human telomerase reverse transcriptase and prevents the malignant transformation of these cells. PMID:27402632

  18. Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis.

    Science.gov (United States)

    Walsh, Kyle M; Rice, Terri; Decker, Paul A; Kosel, Matthew L; Kollmeyer, Thomas; Hansen, Helen M; Zheng, Shichun; McCoy, Lucie S; Bracci, Paige M; Anderson, Erik; Hsuang, George; Wiemels, Joe L; Pico, Alexander R; Smirnov, Ivan; Molinaro, Annette M; Tihan, Tarik; Berger, Mitchell S; Chang, Susan M; Prados, Michael D; Lachance, Daniel H; Sicotte, Hugues; Eckel-Passow, Jeanette E; Wiencke, John K; Jenkins, Robert B; Wrensch, Margaret R

    2013-08-01

    Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma. SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate. Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10(-22) and P = 9.5 × 10(-7), respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10(-4) and P = 2.5 × 10(-4), respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups. Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).

  19. A novel peptide-nucleotide dual vaccine of human telomerase reverse transcriptase induces a potent cytotoxic T-cell response in vivo

    International Nuclear Information System (INIS)

    Guo, Hong; Hao, Jia; Wu, Chao; Shi, Yun; Zhao, Xiao-yan; Fang, Dian-chun

    2007-01-01

    Human telomerase reverse transcriptase (hTERT) is highly expressed in over 85% of human cancers, which makes it a broadly applicable molecular target for cancer therapy. Several groups have demonstrated that hTERT can efficiently evoke specific cytotoxic T lymphocytes (CTL) responses for malignant tumors. In the present study, we developed a novel virus-like particulate peptide-nucleotide dual vaccine (PNDV) of hTERT, which was composed of a low-affinity epitope variant with encoding full-length gene in the same virus-size particulate. We verified the formation of PNDV by DNA retarding assay, DNase I protection assay and transmission electron microscopy, and confirmed its immunogenicity and transfection activities in mammalian cells. Furthermore, in vivo immunization of HLA-A2.1 transgenic mice generated efficient IFN-γ secretion and hTERT-specific CTLs which are known to cause selective cell death of telomerase positive gastrointestinal cancer cells. To our knowledge, this represents the first report on collocating a low-affinity epitope variant with a full-length hTERT gene for anti-cancer vaccine design. This novel strategy for vaccine design not only enables enhanced immunity to a universal tumor antigen, but also has the potential to generate CTLs effective in telomerase-positive tumor cells of diverse tissue origins. Therefore, our findings bear significant implications for immunotherapy of human cancers

  20. A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity.

    Science.gov (United States)

    Lavretsky, H; Epel, E S; Siddarth, P; Nazarian, N; Cyr, N St; Khalsa, D S; Lin, J; Blackburn, E; Irwin, M R

    2013-01-01

    This study examined the effects of brief daily yogic meditation on mental health, cognitive functioning, and immune cell telomerase activity in family dementia caregivers with mild depressive symptoms. Thirty-nine family dementia caregivers (mean age 60.3 years old (SD = 10.2)) were randomized to practicing Kirtan Kriya or listening to relaxation music for 12 min per day for 8 weeks. The severity of depressive symptoms, mental and cognitive functioning were assessed at baseline and follow-up. Telomerase activity in peripheral blood mononuclear cells (PMBC) was examined in peripheral PBMC pre-intervention and post-intervention. The meditation group showed significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning compared with the relaxation group. In the meditation group, 65.2% showed 50% improvement on the Hamilton Depression Rating scale and 52% of the participants showed 50% improvement on the Mental Health Composite Summary score of the Short Form-36 scale compared with 31.2% and 19%, respectively, in the relaxation group (p dementia caregivers can lead to improved mental and cognitive functioning and lower levels of depressive symptoms. This improvement is accompanied by an increase in telomerase activity suggesting improvement in stress-induced cellular aging. These results need to be confirmed in a larger sample. Copyright © 2012 John Wiley & Sons, Ltd.

  1. Antiproliferative Effect of the Isoquinoline Alkaloid Papaverine in Hepatocarcinoma HepG-2 Cells — Inhibition of Telomerase and Induction of Senescence

    Directory of Open Access Journals (Sweden)

    Sakineh Kazemi Noureini

    2014-08-01

    Full Text Available Cancer cells are often immortal through up-regulation of the hTERT gene, which encodes the catalytic subunit of a special reverse transcriptase to overcome end-replication problem of chromosomes. This study demonstrates that papaverine, an isoquinoline alkaloid from the Papaveraceae, can overcome telomerase dependent immortality of HepG-2 cells that was used as a model of hepatocarcinoma. Although this alkaloid does not directly interact with telomeric sequences, papaverine inhibits telomerase through down-regulation of hTERT, which was analysed using thermal FRET and qRT-PCR, respectively. The IC50 values for the reduction of both telomerase activity and hTERT expression was 60 µM, while IC50 for cytotoxicity was 120 µM. Repeated treatments of the cells with very low non-toxic concentrations of papaverine resulted in growth arrest and strong reduction of population doublings after 40 days. This treatment induced senescent morphology in HepG-2 cells, which was evaluated by beta-galactosidase staining. Altogether, papaverine can be regarded as a promising model compound for drug design targeting cancer development.

  2. THE IDENTIFICATION OF THE X-RAY COUNTERPART TO PSR J2021+4026

    Energy Technology Data Exchange (ETDEWEB)

    Weisskopf, Martin C.; Elsner, Ronald F.; O' Dell, Stephen L.; Tennant, Allyn F. [NASA Marshall Space Flight Center, Space Science Office, VP62, Huntsville, AL 35812 (United States); Romani, Roger W. [Department of Physics, Stanford University, Stanford, CA 94305 (United States); Razzano, Massimiliano [Istituto Nazionale di Fisica Nucleare, Sezione di Pisa, I-56127 Pisa (Italy); Belfiore, Andrea; Saz Parkinson, Pablo; Ziegler, Marcus; Dormody, Michael [Santa Cruz Institute for Particle Physics, Department of Physics, University of California at Santa Cruz, Santa Cruz, CA 95064 (United States); Ray, Paul S. [Space Science Division, Naval Research Laboratory, Washington, DC 20375 (United States); Kerr, Matthew [Kavli Institute for Particle Astrophysics and Cosmology, Stanford University, 452 Lomita Mall, Stanford, CA 94305 (United States); Harding, Alice [Astrophysics Science Division, NASA Goddard Space Flight Center, Code 663, Greenbelt, MD 20771 (United States); Swartz, Douglas A. [Universities Space Research Association, NASA Marshall Space Flight Center, Space Science Office, VP62, Huntsville, AL 35812 (United States); Carraminana, Alberto [Instituto Nacional de Astrofisica, Optica y Electronica, Luis Enrique Erro 1, Tonantzintla, Puebla 72840 (Mexico); Becker, Werner; Kanbach, Gottfried [Max-Planck-Institut fuer extraterrestrische Physik, 85741 Garching bei Muenchen (Germany); De Luca, Andrea [INAF-Istituto di Astrofisica Spaziale e Fisica Cosmica, I-20133 Milano (Italy); Thompson, David J. [Astroparticle Physics Laboratory, NASA Goddard Space Flight Center, Code 661, Greenbelt, MD 20771 (United States)

    2011-12-10

    We report the probable identification of the X-ray counterpart to the {gamma}-ray pulsar PSR J2021+4026 using imaging with the Chandra X-ray Observatory Advanced CCD Imaging Spectrometer and timing analysis with the Fermi satellite. Given the statistical and systematic errors, the positions determined by both satellites are coincident. The X-ray source position is R.A. 20{sup h}21{sup m}30.{sup s}733, decl. +40 Degree-Sign 26'46.''04 (J2000) with an estimated uncertainty of 1.''3 combined statistical and systematic error. Moreover, both the X-ray to {gamma}-ray and the X-ray to optical flux ratios are sensible assuming a neutron star origin for the X-ray flux. The X-ray source has no cataloged infrared-to-visible counterpart and, through new observations, we set upper limits to its optical emission of i' > 23.0 mag and r' > 25.2 mag. The source exhibits an X-ray spectrum with most likely both a power law and a thermal component. We also report on the X-ray and visible light properties of the 43 other sources detected in our Chandra observation.

  3. GRB 170817A as a jet counterpart to gravitational wave trigger GW 170817

    Science.gov (United States)

    Lamb, Gavin P.; Kobayashi, Shiho

    2018-05-01

    Fermi/GBM (Gamma-ray Burst Monitor) and INTEGRAL (the International Gamma-ray Astrophysics Laboratory) reported the detection of the γ-ray counterpart, GRB 170817A, to the LIGO (Light Interferometer Gravitational-wave Observatory)/Virgo gravitational wave detected binary neutron star merger, GW 170817. GRB 170817A is likely to have an internal jet or another origin such as cocoon emission, shock-breakout, or a flare from a viscous disc. In this paper we assume that the γ-ray emission is caused by energy dissipation within a relativistic jet and we model the afterglow synchrotron emission from a reverse- and forward-shock in the outflow. We show the afterglow for a low-luminosity γ-ray burst (GRB) jet with a high Lorentz-factor (Γ); a low-Γ and low-kinetic energy jet; a low-Γ, high kinetic energy jet; structured jets viewed at an inclination within the jet-half-opening angle; and an off-axis `typical' GRB jet. All jet models will produce observable afterglows on various timescales. The late-time afterglow from 10-110 days can be fit by a Gaussian structured jet viewed at a moderate inclination, however the GRB is not directly reproduced by this model. These jet afterglow models can be used for future GW detected NS merger counterparts with a jet afterglow origin.

  4. Tribological Response of Heat Treated AISI 52100 Steels Against Steel and Ceramic Counterparts

    Directory of Open Access Journals (Sweden)

    Türedi E.

    2017-09-01

    Full Text Available AISI 52100 bearing steels are commonly used in applications requiring high hardness and abrasion resistance. The bearing steels are working under dynamic loads in service conditions and their toughness properties become important. In order to provide the desired mechanical properties, various heat treatments (austenizing, quenching and tempering are usually applied. In this study, AISI 52100 bearing steel samples were austenized at 900°C for ½ h and water quenched to room temperature. Then tempering was carried out at 795°C, 400°C and 200°C for ½ h. In order to investigate the effect of heat treatment conditions on wear behavior, dry friction tests were performed according to ASTM G99-05 Standard with a ‘ball-on-disk’ type tribometer. The samples were tested against steel and ceramic counterparts using the parameters of 100 m distance and 30 N load and 0.063 m/s rotational speed. After wear test, the surface characterization was carried out using microscopy. Wear loss values were calculated using a novel optical method on both flat and counterpart specimens.

  5. THE IDENTIFICATION OF THE X-RAY COUNTERPART TO PSR J2021+4026

    International Nuclear Information System (INIS)

    Weisskopf, Martin C.; Elsner, Ronald F.; O'Dell, Stephen L.; Tennant, Allyn F.; Romani, Roger W.; Razzano, Massimiliano; Belfiore, Andrea; Saz Parkinson, Pablo; Ziegler, Marcus; Dormody, Michael; Ray, Paul S.; Kerr, Matthew; Harding, Alice; Swartz, Douglas A.; Carramiñana, Alberto; Becker, Werner; Kanbach, Gottfried; De Luca, Andrea; Thompson, David J.

    2011-01-01

    We report the probable identification of the X-ray counterpart to the γ-ray pulsar PSR J2021+4026 using imaging with the Chandra X-ray Observatory Advanced CCD Imaging Spectrometer and timing analysis with the Fermi satellite. Given the statistical and systematic errors, the positions determined by both satellites are coincident. The X-ray source position is R.A. 20 h 21 m 30. s 733, decl. +40°26'46.''04 (J2000) with an estimated uncertainty of 1.''3 combined statistical and systematic error. Moreover, both the X-ray to γ-ray and the X-ray to optical flux ratios are sensible assuming a neutron star origin for the X-ray flux. The X-ray source has no cataloged infrared-to-visible counterpart and, through new observations, we set upper limits to its optical emission of i' > 23.0 mag and r' > 25.2 mag. The source exhibits an X-ray spectrum with most likely both a power law and a thermal component. We also report on the X-ray and visible light properties of the 43 other sources detected in our Chandra observation.

  6. Motor skills in Czech children with attention-deficit/hyperactivity disorder and their neurotypical counterparts.

    Science.gov (United States)

    Scharoun, S M; Bryden, P J; Otipkova, Z; Musalek, M; Lejcarova, A

    2013-11-01

    Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioural disorder. Characterized by recurring problems with impulsiveness and inattention in combination with hyperactivity, motor impairments have also been well documented in the literature. The aim of this study was to compare the fine and gross motor skills of male and female children with ADHD and their neurotypical counterparts within seven skill assessments. This included three fine motor tasks: (1) spiral tracing, (2) dot filling, (3) tweezers and beads; and four gross motor tasks: (1) twistbox, (2) foot tapping, (3) small plate finger tapping, and (4) large plate finger tapping. It was hypothesized that children with ADHD would display poorer motor skills in comparison to neurotypical controls in both fine and gross motor assessments. However, statistically significant differences between the groups only emerged in four of the seven tasks (spiral tracing, dot filling, tweezers and beads and foot tapping). In line with previous findings, the complexity underlying upper limb tasks solidified the divide in performance between children with ADHD and their neurotypical counterparts. In light of similar research, impairments in lower limb motor skill were also observed. Future research is required to further delineate trends in motor difficulties in ADHD, while further investigating the underlying mechanisms of impairment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Probing extra dimension through gravitational wave observations of compact binaries and their electromagnetic counterparts

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Hao; Gu, Bao-Min; Wang, Yong-Qiang; Liu, Yu-Xiao [Institute of Theoretical Physics, Lanzhou University, Lanzhou 730000 (China); Huang, Fa Peng [Theoretical Physics Division, Institute of High Energy Physics, Chinese Academy of Sciences, P.O. Box 918-4, Beijing 100049 (China); Meng, Xin-He, E-mail: yuh13@lzu.edu.cn, E-mail: gubm15@lzu.edu.cn, E-mail: huangfp@ihep.ac.cn, E-mail: yqwang@lzu.edu.cn, E-mail: xhm@nankai.edu.cn, E-mail: liuyx@lzu.edu.cn [School of Physics, Nankai University, Tianjin 300071 (China)

    2017-02-01

    The future gravitational wave (GW) observations of compact binaries and their possible electromagnetic counterparts may be used to probe the nature of the extra dimension. It is widely accepted that gravitons and photons are the only two completely confirmed objects that can travel along null geodesics in our four-dimensional space-time. However, if there exist extra dimensions and only GWs can propagate freely in the bulk, the causal propagations of GWs and electromagnetic waves (EMWs) are in general different. In this paper, we study null geodesics of GWs and EMWs in a five-dimensional anti-de Sitter space-time in the presence of the curvature of the universe. We show that for general cases the horizon radius of GW is longer than EMW within equal time. Taking the GW150914 event detected by the Advanced Laser Interferometer Gravitational-Wave Observatory and the X-ray event detected by the Fermi Gamma-ray Burst Monitor as an example, we study how the curvature k and the constant curvature radius l affect the horizon radii of GW and EMW in the de Sitter and Einstein-de Sitter models of the universe. This provides an alternative method for probing extra dimension through future GW observations of compact binaries and their electromagnetic counterparts.

  8. A CANDIDATE OPTICAL COUNTERPART TO THE MIDDLE AGED γ -RAY PULSAR PSR J1741–2054

    Energy Technology Data Exchange (ETDEWEB)

    Mignani, R. P.; Marelli, M.; Luca, A. De; Salvetti, D.; Belfiore, A. [INAF—Istituto di Astrofisica Spaziale e Fisica Cosmica Milano, via E. Bassini 15, I-20133, Milano (Italy); Testa, V. [INAF—Osservatorio Astronomico di Roma, via Frascati 33, I-00040, Monteporzio (Italy); Pierbattista, M. [Department of Astrophysics and Theory of Gravity, Maria Curie-Sklodowska University, ul. Radziszewskiego 10, 20-031 Lublin (Poland); Razzano, M. [Istituto Nazionale di Fisica Nucleare, Sezione di Pisa, I-56127 Pisa (Italy); Shearer, A.; Moran, P. [Centre for Astronomy, National University of Ireland, Newcastle Road, Galway (Ireland)

    2016-07-10

    We carried out deep optical observations of the middle aged γ -ray pulsar PSR J1741−2054 with the Very Large Telescope (VLT). We identified two objects, of magnitudes m {sub v} = 23.10 ± 0.05 and m {sub v} = 25.32 ± 0.08, at positions consistent with the very accurate Chandra coordinates of the pulsar, the faintest of which is more likely to be its counterpart. From the VLT images we also detected the known bow-shock nebula around PSR J1741−2054. The nebula is displaced by ∼0.″9 (at the 3 σ confidence level) with respect to its position measured in archival data, showing that the shock propagates in the interstellar medium consistently with the pulsar proper motion. Finally, we could not find evidence of large-scale extended optical emission associated with the pulsar wind nebula detected by Chandra , down to a surface brightness limit of ∼28.1 mag arcsec{sup −2}. Future observations are needed to confirm the optical identification of PSR J1741−2054 and characterize the spectrum of its counterpart.

  9. THE VARIABLE NEAR-INFRARED COUNTERPART OF THE MICROQUASAR GRS 1758–258

    International Nuclear Information System (INIS)

    Luque-Escamilla, Pedro L.; Martí, Josep; Muñoz-Arjonilla, Álvaro J.

    2014-01-01

    We present a new study of the microquasar system GRS 1758–258 in the near-infrared domain based on archival observations with the Hubble Space Telescope and the NICMOS camera. In addition to confirming the near-infrared counterpart pointed out by Muñoz-Arjonilla et al., we show that this object displays significant photometric variability. From its average magnitudes, we also find that GRS 1758–258 fits well within the correlation between the optical/near-infrared and X-ray luminosity known to exist for low-mass, black-hole candidate X-ray binaries in a hard state. Moreover, the spectral energy distribution built using all radio, near-infrared, and X-ray data available closest in time to the NICMOS observations can be reasonably interpreted in terms of a self-absorbed radio jet and an irradiated accretion disk model around a stellar-mass black hole. All these facts match the expected behavior of a compact binary system and strengthen our confidence in the counterpart identification

  10. Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

    International Nuclear Information System (INIS)

    Aravindan, Natarajan; Veeraraghavan, Jamunarani; Madhusoodhanan, Rakhesh; Herman, Terence S.; Natarajan, Mohan

    2011-01-01

    Purpose: We recently reported that curcumin attenuates ionizing radiation (IR)-induced survival signaling and proliferation in human neuroblastoma cells. Also, in the endothelial system, we have demonstrated that NFκB regulates IR-induced telomerase activity (TA). Accordingly, we investigated the effect of curcumin in inhibiting IR-induced NFκB-dependent hTERT transcription, TA, and cell survival in neuroblastoma cells. Methods and Materials: SK-N-MC or SH-SY5Y cells exposed to IR and treated with curcumin (10-100 nM) with or without IR were harvested after 1 h through 24 h. NFκB-dependent regulation was investigated either by luciferase reporter assays using pNFκB-, pGL3-354-, pGL3-347-, or pUSE-IκBα-Luc, p50/p65, or RelA siRNA-transfected cells. NFκB activity was analyzed using an electrophoretic mobility shift assay and hTERT expression using the quantitative polymerase chain reaction. TA was determined using the telomerase repeat amplification protocol assay and cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium bromide and clonogenic assay. Results: Curcumin profoundly inhibited IR-induced NFκB. Consequently, curcumin significantly inhibited IR-induced TA and hTERT mRNA at all points investigated. Furthermore, IR-induced TA is regulated at the transcriptional level by triggering telomerase reverse transcriptase (TERT) promoter activation. Moreover, NFκB becomes functionally activated after IR and mediates TA upregulation by binding to the κB-binding region in the promoter region of the TERT gene. Consistently, elimination of the NFκB-recognition site on the telomerase promoter or inhibition of NFκB by the IκBα mutant compromises IR-induced telomerase promoter activation. Significantly, curcumin inhibited IR-induced TERT transcription. Consequently, curcumin inhibited hTERT mRNA and TA in NFκB overexpressed cells. Furthermore, curcumin enhanced the IR-induced inhibition of cell survival. Conclusions: These results

  11. Core-collapse supernovae as possible counterparts of IceCube neutrino multiplets

    Energy Technology Data Exchange (ETDEWEB)

    Strotjohann, Nora Linn; Kowalski, Marek; Franckowiak, Anna [DESY, Zeuthen (Germany); Voge, Markus [Bonn Univ. (Germany). Physikalisches Institut; Collaboration: IceCube-Collaboration

    2016-07-01

    While an astrophysical neutrino flux has been detected by the IceCube Neutrino Observatory its sources remain so far unidentified. IceCube's Optical Follow-up Program is designed to search for the counterparts of neutrino multiplets using the full energy range of the IceCube detector down to 100 GeV. Two or more muon neutrinos arriving from the same direction within few seconds can trigger follow-up observations with optical and X-ray telescopes. Since 2010 the Palomar Transient Factory has followed up about 40 such neutrino alerts and detected several supernovae. Many of the detections are however likely random coincidences. In this talk I describe our search for supernovae and the prospects of identifying a supernova as a source of high-energy neutrinos.

  12. Strategic wholesale pricing for an incumbent supplier facing with a competitive counterpart.

    Science.gov (United States)

    Sun, Jianwu

    2014-01-01

    We introduce a wholesale pricing strategy for an incumbent supplier facing with a competitive counterpart. We propose a profit function which considers both the present loss and future loss from a wholesale price and then study the optimal wholesale prices for different objectives about this profit function for the incumbent supplier. First, we achieve an optimal wholesale price for the incumbent supplier to maximize his expected profit. Then, to reduce the risk originating from the fluctuation in the competitive supplier's wholesale price, we integrate the conditional value-at-risk (CVaR) measure in financial risk management into this study and derive an optimal wholesale price to maximize CVaR about profit for the incumbent supplier. Besides, the properties of the two optimal wholesale prices are discussed. Finally, some management insights are suggested for the incumbent supplier in a competitive setting.

  13. Experiment data report for semiscale Mod-1 test S-06-4 (LOFT counterpart test)

    International Nuclear Information System (INIS)

    Gillins, R.L.; Sackett, K.E.; Coppin, C.E.

    1977-12-01

    Recorded test data are presented for Test S-06-4 of the Semiscale Mod-1 LOFT counterpart test series. These tests are among several Semiscale Mod-1 experiments conducted to investigate the thermal and hydraulic phenomena accompanying a hypothesized loss-of-coolant accident in a pressurized water reactor (PWR) system. Test S-06-4 was conducted from initial conditions of 15,653 kPa and 564 K to investigate the response of the Semiscale Mod-1 system to a depressurization and reflood transient following a simulated double-ended offset shear of the broken loop cold leg piping. During the test, cooling water was injected into the cold leg of the intact loop to simulate emergency core coolant injection in a PWR. The heater rods in the electrically heated core were operated at an axial peak power density which was 100 percent of the maximum peak power density

  14. Experiment data report for semiscale Mod-1 test S-06-1 (LOFT counterpart test)

    International Nuclear Information System (INIS)

    Collins, B.L.; Patton, M.L. Jr.; Sackett, K.E.

    1977-07-01

    Recorded test data are presented for Test S-06-1 of the Semiscale Mod-1 LOFT counterpart test series. These tests are among several Semiscale Mod-1 experiments conducted to investigate the thermal and hydraulic phenomena accompanying an hypothesized loss-of-coolant accident in a pressurized water reactor (PWR) system. Test S-06-1 was conducted from initial conditions of 15 568 kPa and 564 K to investigate the response of the Semiscale Mod-1 system to a depressurization and reflood transient following a simulated double-ended offset shear of the broken loop cold leg piping. During the test, cooling water was injected into the cold leg of the intact loop to simulate emergency core coolant injection in a PWR. The heater rods in the electrically heated core were operated at an axial peak power density which was 30% of the maximum peak power density

  15. Experiment data report for semiscale Mod-1 Test S-06-2 (LOFT counterpart test)

    International Nuclear Information System (INIS)

    Patton, M.L. Jr.; Collins, B.L.; Sackett, K.E.

    1977-08-01

    Recorded test data are presented for Test S-06-2 of the Semiscale Mod-1 LOFT counterpart test series. These tests are among several Semiscale Mod-1 experiments conducted to investigate the thermal and hydraulic phenomena accompanying an hypothesized loss-of-coolant accident in a pressurized water reactor (PWR) system. Test S-06-2 was conducted from initial conditions of 15 513 kPa and 563 K to investigate the response of the Semiscale Mod-1 system to a depressurization and reflood transient following a simulated double-ended offset shear of the broken loop cold leg piping. During the test, cooling water was injected into the cold leg of the intact loop to simulate emergency core coolant injection in a PWR. The heater rods in the electrically heated core were operated at an axial peak power density which was 50% of the maximum peak power density

  16. A systematic search for dwarf counterparts to ultra compact high velocity clouds

    Science.gov (United States)

    Bennet, Paul; Sand, David J.; Crnojevic, Denija; Strader, Jay

    2015-01-01

    Observations of the Universe on scales smaller than typical, massive galaxies challenge the standard Lambda Cold Dark Matter paradigm for structure formation. It is thus imperative to discover and characterize the faintest dwarf galaxy systems, not just within the Local Group, but in relatively isolated environments as well in order to properly connect them with models of structure formation. Here we report on a systematic search of public ultraviolet and optical archives for dwarf galaxy counterparts to so-called Ultra Compact High Velocity Clouds (UCHVCs), which are compact, isolated HI sources recently found in the Galactic Arecibo L-band Feed Array-HI (GALFA-HI) and Arecibo Legacy Fast ALFA (ALFALFA-HI) surveys. Our search has uncovered at least three strong dwarf galaxy candidates, and we present their inferred star formation rate and structural properties here.

  17. Strategic Wholesale Pricing for an Incumbent Supplier Facing with a Competitive Counterpart

    Directory of Open Access Journals (Sweden)

    Jianwu Sun

    2014-01-01

    Full Text Available We introduce a wholesale pricing strategy for an incumbent supplier facing with a competitive counterpart. We propose a profit function which considers both the present loss and future loss from a wholesale price and then study the optimal wholesale prices for different objectives about this profit function for the incumbent supplier. First, we achieve an optimal wholesale price for the incumbent supplier to maximize his expected profit. Then, to reduce the risk originating from the fluctuation in the competitive supplier’s wholesale price, we integrate the conditional value-at-risk (CVaR measure in financial risk management into this study and derive an optimal wholesale price to maximize CVaR about profit for the incumbent supplier. Besides, the properties of the two optimal wholesale prices are discussed. Finally, some management insights are suggested for the incumbent supplier in a competitive setting.

  18. A SEARCH FOR AN OPTICAL COUNTERPART TO THE GRAVITATIONAL-WAVE EVENT GW151226

    Energy Technology Data Exchange (ETDEWEB)

    Smartt, S. J.; Smith, K. W.; Young, D. R.; Inserra, C.; Wright, D. E.; Jerkstrand, A.; Maguire, K.; Mueller, B. [Astrophysics Research Centre, School of Mathematics and Physics, Queens University Belfast, Belfast BT7 1NN (United Kingdom); Chambers, K. C.; Huber, M. E.; Denneau, L.; Flewelling, H.; Heinze, A.; Magnier, E. A.; Sherstyuk, A.; Stalder, B.; Schultz, A. S. B. [Institute of Astronomy, University of Hawaii, 2680 Woodlawn Drive, Honolulu, HI 96822 (United States); Chen, T.-W. [Max-Planck-Institut für Extraterrestrische Physik, Giessenbachstraße 1, D-85748, Garching (Germany); Coughlin, M. [Department of Physics, Harvard University, Cambridge, MA 02138 (United States); Rest, A., E-mail: s.smartt@qub.ac.uk [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); and others

    2016-08-20

    We present a search for an electromagnetic counterpart of the gravitational-wave source GW151226. Using the Pan-STARRS1 telescope we mapped out 290 square degrees in the optical i {sub P1} filter, starting 11.5 hr after the LIGO information release and lasting for an additional 28 days. The first observations started 49.5 hr after the time of the GW151226 detection. We typically reached sensitivity limits of i {sub P1} = 20.3–20.8 and covered 26.5% of the LIGO probability skymap. We supplemented this with ATLAS survey data, reaching 31% of the probability region to shallower depths of m ≃ 19. We found 49 extragalactic transients (that are not obviously active galactic nuclei), including a faint transient in a galaxy at 7 Mpc (a luminous blue variable outburst) plus a rapidly decaying M-dwarf flare. Spectral classification of 20 other transient events showed them all to be supernovae. We found an unusual transient, PS15dpn, with an explosion date temporally coincident with GW151226, that evolved into a type Ibn supernova. The redshift of the transient is secure at z = 0.1747 ± 0.0001 and we find it unlikely to be linked, since the luminosity distance has a negligible probability of being consistent with that of GW151226. In the 290 square degrees surveyed we therefore do not find a likely counterpart. However we show that our survey strategy would be sensitive to NS–NS mergers producing kilonovae at D{sub L} ≲ 100 Mpc, which is promising for future LIGO/Virgo searches.

  19. Subaru Hyper Suprime-Cam Survey for an optical counterpart of GW170817

    Science.gov (United States)

    Tominaga, Nozomu; Tanaka, Masaomi; Morokuma, Tomoki; Utsumi, Yousuke; Yamaguchi, Masaki S.; Yasuda, Naoki; Tanaka, Masayuki; Yoshida, Michitoshi; Fujiyoshi, Takuya; Furusawa, Hisanori; Kawabata, Koji S.; Lee, Chien-Hsiu; Motohara, Kentaro; Ohsawa, Ryou; Ohta, Kouji; Terai, Tsuyoshi; Abe, Fumio; Aoki, Wako; Asakura, Yuichiro; Barway, Sudhanshu; Bond, Ian A.; Fujisawa, Kenta; Honda, Satoshi; Ioka, Kunihito; Itoh, Youichi; Kawai, Nobuyuki; Kim, Ji Hoon; Koshimoto, Naoki; Matsubayashi, Kazuya; Miyazaki, Shota; Saito, Tomoki; Sekiguchi, Yuichiro; Sumi, Takahiro; Tristram, Paul J.

    2018-03-01

    We perform a z-band survey for an optical counterpart of the binary neutron star coalescence GW170817 with Subaru/Hyper Suprime-Cam. Our untargeted transient search covers 23.6 deg2 corresponding to the 56.6% credible region of GW170817 and reaches the 50% completeness magnitude of 20.6 mag on average. As a result, we find 60 candidate extragalactic transients, including J-GEM17btc (also known as SSS17a/DLT17ck). While J-GEM17btc is associated with NGC 4993, which is firmly located inside the 3D skymap of GW170817, the other 59 candidates do not have distance information in the GLADE v2 catalog or NASA/IPAC Extragalactic Database. Among 59 of the candidates, 58 are located at the center of extended objects in the Pan-STARRS1 catalog, while one candidate has an offset. We present location, z-band apparent magnitude, and time variability of the candidates and evaluate the probabilities that they are located within the 3D skymap of GW170817. The probability for J-GEM17btc is 64%, which is much higher than for the other 59 candidates (9.3 × 10-3-2.1 × 10-1%). Furthermore, the possibility that at least one of the other 59 candidates is located within the 3D skymap is only 3.2%. Therefore, we conclude that J-GEM17btc is the most likely and distinguished candidate to be the optical counterpart of GW170817.

  20. Subaru Hyper Suprime-Cam Survey for an optical counterpart of GW170817‡

    Science.gov (United States)

    Tominaga, Nozomu; Tanaka, Masaomi; Morokuma, Tomoki; Utsumi, Yousuke; Yamaguchi, Masaki S.; Yasuda, Naoki; Tanaka, Masayuki; Yoshida, Michitoshi; Fujiyoshi, Takuya; Furusawa, Hisanori; Kawabata, Koji S.; Lee, Chien-Hsiu; Motohara, Kentaro; Ohsawa, Ryou; Ohta, Kouji; Terai, Tsuyoshi; Abe, Fumio; Aoki, Wako; Asakura, Yuichiro; Barway, Sudhanshu; Bond, Ian A.; Fujisawa, Kenta; Honda, Satoshi; Ioka, Kunihito; Itoh, Youichi; Kawai, Nobuyuki; Kim, Ji Hoon; Koshimoto, Naoki; Matsubayashi, Kazuya; Miyazaki, Shota; Saito, Tomoki; Sekiguchi, Yuichiro; Sumi, Takahiro; Tristram, Paul J.

    2018-02-01

    We perform a z-band survey for an optical counterpart of the binary neutron star coalescence GW170817 with Subaru/Hyper Suprime-Cam. Our untargeted transient search covers 23.6 deg2 corresponding to the 56.6% credible region of GW170817 and reaches the 50% completeness magnitude of 20.6 mag on average. As a result, we find 60 candidate extragalactic transients, including J-GEM17btc (also known as SSS17a/DLT17ck). While J-GEM17btc is associated with NGC 4993, which is firmly located inside the 3D skymap of GW170817, the other 59 candidates do not have distance information in the GLADE v2 catalog or NASA/IPAC Extragalactic Database. Among 59 of the candidates, 58 are located at the center of extended objects in the Pan-STARRS1 catalog, while one candidate has an offset. We present location, z-band apparent magnitude, and time variability of the candidates and evaluate the probabilities that they are located within the 3D skymap of GW170817. The probability for J-GEM17btc is 64%, which is much higher than for the other 59 candidates (9.3 × 10-3-2.1 × 10-1%). Furthermore, the possibility that at least one of the other 59 candidates is located within the 3D skymap is only 3.2%. Therefore, we conclude that J-GEM17btc is the most likely and distinguished candidate to be the optical counterpart of GW170817.

  1. A Search for Optical Counterparts of Chandra Sources in Omega Centauri using ACS

    Science.gov (United States)

    Haggard, D.; Fuller, A. D.; Dorfman, J. L.; Cool, A. M.; Anderson, J.; Edmonds, P. D.; Davies, M. B.

    2002-12-01

    The globular cluster Omega Centauri, with its high mass and large, moderate density core, is of interest both for its population of primordial binaries and for the large number of tidal-capture and/or exchange-collision binaries it may harbor. We have obtained a 3x3 mosaic of Wide Field Camera pointings with HST's Advanced Camera for Surveys, covering a 10'x10' field out to the cluster's half-mass radius. Containing ~1.7 million detected stars, the resulting mosaic represents the most complete image of Omega Cen yet obtained. Here we report preliminary findings of a search in these data for optical counterparts to more than 100 faint X-ray sources (Lx ~ 2 x 1030 - 5 x 1032 erg-s-1) detected in our prior study of Omega Cen using the Chandra X-ray Observatory. Cluster X-ray sources are likely to consist primarily of accreting binary stars and close detached binaries with active coronae. Significant numbers of active galaxies in the background are also expected to be present. Using B, R, and H-alpha images, we are searching for optical counterparts that are H-alpha-bright and blue, as signatures of accretion in cataclysmic variables and/or quiescent low-mass X-ray binaries. Active binaries (e.g., BY Draconis stars) may appear as weaker H-alpha emitters lying on or slightly redward of the main sequence. This work is supported by NASA grant GO-9442 from the Space Telescope Science Institute.

  2. Follow Up of GW170817 and Its Electromagnetic Counterpart by Australian-Led Observing Programmes

    Science.gov (United States)

    Andreoni, I.; Ackley, K.; Cooke, J.; Acharyya, A.; Allison, J. R.; Anderson, G. E.; Ashley, M. C. B.; Baade, D.; Bailes, M.; Bannister, K.; Beardsley, A.; Bessell, M. S.; Bian, F.; Bland, P. A.; Boer, M.; Booler, T.; Brandeker, A.; Brown, I. S.; Buckley, D. A. H.; Chang, S.-W.; Coward, D. M.; Crawford, S.; Crisp, H.; Crosse, B.; Cucchiara, A.; Cupák, M.; de Gois, J. S.; Deller, A.; Devillepoix, H. A. R.; Dobie, D.; Elmer, E.; Emrich, D.; Farah, W.; Farrell, T. J.; Franzen, T.; Gaensler, B. M.; Galloway, D. K.; Gendre, B.; Giblin, T.; Goobar, A.; Green, J.; Hancock, P. J.; Hartig, B. A. D.; Howell, E. J.; Horsley, L.; Hotan, A.; Howie, R. M.; Hu, L.; Hu, Y.; James, C. W.; Johnston, S.; Johnston-Hollitt, M.; Kaplan, D. L.; Kasliwal, M.; Keane, E. F.; Kenney, D.; Klotz, A.; Lau, R.; Laugier, R.; Lenc, E.; Li, X.; Liang, E.; Lidman, C.; Luvaul, L. C.; Lynch, C.; Ma, B.; Macpherson, D.; Mao, J.; McClelland, D. E.; McCully, C.; Möller, A.; Morales, M. F.; Morris, D.; Murphy, T.; Noysena, K.; Onken, C. A.; Orange, N. B.; Osłowski, S.; Pallot, D.; Paxman, J.; Potter, S. B.; Pritchard, T.; Raja, W.; Ridden-Harper, R.; Romero-Colmenero, E.; Sadler, E. M.; Sansom, E. K.; Scalzo, R. A.; Schmidt, B. P.; Scott, S. M.; Seghouani, N.; Shang, Z.; Shannon, R. M.; Shao, L.; Shara, M. M.; Sharp, R.; Sokolowski, M.; Sollerman, J.; Staff, J.; Steele, K.; Sun, T.; Suntzeff, N. B.; Tao, C.; Tingay, S.; Towner, M. C.; Thierry, P.; Trott, C.; Tucker, B. E.; Väisänen, P.; Krishnan, V. Venkatraman; Walker, M.; Wang, L.; Wang, X.; Wayth, R.; Whiting, M.; Williams, A.; Williams, T.; Wolf, C.; Wu, C.; Wu, X.; Yang, J.; Yuan, X.; Zhang, H.; Zhou, J.; Zovaro, H.

    2017-12-01

    The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement ( 2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.

  3. Inhibition of cell proliferation and induction of apoptosis by oleanane triterpenoid (CDDO-Me) in pancreatic cancer cells is associated with the suppression of hTERT gene expression and its telomerase activity

    International Nuclear Information System (INIS)

    Deeb, Dorrah; Gao, Xiaohua; Liu, Yongbo; Kim, Sahn-Ho; Pindolia, Kirit R.; Arbab, Ali S.; Gautam, Subhash C.

    2012-01-01

    Highlights: ► CDDO-Me inhibits hTERT gene expression. ► CDDO-Me inhibits hTERT protein expression. ► CDDO-Me inhibits hTERT telomerase activity. ► CDDO-Me inhibits hTERT regulatory proteins. -- Abstract: Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a multifunctional oleanane synthetic triterpenoid with potent anti-inflammatory and antitumorigenic properties. The mechanisms of the antisurvival and apoptosis-inducing activities of CDDO-Me and related derivatives of oleanolic acid have been defined; however, to date, no study has been carried out on the effect of CDDOs on human telomerase reverse transcriptase (hTERT) gene or telomerase activity. Here we report for the first time that inhibition of cell proliferation and induction of apoptosis by CDDO-Me in pancreatic cancer cell lines is associated with the inhibition of hTERT gene expression, hTERT telomerase activity and a number of proteins that regulate hTERT expression and activity. Furthermore, abrogation or overexpression of hTERT protein altered the susceptibility of tumor cells to CDDO-Me. These findings suggest that telomerase (hTERT) is a relevant target of CDDO-Me in pancreatic cancer cells.

  4. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    International Nuclear Information System (INIS)

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S.

    2006-01-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents

  5. The Transition between Telomerase and ALT Mechanisms in Hodgkin Lymphoma and Its Predictive Value in Clinical Outcomes

    Directory of Open Access Journals (Sweden)

    Radhia M’kacher

    2018-05-01

    Full Text Available Background: We analyzed telomere maintenance mechanisms (TMMs in lymph node samples from HL patients treated with standard therapy. The TMMs correlated with clinical outcomes of patients. Materials and Methods: Lymph node biopsies obtained from 38 HL patients and 24 patients with lymphadenitis were included in this study. Seven HL cell lines were used as in vitro models. Telomerase activity (TA was assessed by TRAP assay and verified through hTERT immunofluorescence expression; alternative telomere lengthening (ALT was also assessed, along with EBV status. Results: Both TA and ALT mechanisms were present in HL lymph nodes. Our findings were reproduced in HL cell lines. The highest levels of TA were expressed in CD30−/CD15− cells. Small cells were identified with ALT and TA. Hodgkin and Reed Sternberg cells contained high levels of PML bodies, but had very low hTERT expression. There was a significant correlation between overall survival (p < 10−3, event-free survival (p < 10−4, and freedom from progression (p < 10−3 and the presence of an ALT profile in lymph nodes of EBV+ patients. Conclusion: The presence of both types of TMMs in HL lymph nodes and in HL cell lines has not previously been reported. TMMs correlate with the treatment outcome of EBV+ HL patients.

  6. South Asian women with polycystic ovary syndrome exhibit greater sensitivity to gonadotropin stimulation with reduced fertilization and ongoing pregnancy rates than their Caucasian counterparts.

    Science.gov (United States)

    Palep-Singh, M; Picton, H M; Vrotsou, K; Maruthini, D; Balen, A H

    2007-10-01

    Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome. In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is required for PCOS cases that are refractory to standard ovulation induction or have co-existing infertility factors in women with PCOS and Tubal factor subfertility. Assess ethnic variations in response to IVF/ICSI treatment. Observational Comparative study in a University hospital fertility clinic in women with PCOS and Tubal factor subfertility. Women with PCOS (Asians: AP=104; Caucasians: CP=220) and those with tubal factor infertility seeking fertility treatment were assessed (Asians: AC=84; Caucasians: CC=200). Six hundred and eight fresh IVF or ICSI cycles using long protocol of GnRHa suppression and resulting in a fresh embryo transfer were compared. The primary endpoint was to assess the dose of gonadotropins used in the cycles. The secondary outcomes were: total number of oocytes retrieved, fertilization and ongoing clinical pregnancy rates. We found that the South Asian women presented at a younger age for the management of sub-fertility. An extended stimulation phase and Caucasian ethnicity showed an inverse correlation with the number of oocytes retrieved in the PCOS subgroup. Caucasian ethnicity was associated with a higher fertilization rate however increase in body mass index (BMI) and the laboratory technique of IVF appeared to have a negative impact on fertilization rates in the PCOS subgroup. Commencing down regulation on day 1 of the cycles was negatively associated with fertilization rates in the tubal group. In terms of clinical pregnancy rates, the Caucasian PCOS had a 2.5 times (95% CI: 1.25-5) higher chance of an ongoing clinical pregnancy as compared with their Asian counterpart. Also, a unit increase in the basal FSH concentration reduced the odds of pregnancy by 18.6% (95% CI: 1.8-32.6%) in the PCOS group. The Asian PCOS have a greater sensitivity to gonadotropin stimulation with lower fertilization and

  7. AT 2017gfo: An Anisotropic and Three-component Kilonova Counterpart of GW170817

    Science.gov (United States)

    Perego, Albino; Radice, David; Bernuzzi, Sebastiano

    2017-12-01

    The detection of a kilo/macronova electromagnetic counterpart (AT 2017gfo) of the first gravitational-wave signal compatible with the merger of two neutron stars (GW170817) has confirmed the occurrence of r-process nucleosynthesis in this kind of event. The blue and red components of AT 2017gfo have been interpreted as the signature of multi-component ejecta in the merger dynamics. However, the explanation of AT 2017gfo in terms of the properties of the ejecta and of the ejection mechanisms is still incomplete. In this work, we analyze AT 2017gfo with a new semi-analytic model of kilo/macronova inferred from general-relativistic simulations of the merger and long-term numerical models of the merger aftermath. The model accounts for the anisotropic emission from the three known mass ejecta components: dynamic, winds, and secular outflows from the disk. The early multi-band light curves of AT 2017gfo can only be explained by the presence of a relatively low-opacity component of the ejecta at high latitudes. This points to the key role of weak interactions in setting the ejecta properties and determining the nucleosynthetic yields. Our model also constrains the total ejected mass associated to AT 2017gfo to be between 0.042 and 0.077 {M}⊙ , the observation angle of the source to be between π /12 and 7π /36, and the mass of the disk to be ≳ 0.08 {M}⊙ .

  8. Moringa oleifera Root Induces Cancer Apoptosis more Effectively than Leave Nanocomposites and Its Free Counterpart

    Science.gov (United States)

    Abd-Rabou, Ahmed A; Abdalla, Aboelfetoh M; Ali, Naglaa A; Zoheir, Khairy MA

    2017-01-01

    Medicinal plants are important elements of indigenous medical system that have persisted in developing countries. Many of the botanical chemo-preventions currently used as potent anticancer agents. However, some important anticancer agents are still extracted from plants because they cannot be synthesized chemically on a commercial scale due to their complex structures that often contain several chiral centers. The aim of this study was to test different extracts from the Moringa oleifera leaves (ML), its PLGA-CS-PEG nanocomposites (MLn), as well as root core (Rc) and outer (Ro) parts for activity against hepatocarcinoma HepG2, breast MCF7, and colorectal HCT 116/ Caco-2 cells in vitro. Nano-composites were prepared and characterized. Then, the nanocomposites and the free counterparts were screened on different propagated cancer cell lines. The underlying cytotoxic impact was followed using apoptosis measurements. All extracts kill the different cancer cells with different ratios, but intriguingly, the root core extract could kill the majority of cancer cells (approximately 70-80%), while sparing normal BHK-21 cells with minimal inhibitory effect (approximately 30-40%). Apoptotic cell increment came to confirm the cytotoxic effects of these extracts on HCT 116 cells (Rc: 212% and Ro: 180%, respectively) and HepG2 cells (ML: 567.5% and MLn: 608%, respectively) compared to control (100%) mechanistically wise. Moringa oleifera nanocomposites may have potential for use as a natural source of anti-cancer compounds. PMID:28843248

  9. Do Asian women do as well as their Caucasian counterparts in IVF treatment: Cohort study.

    Science.gov (United States)

    Kan, Andrew; Leung, Peter; Luo, Kehui; Fay, Louise; Tan, Chunyan Leeann

    2015-06-01

    To evaluate if there is a difference in pregnancy rate between Asian and Caucasian women when they undergo in vitro fertilization (IVF). This was a retrospective cohort study set in a private reproductive medicine clinic. The study consisted of a total of 2594 patients (Asian, n = 522; Caucasian, n = 2072) undergoing IVF managed by a single doctor over a 10 year period. The main outcome measures were clinical pregnancy rate and live birth rate. Logistic regression was used to control for confounding factors. Asian women achieved a significantly lower clinical pregnancy and live birth rate than their Caucasian counterparts, despite replacement of more embryos. This difference was not significant after controlling for age and duration of infertility. Despite higher doses of gonadotrophin, they achieved fewer oocytes and had resultant fewer embryos for transfer or cryopreservation. In a study designed to reduce the effect of confounding factors by looking at a large number of patients from a single IVF unit under the care of a single doctor, there does not appear to be a difference in IVF pregnancy rate as a result of race. Asian women tend to present for IVF treatment at a later age after having tried for a longer period of time and this contributes significantly to their lower pregnancy rate. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  10. iPTF SEARCH FOR AN OPTICAL COUNTERPART TO GRAVITATIONAL-WAVE TRANSIENT GW150914

    Energy Technology Data Exchange (ETDEWEB)

    Kasliwal, M. M.; Cao, Y.; Barlow, T.; Bellm, E.; Cook, D.; Duggan, G. E.; Kulkarni, S. R.; Lunnan, R. [Cahill Center for Astrophysics, California Institute of Technology, Pasadena, CA 91125 (United States); Cenko, S. B.; Singer, L. P. [Astrophysics Science Division, NASA Goddard Space Flight Center, Code 661, Greenbelt, MD 20771 (United States); Corsi, A.; Palliyaguru, N. [Texas Tech University, Physics Department, Lubbock, TX 79409-1051 (United States); Bhalerao, V. [Inter-University Centre for Astronomy and Astrophysics (IUCAA), Post Bag 4, Ganeshkhind, Pune 411007 (India); Ferretti, R. [The Oskar Klein Centre, Department of Physics, Stockholm University, SE-106 91 Stockholm (Sweden); Frail, D. A. [National Radio Astronomy Observatory, Socorro, NM (United States); Horesh, A.; Manulis, I. [Department of Particle Physics and Astrophysics, Weizmann Institute of Science, 76100 Rehovot (Israel); Kendrick, R. [Lockheed Martin Space Systems Company, Palo Alto, CA (United States); Laher, R. [Spitzer Science Center, California Institute of Technology, M/S 314-6, Pasadena, CA 91125 (United States); Masci, F. [Infrared Processing and Analysis Center, California Institute of Technology, Pasadena, CA 91125 (United States); and others

    2016-06-20

    The intermediate Palomar Transient Factory (iPTF) autonomously responded to and promptly tiled the error region of the first gravitational-wave event GW150914 to search for an optical counterpart. Only a small fraction of the total localized region was immediately visible in the northern night sky, due both to Sun-angle and elevation constraints. Here, we report on the transient candidates identified and rapid follow-up undertaken to determine the nature of each candidate. Even in the small area imaged of 126 deg{sup 2}, after extensive filtering, eight candidates were deemed worthy of additional follow-up. Within two hours, all eight were spectroscopically classified by the Keck II telescope. Curiously, even though such events are rare, one of our candidates was a superluminous supernova. We obtained radio data with the Jansky Very Large Array and X-ray follow-up with the Swift satellite for this transient. None of our candidates appear to be associated with the gravitational-wave trigger, which is unsurprising given that GW150914 came from the merger of two stellar-mass black holes. This end-to-end discovery and follow-up campaign bodes well for future searches in this post-detection era of gravitational waves.

  11. Intramuscular keratocyst as a soft tissue counterpart of keratocystic odontogenic tumor: differential diagnosis by immunohistochemistry.

    Science.gov (United States)

    Abé, Tatsuya; Maruyama, Satoshi; Yamazaki, Manabu; Essa, Ahmed; Babkair, Hamzah; Mikami, Toshihiko; Shingaki, Susumu; Kobayashi, Tadaharu; Hayashi, Takafumi; Cheng, Jun; Saku, Takashi

    2014-01-01

    Keratocystic odontogenic tumor (KCOT), a developmental jaw cyst previously referred to as odontogenic keratocyst (OKC), typically arises in the jawbone. In this article, however, we report a case of KCOT located within the temporalis muscle. We compared its immunohistochemical profiles with those of authentic jaw KCOT, orthokeratinized odontogenic cyst, and epidermoid cyst in order to consider whether a soft tissue counterpart of KCOT could be a separate disease entity. The patient was a 46-year-old man with a well-defined cystic lesion within the left temporalis muscle. On computed tomographic images, the lesion was recognized as a cystic lesion, although KCOT was not included in the clinical differential diagnoses. The location of the lesion was not within bone but, rather, within the temporalis muscle that was attached to the jawbones. Our review of the literature has disclosed more than 20 peripheral KCOT cases of the oral mucosa and more than 10 cases of the skin, but only 1 case arising in muscle. Immunohistochemical investigation of the present intramuscular case reveals KCOT-characteristic profiles distinct from the other 3 types of cysts investigated. The results indicate that KCOT-like lesions can arise within soft tissues, although use of the term odontogenic might seem inappropriate in those cases. © 2013.

  12. Comparing gas separation performance between all known zeolites and their zeolitic imidazolate framework counterparts.

    Science.gov (United States)

    Gómez-Álvarez, Paula; Hamad, Said; Haranczyk, Maciej; Ruiz-Salvador, A Rabdel; Calero, Sofia

    2016-01-07

    To find optimal porous materials for adsorption-based separations is a challenging task due to the extremely large number of possible pore topologies and compositions. New porous material classes such as Metal Organic Frameworks (MOFs) are emerging, and hope to replace traditionally used materials such as zeolites. Computational screening offers relatively fast searching for candidate structures as well as side-by-side comparisons between material families. This work is pioneering at examining the families comprised by the experimentally known zeolites and their respective Zeolitic Imidazolate Framework (ZIF) counterparts in the context of a number of environmental and industrial separations involving carbon dioxide, nitrogen, methane, oxygen, and argon. Additionally, unlike related published work, here all the targeted structures have been previously relaxed through energy minimization. On the first level of characterization, we considered a detailed pore characterization, identifying 24 zeolites as promising candidates for gas separation based on adsorbate sizes. The second level involved interatomic potential-based calculations to assess the adsorption performance of the materials. We found no correlation in the values of heat of adsorption between zeolites and ZIFs sharing the same topology. A number of structures were identified as potential experimental targets for CO2/N2, and CO2/CH4 affinity-based separations.

  13. Experiment data report for semiscale Mod-1 Test S-06-5. (LOFT counterpart test)

    International Nuclear Information System (INIS)

    1977-06-01

    Recorded test data are presented for Test S-06-5 of the Semiscale Mod-1 LOFT counterpart test series. These tests are among several Semiscale Mod-1 experiments conducted to investigate the thermal and hydraulic phenomena accompanying a hypothesized loss-of-coolant accident in a pressurized water reactor (PWR) system. Test S-06-5 was conducted from initial conditions of 2272 psia and 536 0 F to investigate the response of the Semiscale Mod-1 system to a depressurization and reflood transient following a simulated double-ended offset shear of the broken loop cold leg piping. During the test, cooling water was injected into the cold legs of the intact and broken loops to simulate emergency core coolant injection in a PWR. The purpose of Test S-06-5 was to assess the influence of the break nozzle geometry on core thermal and system response and on the subcooled and low quality mass flow rates at the break locations

  14. VERY LONG BASELINE INTERFEROMETRY SEARCH FOR THE RADIO COUNTERPART OF HESS J1943+213

    Energy Technology Data Exchange (ETDEWEB)

    Gabanyi, K. E. [Konkoly Observatory, Research Centre for Astronomy and Earth Sciences of the Hungarian Academy of Sciences, P.O. Box 67, Budapest H-1525 (Hungary); Dubner, G.; Giacani, E. [Instituto de Astronomia y Fisica del Espacio (CONICET-UBA), CC 67, Suc. 28, 1428 Buenos Aires (Argentina); Paragi, Z.; Pidopryhora, Y. [Joint Institute for VLBI in Europe, Postbus 2, 7990 AA Dwingeloo (Netherlands); Frey, S., E-mail: gabanyi@konkoly.hu [FOeMI Satellite Geodetic Observatory, P.O. Box 585, H-1592 Budapest (Hungary)

    2013-01-01

    HESS J1943+213, a TeV point source close to the Galactic plane recently discovered by the H.E.S.S. Collaboration, was proposed to be an extreme BL Lacertae object, though a pulsar wind nebula (PWN) nature could not be completely discarded. To investigate its nature, we performed high-resolution radio observations with the European Very Long Baseline Interferometry Network (EVN) and reanalyzed archival continuum and H I data. The EVN observations revealed a compact radio counterpart of the TeV source. The low brightness temperature and the resolved nature of the radio source are indications against the beamed BL Lacertae hypothesis. The radio/X-ray source appears immersed in a {approx}1' elliptical feature, suggesting a possible galactic origin (PWN nature) for the HESS source. We found that HESS J1943+213 is located in the interior of a {approx}1 Degree-Sign diameter H I feature and explored the possibility of them being physically related.

  15. Phylogenetic comparisons of a coastal bacterioplankton community with its counterparts in open ocean and freshwater systems.

    Science.gov (United States)

    Rappé; Vergin; Giovannoni

    2000-09-01

    In order to extend previous comparisons between coastal marine bacterioplankton communities and their open ocean and freshwater counterparts, here we summarize and provide new data on a clone library of 105 SSU rRNA genes recovered from seawater collected over the western continental shelf of the USA in the Pacific Ocean. Comparisons to previously published data revealed that this coastal bacterioplankton clone library was dominated by SSU rRNA gene phylotypes originally described from surface waters of the open ocean, but also revealed unique SSU rRNA gene lineages of beta Proteobacteria related to those found in clone libraries from freshwater habitats. beta Proteobacteria lineages common to coastal and freshwater samples included members of a clade of obligately methylotrophic bacteria, SSU rRNA genes affiliated with Xylophilus ampelinus, and a clade related to the genus Duganella. In addition, SSU rRNA genes were recovered from such previously recognized marine bacterioplankton SSU rRNA gene clone clusters as the SAR86, SAR11, and SAR116 clusters within the class Proteobacteria, the Roseobacter clade of the alpha subclass of the Proteobacteria, the marine group A/SAR406 cluster, and the marine Actinobacteria clade. Overall, these results support and extend previous observations concerning the global distribution of several marine planktonic prokaryote SSU rRNA gene phylotypes, but also show that coastal bacterioplankton communities contain SSU rRNA gene lineages (and presumably bacterioplankton) shown previously to be prevalent in freshwater habitats.

  16. Comparative evaluation of corrosion behaviour of type K thin film thermocouple and its bulk counterpart

    International Nuclear Information System (INIS)

    Mukherjee, S.K.; Barhai, P.K.; Srikanth, S.

    2011-01-01

    Highlights: → Anodic vacuum arc deposited chromel and alumel films are more 'noble' in 5% NaCl solution than their respective wires. → Chromel undergoes localised corrosion while alumel shows uniform corrosion. → Virgin samples of chromel-alumel TFTCs exhibit good thermoelectric response. → Their thermoelectric outputs remain largely unaffected when shelved under normal atmospheric conditions. → After 288 h of exposure in salt spray environment, their thermoelectric outputs show noticeable change due to size effects. - Abstract: This paper investigates the corrosion behaviour of type K thermoelements and their thin films, and compares the performance of chromel-alumel thin film thermocouple with its wire counterpart before and after exposure to 5% NaCl medium. Potentiodynamic polarisation tests reveal that chromel and alumel films are more 'noble' than their respective wires. Alumel corrodes faster when coupled with chromel in films than as wires. Secondary electron micrographs and electrochemical impedance spectroscopy measurements suggest that chromel shows localised corrosion while alumel undergoes uniform corrosion. Corrosion adversely affects the thermocouple output and introduces an uncertainty in the measurement.

  17. UPTF test 21D counterpart test in the MIDAS test facility

    International Nuclear Information System (INIS)

    Yoon, B. C.; Ah, D. J.; Joo, I. C.; Kwon, T. S.; Park, W. M.; Song, C. H.

    2002-01-01

    This paper describes the experimental results of UPTF Test 21D counterpart tests in the downcomer during the late reflood phase of LBLOCA. The experiments have been performed in the MIDAS test facility using superheated steam and water. The test condition was determined,based on the test results of UPTF Test 21D, by applying the 'modified linear scaling method of 1/4.077 length scale. The tests of ECC direct bypass and void height are performed separately to estimate each phenomena quantitatively. The tests were carried out by varying the injection steam flow rate of intact cold legs widely to investigate the effect of steam flow rate on the direct bypass fraction and void height. In the tests, separate effect tests have been performed in cases of DVI-1,DVI- 2 and DVI-1 and 2 injections to see the direct bypass fraction according to the DVI nozzle combination. From the tests, we found that the fraction of direct ECC bypass and the void height observed in the MIDAS test facility reasonably well agree with those of UPTF test 21- D. It confirms that the applied 'modified linear scaling law' reproduces major thermal hydraulics phenomena in the downcomer during the LBLOCA reflood phase

  18. Elaboration of a guideline for counterpart testing of integral loop systems

    International Nuclear Information System (INIS)

    Karwat, H.

    1988-01-01

    A previous study on the problems of scaling and extrapolation of experimental results indicated the necessity to overcome some uncertainty in the achievable code accuracy when applied to full size reactor systems. The empirical approach in simulating interfacial relationships within systems behaviour codes in combination with the liberty of nodalisation requires a careful assessment of the overall validity of the code verification concept. Several new test facilities are presently under construction to study fluid-dynamic effects of interest for the behaviour of PWRs under small break LOCA conditions in a larger dimension and with somewhat modified scaling considerations. The test results expected from these new facilities may be useful to assess the overall validity of the analytical simulation concept of the applied computer codes. Test facilities of interest within the European Community are the - LOBI Test Facility (vol. scaling 1/700) at JRC-Ispra - SPES Test Facility (vol. scaling 1/425) in Italy - BETHSY Facility (vol scaling 1/100) in France and outside Europe the - ROSA IV Facility (vol. scaling 1/50) in Japan. Main objective of the study was the elaboration of a guideline for the particular requirements of meaningful counterpart testing with the final aim to qualify the overall validity of code simulation concepts and the expected predictive accuracy of code applications for full size prototype PWRs

  19. THE SOCIALIST YOUTH UNION (1957–1976 – POLISH COUNTERPART OF KOMSOMOL

    Directory of Open Access Journals (Sweden)

    Joanna Sadowska

    2016-10-01

    Full Text Available The political system of the Polish People’s Republic was modelled on the Soviet one. Polish youth organizations had the ambitions of being counterparts of Komsomol: they adopted similar work methods and tried to play a similar role in the country. The obvious differences resulted from the specificity of each country and the differences in the societies. The most deeply rooted in the memory of Poles is the Socialist Youth Union, which, being the most stable, existed for almost 20 years with nearly 1.3 million members in the early 1970s. The Union was closely connected with the Polish United Workers’ Party and it had to accomplish two main kinds of political task: to select and prepare future members of the Party, both ordinary and those in the managerial positions, and to educate the whole young generation. The Party indeed treated the organization as its agency, an office dealing with the affairs of youths. However, non-political activity of the Union (culture, entertainment, tourism, etc. was much more effective and evaluated more positively. Actually, there was much more falsehood in the Union: many members were almost completely passive and the work was often only simulated.

  20. Water adsorption and dissociation on Ni(110): How is it different from its close packed counterparts?

    Energy Technology Data Exchange (ETDEWEB)

    Seenivasan, H.; Tiwari, Ashwani K., E-mail: ashwani@iiserkol.ac.in [Indian Institute of Science Education and Research Kolkata, Mohanpur 741252 (India)

    2014-05-07

    Water adsorption and dissociation on Ni(110) surface is studied in detail and compared with its close packed counterparts using density functional theory calculations. Water adsorption occurs on the top site as found on Ni(100) and Ni(111) but the adsorption is stronger on Ni(110). H and OH preferably adsorb on the short bridge sites (brgshort) opposed to hollow sites on (100) and (111) surfaces. Energy barriers for water molecule dissociation on Ni(110) as obtained from the transition state (TS) calculations were low compared to other Ni low indexed surfaces. TS geometries at different positions of the lattice coordinate, Q, were obtained to study the effect of surface temperature on dissociation of H{sub 2}O molecules. These calculations revealed that second layer atoms were also involved in the TS. Dissociation probabilities are obtained using a semi-classical approximation by sampling Q for a Boltzmann distribution at different temperatures. Results showed that the increasing surface temperature significantly increases the dissociation probabilities at lower energies and saturates near the barrier for dissociation. Although the contribution from both top and second layers is similar at low surface temperatures, motion of top layer atoms contribute more towards dissociation probability at higher surface temperatures. Dissociation probabilities obtained are more than one order of magnitude higher than that on Ni(100) and Ni(111) surfaces suggesting Ni(110) to be more reactive among the low indexed Ni surfaces.

  1. The cocoon emission - an electromagnetic counterpart to gravitational waves from neutron star mergers

    Science.gov (United States)

    Gottlieb, Ore; Nakar, Ehud; Piran, Tsvi

    2018-01-01

    Short gamma-ray bursts are believed to arise from compact binary mergers (either neutron star-neutron star or black hole-neutron star). If so, their jets must penetrate outflows that are ejected during the merger. As a jet crosses the ejecta, it dissipates its energy, producing a hot cocoon that surrounds it. We present here 3D numerical simulations of jet propagation in mergers' outflows, and we calculate the resulting emission. This emission consists of two components: the cooling emission, the leakage of the thermal energy of the hot cocoon, and the cocoon macronova that arises from the radioactive decay of the cocoon's material. This emission gives a brief (∼1 h) blue, wide angle signal. While the parameters of the outflow and jet are uncertain, for the configurations we have considered, the signal is bright (∼-14 to -15 absolute magnitude) and outshines all other predicted ultraviolet-optical signals. The signal is brighter when the jet breakout time is longer, and its peak brightness does not depend strongly on the highly uncertain opacity. A rapid search for such a signal is a promising strategy to detect an electromagnetic merger counterpart. A detected candidate could be then followed by deep infrared searches for the longer but weaker macronova arising from the rest of the ejecta.

  2. Identifying open magnetic field regions of the Sun and their heliospheric counterparts

    Science.gov (United States)

    Krista, L. D.; Reinard, A.

    2017-12-01

    Open magnetic regions on the Sun are either long-lived (coronal holes) or transient (dimmings) in nature. Both phenomena are fundamental to our understanding of the solar behavior as a whole. Coronal holes are the sources of high-speed solar wind streams that cause recurrent geomagnetic storms. Furthermore, the variation of coronal hole properties (area, location, magnetic field strength) over the solar activity cycle is an important marker of the global evolution of the solar magnetic field. Dimming regions, on the other hand, are short-lived coronal holes that often emerge in the wake of solar eruptions. By analyzing their physical properties and their temporal evolution, we aim to understand their connection with their eruptive counterparts (flares and coronal mass ejections) and predict the possibility of a geomagnetic storm. The author developed the Coronal Hole Automated Recognition and Monitoring (CHARM) and the Coronal Dimming Tracker (CoDiT) algorithms. These tools not only identify but track the evolution of open magnetic field regions. CHARM also provides daily coronal hole maps, that are used for forecasts at the NOAA Space Weather Prediction Center. Our goal is to better understand the processes that give rise to eruptive and non-eruptive open field regions and investigate how these regions evolve over time and influence space weather.

  3. “The Scum of the Earth”? Foreign People Smugglers and Their Local Counterparts in Indonesia

    Directory of Open Access Journals (Sweden)

    Antje Missbach

    2011-01-01

    Full Text Available Since 2008, the number of asylum seekers and refugees trying to reach Australia from Indonesia by boat has increased. With many of them hailing from conflict-ridden countries such as Afghanistan, Iraq and Sri Lanka, most entered Indonesia with short-term tourist visas or fraudulent papers or no documents at all. It is widely known that a significant number of these ‘irregular’ migrants pay various types of brokers (often labelled, accurately or otherwise, ‘human smugglers’ at least at one stage – either to enter the country or to escape it. As a non-signatory to the UN Refugee Convention, Indonesia does not permit local integration. While a substantial part of these migrants are detained in the 13 immigration detention centres scattered around the archipelago, many roam freely, looking for opportunities for onward migration. Due to the restrictive border protection arrangements between Australia and Indonesia and a number of bilateral intelligence measures for deterring ‘unwanted’ migrants, human smugglers have been gradually forced to adapt strategies, routes and prices. According to much of the available data, most human smugglers are not Indonesians but foreigners who have been lingering in Indonesia for many years. This article demonstrates, moreover, that these foreigners depend upon local contacts to successfully carry out their risky business. Most often, the Indonesian counterparts are solely facilitators or handymen, but in a number of cases Indonesian authorities have also been involved in this highly lucrative business.

  4. Access and Social Capital: A Profile of Community College and Global Counterparts

    Directory of Open Access Journals (Sweden)

    Rosalind Latiner Raby

    2014-12-01

    Full Text Available Alternatives to the traditional four-year public and private university include a sector of higher education that offers a more advanced curriculum than secondary school and serves as a local and often lower-cost pathway that gives options for university overflow for adult learners, displaced workers, life-long learners, workforce learners, developmental learners, and non-traditional learners (Raby and Valeau 2009. These institutional types are known by several names including College of Further Education, Community College, Polytechnic, Technical College, and Technical and Further Education (TAFE and are found on all continents. Based on a literature review of 1,083 academic publications these institutions share a mission that views educational access as necessary for growing the economic and social capital that is needed to help students improve lives. Central to this mission is the belief that any amount of post-secondary education is life-enhancing, regardless of length of study or level of completion. This article examines application of this mission at community colleges and global counterparts throughout the world.

  5. A Search for High-Energy Counterparts to Fast Radio Bursts

    Science.gov (United States)

    Cunningham, Virginia A.; Cenko, Bradley

    2018-01-01

    We report on a search for high-energy counterparts to Fast Radio Bursts (FRBs) with the Fermi Gamma-ray Burst Monitor (GBM), Fermi Large Area Telescope (LAT), and the Swift Burst Alert Telescope (BAT). We find no significant associations for any of the 14 FRBs in our sample, but report upper limits to the high-energy fluence for each on timescales of ∼0.1, 1, 10, and 100 s. We report lower limits on the radio to high-energy fluence, fr / fγ, for timescales of ∼0.1 and 100 s. The non-detection of high-energy emission is expected if FRBs are analogous to the giant pulses seen from the Crab pulsar, but the observed radio fluences of FRBs are orders of magnitude larger than even the most extreme giant pulses would be at the implied cosmological distances. It has also been proposed that events similar to magnetar hyperflares produce FRBs; this might be a viable model, but our fr / fγ lower limits are in tension with the fr / fγ upper limit for the 2004 superburst of SGR 1806‑20, for 6 out of the 12 FRBs that we study. This demonstrates the utility of analyses of high-energy data for FRBs in tracking down the nature of these elusive sources.

  6. X-ray counterpart candidates for six new γ-ray pulsars

    Science.gov (United States)

    Zyuzin, Dmitry A.; Karpova, Anna V.; Shibanov, Yuriy A.

    2018-05-01

    Using archival X-ray data, we have found point-like X-ray counterpart candidates positionally coincident with six γ-ray pulsars discovered recently in the Fermi Gamma-ray Space Telescope data by the Einstein@Home project. The candidates for PSRs J0002+6216, J0554+3107, J1844-0346, and J1105-6037 are detected with Swift, and those for PSRs J0359+5414 and J2017+3625 are detected with Chandra. Despite a low count statistics for some candidates, assuming plausible constraints on the absorbing column density towards the pulsars, we show that X-ray spectral properties for all of them are consistent with those observed for other pulsars. J0359+5414 is the most reliably identified object. We detect a nebula around it, whose spectrum and extent suggest that this is a pulsar wind nebula powered by the pulsar. Associations of J0002+6216 and J1844-0346 with supernova remnants CTB 1 and G28.6-0.1 are proposed.

  7. Real-time Automatic Search for Multi-wavelength Counterparts of DWF Transients

    Science.gov (United States)

    Murphy, Christopher; Cucchiara, Antonino; Andreoni, Igor; Cooke, Jeff; Hegarty, Sarah

    2018-01-01

    The Deeper Wider Faster (DWF) survey aims to find and classify the fastest transients in the Universe. DWF utilizes the Dark Energy Camera (DECam), collecting a continuous sequence of 20s images over a 3 square degree field of view.Once an interesting transient is detected during DWF observations, the DWF collaboration has access to several facilities for rapid follow-up in multiple wavelengths (from gamma to radio).An online web tool has been designed to help with real-time visual classification of possible astrophysical transients in data collected by the DWF observing program. The goal of this project is to create a python-based code to improve the classification process by querying several existing archive databases. Given the DWF transient location and search radius, the developed code will extract a list of possible counterparts and all available information (e.g. magnitude, radio fluxes, distance separation).Thanks to this tool, the human classifier can make a quicker decision in order to trigger the collaboration rapid-response resources.

  8. NEVER forget: negative emotional valence enhances recapitulation.

    Science.gov (United States)

    Bowen, Holly J; Kark, Sarah M; Kensinger, Elizabeth A

    2017-07-10

    A hallmark feature of episodic memory is that of "mental time travel," whereby an individual feels they have returned to a prior moment in time. Cognitive and behavioral neuroscience methods have revealed a neurobiological counterpart: Successful retrieval often is associated with reactivation of a prior brain state. We review the emerging literature on memory reactivation and recapitulation, and we describe evidence for the effects of emotion on these processes. Based on this review, we propose a new model: Negative Emotional Valence Enhances Recapitulation (NEVER). This model diverges from existing models of emotional memory in three key ways. First, it underscores the effects of emotion during retrieval. Second, it stresses the importance of sensory processing to emotional memory. Third, it emphasizes how emotional valence - whether an event is negative or positive - affects the way that information is remembered. The model specifically proposes that, as compared to positive events, negative events both trigger increased encoding of sensory detail and elicit a closer resemblance between the sensory encoding signature and the sensory retrieval signature. The model also proposes that negative valence enhances the reactivation and storage of sensory details over offline periods, leading to a greater divergence between the sensory recapitulation of negative and positive memories over time. Importantly, the model proposes that these valence-based differences occur even when events are equated for arousal, thus rendering an exclusively arousal-based theory of emotional memory insufficient. We conclude by discussing implications of the model and suggesting directions for future research to test the tenets of the model.

  9. A Comparative Theoretical and Computational Study on Robust Counterpart Optimization: I. Robust Linear Optimization and Robust Mixed Integer Linear Optimization

    Science.gov (United States)

    Li, Zukui; Ding, Ran; Floudas, Christodoulos A.

    2011-01-01

    Robust counterpart optimization techniques for linear optimization and mixed integer linear optimization problems are studied in this paper. Different uncertainty sets, including those studied in literature (i.e., interval set; combined interval and ellipsoidal set; combined interval and polyhedral set) and new ones (i.e., adjustable box; pure ellipsoidal; pure polyhedral; combined interval, ellipsoidal, and polyhedral set) are studied in this work and their geometric relationship is discussed. For uncertainty in the left hand side, right hand side, and objective function of the optimization problems, robust counterpart optimization formulations induced by those different uncertainty sets are derived. Numerical studies are performed to compare the solutions of the robust counterpart optimization models and applications in refinery production planning and batch process scheduling problem are presented. PMID:21935263

  10. Association of telomerase reverse transcriptase promoter mutations with clinicopathological features and prognosis of thyroid cancer: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Su X

    2016-11-01

    Full Text Available Xingyun Su,1 Xiaoxia Jiang,1 Weibin Wang,1 Haiyong Wang,1 Xin Xu,2 Aihui Lin,1 Xiaodong Teng,3 Huiling Wu,4 Lisong Teng1 1Department of Surgical Oncology, 2Department of Medical Oncology, 3Department of Pathology, 4Department of Plastic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: The clinicopathological and prognostic significance of telomerase reverse transcriptase (TERT promoter mutations have been widely investigated in thyroid cancer; however, the results are still discrepant. Systematic searches were performed in PubMed, Web of Science, Scopus, Ovid, and the Cochran Library databases for relevant articles prior to April 2016. Mutation rates were synthesized by R statistical software. The odds ratio or standardized mean difference with 95% confidence interval was pooled by Stata. A total of 22 studies with 4,907 cases were included in this meta-analysis. TERT promoter mutations tended to present in aggressive histological types including poorly differentiated thyroid cancer (33.37%, anaplastic thyroid cancer (38.69%, and tall-cell variant papillary thyroid cancer (30.23%. These promoter mutations were likely to exist in older patients and males and were well associated with larger tumor size, extrathyroidal extension, vascular invasion, lymph node metastasis, distant metastasis, advanced tumor stage, disease recurrence/persistence, and mortality. In addition, TERT promoter mutations (especially C228T tended to coexist with BRAFV600E mutation, which indicated more aggressive tumor behavior. Therefore, TERT promoter mutations may be promising biomarkers for early diagnosis, risk stratification, prognostic prediction, and management of thyroid cancer. Keywords: TERT promoter mutations, thyroid cancer, clinicopathological features, prognosis, BRAFV600E mutation

  11. MNS16A tandem repeat minisatellite of human telomerase gene: functional studies in colorectal, lung and prostate cancer.

    Science.gov (United States)

    Hofer, Philipp; Zöchmeister, Cornelia; Behm, Christian; Brezina, Stefanie; Baierl, Andreas; Doriguzzi, Angelina; Vanas, Vanita; Holzmann, Klaus; Sutterlüty-Fall, Hedwig; Gsur, Andrea

    2017-04-25

    MNS16A, a functional polymorphic tandem repeat minisatellite, is located in the promoter region of an antisense transcript of the human telomerase reverse transcriptase gene. MNS16A promoter activity depends on the variable number of tandem repeats (VNTR) presenting varying numbers of transcription factor binding sites for GATA binding protein 1. Although MNS16A has been investigated in multiple cancer epidemiology studies with incongruent findings, functional data of only two VNTRs (VNTR-243 and VNTR-302) were available thus far, linking the shorter VNTR to higher promoter activity.For the first time, we investigated promoter activity of all six VNTRs of MNS16A in cell lines of colorectal, lung and prostate cancer using Luciferase reporter assay. In all investigated cell lines shorter VNTRs showed higher promoter activity. While this anticipated indirect linear relationship was affirmed for colorectal cancer SW480 (P = 0.006), a piecewise linear regression model provided significantly better model fit in lung cancer A-427 (P = 6.9 × 10-9) and prostate cancer LNCaP (P = 0.039). In silico search for transcription factor binding sites in MNS16A core repeat element suggested a higher degree of complexity involving X-box binding protein 1, general transcription factor II-I, and glucocorticoid receptor alpha in addition to GATA binding protein 1.Further functional studies in additional cancers are requested to extend our knowledge of MNS16A functionality uncovering potential cancer type-specific differences. Risk alleles may vary in different malignancies and their determination in vitro could be relevant for interpretation of genotype data.

  12. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways.

    Science.gov (United States)

    Kashafi, Elham; Moradzadeh, Maliheh; Mohamadkhani, Ashraf; Erfanian, Saiedeh

    2017-05-01

    Cervical cancer is one of the most frequent cancers in women worldwide. Defects in the apoptotic pathways are responsible for both the disease pathogenesis and its therapy resistance. It is thus a good candidate for treatment by pro-apoptotic agents. Kaempferol as a flavonoid has antioxidant and anti-tumor properties. Kaempferol has been shown to induce apoptosis and cell death in cancer cells. However, due to the problems in the treatment of cervical cancer, this study is designed to investigate the molecular mechanism by which kaempferol suppresses the growth of cervical cancer HeLa cell as compared with HFF cells (normal cells). Cells treated with kaempferol (12-100μM) and 5-FU (1-10μM), as the positive control, up to 72h. Cell viability was determined by MTT assay and real time PCR was used to investigate apoptosis and telomerase genes expression. The results showed that kaempferol decreased cell viability as concentration- and time-dependently. IC 50 values were 10.48μM for HeLa and 707.00μM for HFF cells, as compared with 1.40μM and 16.38μM for 5-FU after 72h treatment, respectively. Also, kaempferol induced cellular apoptosis and aging through down-regulating the PI3K/AKT and hTERT pathways. This study suggests that kaempferol may be a useful adjuvant therapeutic agent in the treatment of cervical cancer. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma.

    Science.gov (United States)

    Annunziata, Clorinda; Pezzuto, Francesca; Greggi, Stefano; Ionna, Franco; Losito, Simona; Botti, Gerardo; Buonaguro, Luigi; Buonaguro, Franco M; Tornesello, Maria Lina

    2018-03-31

    Two recurrent mutations (-124 G > A and -146 G > A) in the core promoter region of the human telomerase reverse transcriptase (TERT) gene create consensus binding sites for ETS transcription factors and cause increased TERT expression in several tumour types. We analyzed TERT promoter mutations and TERT mRNA levels in head and neck cancer, cervical carcinoma and cervical intraepithelial neoplasia (CIN) as well as in C-4I, CaSki, HeLa and SiHa cervical cell lines. Nucleotide sequence analysis of TERT promoter region showed that 33.3% of oral squamous cell carcinoma (SCC) and 16.8% of cervical SCC harboured mutually exclusive G to A transitions at nucleotide position -124 or -146. TERT promoter was mutated at nucleotide -146 (G > A) in SiHa cell line. Other nucleotide changes creating in some cases putative ETS binding sites were more frequent in oral SCC (26.7%) than in cervical carcinoma (4.8%). The frequency of mutations was independent of human papillomavirus (HPV) tumour status in both cervical and oral cancer. Expression of TERT gene was significantly higher in TERT promoter mutated (-124G > A or -146G > A) cervical SCC compared to not mutated SCC irrespective of HPV16 E6 and E7 levels. Such hot spot changes were not detected in oropharyngeal SCC, cervical adenocarcinoma and CIN lesions. Our results suggest that TERT promoter mutations play a relevant role in oral SCC as well as in cervical SCC, besides the already known effect of HPV16 E6 protein on TERT expression. © 2018 UICC.

  14. Energetic particle counterparts for geomagnetic pulsations of Pc1 and IPDP types

    Directory of Open Access Journals (Sweden)

    T. A. Yahnina

    Full Text Available Using the low-altitude NOAA satellite particle data, we study two kinds of localised variations of energetic proton fluxes at low altitude within the anisotropic zone equatorward of the isotropy boundary. These flux variation types have a common feature, i.e. the presence of precipitating protons measured by the MEPED instrument at energies more than 30 keV, but they are distinguished by the fact of the presence or absence of the lower-energy component as measured by the TED detector on board the NOAA satellite. The localised proton precipitating without a low-energy component occurs mostly in the morning-day sector, during quiet geomagnetic conditions, without substorm injections at geosynchronous orbit, and without any signatures of plasmaspheric plasma expansion to the geosynchronous distance. This precipitation pattern closely correlates with ground-based observations of continuous narrow-band Pc1 pulsations in the frequency range 0.1–2 Hz (hereafter Pc1. The precipitation pattern containing the low energy component occurs mostly in the evening sector, under disturbed geomagnetic conditions, and in association with energetic proton injections and significant increases of cold plasma density at geosynchronous orbit. This precipitation pattern is associated with geomagnetic pulsations called Intervals of Pulsations with Diminishing Periods (IPDP, but some minor part of the events is also related to narrow-band Pc1. Both Pc1 and IPDP pulsations are believed to be the electromagnetic ion-cyclotron waves generated by the ion-cyclotron instability in the equatorial plane. These waves scatter energetic protons in pitch angles, so we conclude that the precipitation patterns studied here are the particle counterparts of the ion-cyclotron waves.

    Key words. Ionosphere (particle precipitation – Magnetospheric physics (energetic particles, precipitating – Space plasma physics (wave-particle interactions

  15. Energetic particle counterparts for geomagnetic pulsations of Pc1 and IPDP types

    Directory of Open Access Journals (Sweden)

    T. A. Yahnina

    2003-12-01

    Full Text Available Using the low-altitude NOAA satellite particle data, we study two kinds of localised variations of energetic proton fluxes at low altitude within the anisotropic zone equatorward of the isotropy boundary. These flux variation types have a common feature, i.e. the presence of precipitating protons measured by the MEPED instrument at energies more than 30 keV, but they are distinguished by the fact of the presence or absence of the lower-energy component as measured by the TED detector on board the NOAA satellite. The localised proton precipitating without a low-energy component occurs mostly in the morning-day sector, during quiet geomagnetic conditions, without substorm injections at geosynchronous orbit, and without any signatures of plasmaspheric plasma expansion to the geosynchronous distance. This precipitation pattern closely correlates with ground-based observations of continuous narrow-band Pc1 pulsations in the frequency range 0.1–2 Hz (hereafter Pc1. The precipitation pattern containing the low energy component occurs mostly in the evening sector, under disturbed geomagnetic conditions, and in association with energetic proton injections and significant increases of cold plasma density at geosynchronous orbit. This precipitation pattern is associated with geomagnetic pulsations called Intervals of Pulsations with Diminishing Periods (IPDP, but some minor part of the events is also related to narrow-band Pc1. Both Pc1 and IPDP pulsations are believed to be the electromagnetic ion-cyclotron waves generated by the ion-cyclotron instability in the equatorial plane. These waves scatter energetic protons in pitch angles, so we conclude that the precipitation patterns studied here are the particle counterparts of the ion-cyclotron waves.Key words. Ionosphere (particle precipitation – Magnetospheric physics (energetic particles, precipitating – Space plasma physics (wave-particle interactions

  16. Transcriptome analysis of adiposity in domestic ducks by transcriptomic comparison with their wild counterparts.

    Science.gov (United States)

    Chen, L; Luo, J; Li, J X; Li, J J; Wang, D Q; Tian, Y; Lu, L Z

    2015-06-01

    Excessive adiposity is a major problem in the duck industry, but its molecular mechanisms remain unknown. Genetic comparisons between domestic and wild animals have contributed to the exploration of genetic mechanisms responsible for many phenotypic traits. Significant differences in body fat mass have been detected between domestic and wild ducks. In this study, we used the Peking duck and Anas platyrhynchos as the domestic breed and wild counterpart respectively and performed a transcriptomic comparison of abdominal fat between the two breeds to comprehensively analyze the transcriptome basis of adiposity in ducks. We obtained approximately 350 million clean reads; assembled 61 250 transcripts, including 23 699 novel ones; and identified alternative 5' splice sites, alternative 3' splice sites, skipped exons and retained intron as the main alternative splicing events. A differential expression analysis between the two breeds showed that 753 genes exhibited differential expression. In Peking ducks, some lipid metabolism-related genes (IGF2, FABP5, BMP7, etc.) and oncogenes (RRM2, AURKA, CYR61, etc.) were upregulated, whereas genes related to tumor suppression and immunity (TNFRSF19, TNFAIP6, IGSF21, NCF1, etc.) were downregulated, suggesting adiposity might closely associate with tumorigenesis in ducks. Furthermore, 280 576 single-nucleotide variations were found differentiated between the two breeds, including 8641 non-synonymous ones, and some of the non-synonymous ones were found enriched in genes involved in lipid-associated and immune-associated pathways, suggesting abdominal fat of the duck undertakes both a metabolic function and immune-related function. These datasets enlarge our genetic information of ducks and provide valuable resources for analyzing mechanisms underlying adiposity in ducks. © 2015 Stichting International Foundation for Animal Genetics.

  17. Independent introductions and admixtures have contributed to adaptation of European maize and its American counterparts.

    Directory of Open Access Journals (Sweden)

    Jean-Tristan Brandenburg

    2017-03-01

    Full Text Available Through the local selection of landraces, humans have guided the adaptation of crops to a vast range of climatic and ecological conditions. This is particularly true of maize, which was domesticated in a restricted area of Mexico but now displays one of the broadest cultivated ranges worldwide. Here, we sequenced 67 genomes with an average sequencing depth of 18x to document routes of introduction, admixture and selective history of European maize and its American counterparts. To avoid the confounding effects of recent breeding, we targeted germplasm (lines directly derived from landraces. Among our lines, we discovered 22,294,769 SNPs and between 0.9% to 4.1% residual heterozygosity. Using a segmentation method, we identified 6,978 segments of unexpectedly high rate of heterozygosity. These segments point to genes potentially involved in inbreeding depression, and to a lesser extent to the presence of structural variants. Genetic structuring and inferences of historical splits revealed 5 genetic groups and two independent European introductions, with modest bottleneck signatures. Our results further revealed admixtures between distinct sources that have contributed to the establishment of 3 groups at intermediate latitudes in North America and Europe. We combined differentiation- and diversity-based statistics to identify both genes and gene networks displaying strong signals of selection. These include genes/gene networks involved in flowering time, drought and cold tolerance, plant defense and starch properties. Overall, our results provide novel insights into the evolutionary history of European maize and highlight a major role of admixture in environmental adaptation, paralleling recent findings in humans.

  18. Optical Counterparts for Low-Luminosity X-ray Sources in Omega Centauri

    Science.gov (United States)

    Cool, Adrienne

    2002-07-01

    We propose to use narrow-band HAlpha imaging with ACS to search for the optical counterparts of low-luminosity X-ray sources {Lx 2 x 10^30 - 5 x 10^32 erg/s} in the globular cluster Omega Centauri. With 9 WFC fields, we will cover the inner two core radii of the cluster, and encompass about 90 of the faint sources we have identified with Chandra. Approximately 30-50 of these sources should be cluster members, the remainder being mostly background galaxies plus a smaller number of foreground stars. This large population of low-Lx cluster X-ray sources is second only to the more than 100 faint sources recently discovered in 47 Tuc with Chandra {Grindlay et al. 2001a}, which have been identified as a mixture of cataclysmic variables, quiescent low-mass X-ray binaries, millisecond pulsars, and coronally active main-sequence binaries. Our Cycle 6 WFPC2 program successfully identified 2 of the 3 then-known faint X-ray sources in the core of Omega Cen using H-alpha imaging. We now propose to expand the areal coverage by a factor of about 18 to encompass the much larger number of sources that have since been discovered with Chandra. The extreme crowding in the central regions of Omega Cen requires the resolution of HST to obtain optical IDs. These identifications are key to making meaningful comparisons between the populations of faint X-ray sources in different clusters, in an effort to understand their origins and role in cluster dynamics.

  19. Reversal of functional disorders by aspiration, expiration and cough reflexes and their voluntary counterparts

    Directory of Open Access Journals (Sweden)

    Zoltan eTomori

    2012-12-01

    Full Text Available Agonal gasping provoked by asphyxia can save ~15% of mammals even from untreated ventricular fibrillation, but it fails to revive infants with sudden infant death syndrome. Our systematic study of airway reflexes in cats and other animals indicated that in addition to cough, there are 2 distinct airway reflexes that may contribute to auto-resuscitation. Gasp- and sniff-like spasmodic inspirations can be elicited by nasopharyngeal stimulation, strongly activating the brainstem generator for inspiration, which is also involved in the control of gasping. This aspiration reflex (AspR is characterized by spasmodic inspiration without subsequent active expiration and can be elicited during agonal gasping, caused by brainstem trans-sections in cats. Stimulation of the larynx can activate the generator for expiration to evoke the expiration reflex, manifesting with prompt expiration without preceding inspiration. Stimulation of the oro-pharynx and lower airways provokes the cough reflex which results from activating of both generators. The powerful potential of the AspR resembling auto-resuscitation by gasping can influence the control mechanisms of vital functions, mediating reversal of various functional disorders.The AspR in cats interrupted hypoxic apnea, laryngo- and bronchospasm, apneusis and even transient asphyxic coma, and can normalize various hypo- and hyper-functional disorders. Introduction of a nasogastric catheter evoked similar spasmodic inspirations in premature infants and interrupted hiccough attacks in adults. Coughing on demand can prevent anaphylactic shock and resuscitate the pertinent subject. Sniff representing nasal inspiratory pressure and maximal inspiratory and expiratory pressures are voluntary counterparts of airway reflexes, and are useful for diagnosis and therapy of various cardio-respiratory and neuromuscular disorders.

  20. Multiband counterparts of two eclipsing ultraluminous X-ray sources in M 51

    Science.gov (United States)

    Urquhart, R.; Soria, R.; Johnston, H. M.; Pakull, M. W.; Motch, C.; Schwope, A.; Miller-Jones, J. C. A.; Anderson, G. E.

    2018-04-01

    We present the discovery and interpretation of ionized nebulae around two ultraluminous X-ray sources in M 51; both sources share the rare property of showing X-ray eclipses by their companion stars and are therefore prime targets for follow-up studies. Using archival Hubble Space Telescope images, we found an elongated, 100-pc-long emission-line structure associated with one X-ray source (CXOM51 J132940.0+471237; ULX-1 for simplicity), and a more circular, ionized nebula at the location of the second source (CXOM51 J132939.5+471244; ULX-2 for simplicity). We observed both nebulae with the Large Binocular Telescope's Multi-Object Double Spectrograph. From our analysis of the optical spectra, we argue that the gas in the ULX-1 bubble is shock-ionized, consistent with the effect of a jet with a kinetic power of ≈2 × 1039 erg s-1. Additional X-ray photoionization may also be present, to explain the strength of high-ionization lines such as He II λ4686 and [Ne V] λ3426. On the other hand, the emission lines from the ULX-2 bubble are typical for photoionization by normal O stars suggesting that the nebula is actually an H II region not physically related to the ULX but is simply a chance alignment. From archival Very Large Array data, we also detect spatially extended, steep-spectrum radio emission at the location of the ULX-1 bubble (consistent with its jet origin), but no radio counterpart for ULX-2 (consistent with the lack of shock-ionized gas around that source).

  1. THE X-RAY COUNTERPART OF THE HIGH-B PULSAR PSR J0726–2612

    International Nuclear Information System (INIS)

    Speagle, J. S.; Kaplan, D. L.; Van Kerkwijk, M. H.

    2011-01-01

    Middle-aged, cooling neutron stars are observed both as relatively rapidly spinning radio pulsars and as more slowly spinning, strongly magnetized isolated neutron stars (INSs), which stand out by their thermal X-ray spectra. The difference between the two classes may be that the INSs initially had much stronger magnetic fields, which decayed. To test this, we used the Chandra X-ray Observatory to observe 1RXS J072559.8–261229, a possible X-ray counterpart to PSR J0726–2612, which, with its 3.44 s period and 3 × 10 13 G inferred magnetic field strength, is the nearest and least extincted among the possible slowly spinning, strong-field INS progenitors (it likely is in the Gould Belt, at ∼1 kpc). We confirm the identification and find that the pulsar has a spectrum consistent with being purely thermal, with blackbody temperature kT = 87 ± 5 eV and radius R = 5.7 +2.6 –1.3 km at a distance of 1 kpc. We detect sinusoidal pulsations at twice the radio period with a semi-amplitude of 27% ± 5%. The properties of PSR J0726–2612 strongly resemble those of the INSs, except for its much shorter characteristic age of 200 kyr (instead of several Myr). We conclude that PSR J0726–2612 is indeed an example of a young INS, one that started with a magnetic field strength on the low end of those inferred for the INSs, and that, therefore, decayed by a relatively small amount. Our results suggest that the long-period, strong-field pulsars and the INSs are members of the same class, and open up new opportunities to understand the puzzling X-ray and optical emission of the INSs through radio observations of PSR J0726–2612.

  2. THE X-RAY COUNTERPART OF THE HIGH-B PULSAR PSR J0726-2612

    Energy Technology Data Exchange (ETDEWEB)

    Speagle, J. S.; Kaplan, D. L. [Physics Department, University of Wisconsin-Milwaukee, Milwaukee, WI 53211 (United States); Van Kerkwijk, M. H., E-mail: kaplan@uwm.edu, E-mail: joshuaspeagle@college.harvard.edu, E-mail: mhvk@astro.utoronto.ca [Department of Astronomy and Astrophysics, University of Toronto, 60 St. George Street, Toronto, ON M5S 3H8 (Canada)

    2011-12-20

    Middle-aged, cooling neutron stars are observed both as relatively rapidly spinning radio pulsars and as more slowly spinning, strongly magnetized isolated neutron stars (INSs), which stand out by their thermal X-ray spectra. The difference between the two classes may be that the INSs initially had much stronger magnetic fields, which decayed. To test this, we used the Chandra X-ray Observatory to observe 1RXS J072559.8-261229, a possible X-ray counterpart to PSR J0726-2612, which, with its 3.44 s period and 3 Multiplication-Sign 10{sup 13} G inferred magnetic field strength, is the nearest and least extincted among the possible slowly spinning, strong-field INS progenitors (it likely is in the Gould Belt, at {approx}1 kpc). We confirm the identification and find that the pulsar has a spectrum consistent with being purely thermal, with blackbody temperature kT = 87 {+-} 5 eV and radius R = 5.7{sup +2.6}{sub -1.3} km at a distance of 1 kpc. We detect sinusoidal pulsations at twice the radio period with a semi-amplitude of 27% {+-} 5%. The properties of PSR J0726-2612 strongly resemble those of the INSs, except for its much shorter characteristic age of 200 kyr (instead of several Myr). We conclude that PSR J0726-2612 is indeed an example of a young INS, one that started with a magnetic field strength on the low end of those inferred for the INSs, and that, therefore, decayed by a relatively small amount. Our results suggest that the long-period, strong-field pulsars and the INSs are members of the same class, and open up new opportunities to understand the puzzling X-ray and optical emission of the INSs through radio observations of PSR J0726-2612.

  3. Life-cycle Analysis of Bioproducts and Their Conventional Counterparts in GREET

    Energy Technology Data Exchange (ETDEWEB)

    Dunn, Jennifer B. [Argonne National Lab. (ANL), Argonne, IL (United States); Adom, Felix [Argonne National Lab. (ANL), Argonne, IL (United States); Sather, Norm [Argonne National Lab. (ANL), Argonne, IL (United States); Han, Jeongwoo [Argonne National Lab. (ANL), Argonne, IL (United States); Snyder, Seth [Argonne National Lab. (ANL), Argonne, IL (United States); He, Chang [Northwestern Univ., Evanston, IL (United States); Gong, Jian [Northwestern Univ., Evanston, IL (United States); Yue, Dajun [Northwestern Univ., Evanston, IL (United States); You, Fengqi [Northwestern Univ., Evanston, IL (United States)

    2015-09-01

    To further expand upon the literature in this field and to develop a platform for bioproduct LCA, we developed LCA results for ten bioproducts produced either from algal glycerol or from corn stover-derived sugars. We used Argonne National Laboratory’s Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREETTM) model as the platform for this study. The data and calculations reported herein are available to GREET users in a bioproducts module included in the fall 2015 GREET release. This report documents our approach to this analysis and the results. In Chapter 2, we review the process we underwent to select the bioproducts for analysis based on market and technology readiness criteria. In Chapter 3, we review key parameters for production of the two feedstocks we considered: corn stover and algae. Given the lack of publicly available information about the production of bioproducts, which is caused in large part by the emerging nature of the industry, we developed Aspen Plus® simulations of the processes that could be used to produce each bioproduct. From these simulations, we extracted the energy and material flows of these processes, which were important inputs to the GREET bioproducts module. Chapter 4 provides the details of these Aspen Plus simulations. It is important to compare the LCA results for bioproducts to those for their petroleum counterparts. We therefore also developed material and energy flow data for conventional products based mostly on the literature. These data are described in Chapter 5 and are also included in the GREET bioproducts module. In Chapter 6, we present results from this analysis and examine areas for refinement and future research.

  4. Negative-ion states

    International Nuclear Information System (INIS)

    Compton, R.N.

    1982-01-01

    In this brief review, we discuss some of the properties of atomic and molecular negative ions and their excited states. Experiments involving photon reactions with negative ions and polar dissociation are summarized. 116 references, 14 figures

  5. Negative ion detachment processes

    International Nuclear Information System (INIS)

    Champion, R.L.; Doverspike, L.D.

    1990-10-01

    This paper discusses the following topics: H - and D - collisions with atomic hydrogen; collisional decomposition of SF 6 - ; two-electron loss processes in negative ion collisions; associative electron detachment; and negative ion desorption from surfaces

  6. Sentential Negation in English

    Science.gov (United States)

    Mowarin, Macaulay

    2009-01-01

    This paper undertakes a detailed analysis of sentential negation in the English language with Chomsky's Government-Binding theory of Transformational Grammar as theoretical model. It distinguishes between constituent and sentential negation in English. The essay identifies the exact position of Negation phrase in an English clause structure. It…

  7. Negative ion sources

    International Nuclear Information System (INIS)

    Ishikawa, Junzo; Takagi, Toshinori

    1983-01-01

    Negative ion sources have been originally developed at the request of tandem electrostatic accelerators, and hundreds of nA to several μA negative ion current has been obtained so far for various elements. Recently, the development of large current hydrogen negative ion sources has been demanded from the standpoint of the heating by neutral particle beam injection in nuclear fusion reactors. On the other hand, the physical properties of negative ions are interesting in the thin film formation using ions. Anyway, it is the present status that the mechanism of negative ion action has not been so fully investigated as positive ions because the history of negative ion sources is short. In this report, the many mechanisms about the generation of negative ions proposed so far are described about negative ion generating mechanism, negative ion source plasma, and negative ion generation on metal surfaces. As a result, negative ion sources are roughly divided into two schemes, plasma extraction and secondary ion extraction, and the former is further classified into the PIG ion source and its variation and Duoplasmatron and its variation; while the latter into reflecting and sputtering types. In the second half of the report, the practical negative ion sources of each scheme are described. If the mechanism of negative ion generation will be investigated more in detail and the development will be continued under the unified know-how as negative ion sources in future, the development of negative ion sources with which large current can be obtained for any element is expected. (Wakatsuki, Y.)

  8. Polemic and Descriptive Negations

    DEFF Research Database (Denmark)

    Horslund, Camilla Søballe

    2011-01-01

    to semantics and pragmatics, negations can be used in three different ways, which gives rise to a typology of three different types of negations: 1) the descriptive negation, 2) the polemic negation, and 3) the meta-linguistic negation (Nølke 1999, 4). This typology illuminates the fact that the negation...... common in certain social context or genres, while polemic negations are more likely to come up in other genres and social settings. Previous studies have shown a relation between articulatory prominence and register, which may further inform the analysis. Hence, the paper investigates how articulatory...... prominence and register may either work in concert or oppose each other with respect to the cues they provide for the interpretation....

  9. Apoptosis and reduced cell proliferation of HL-60 cell line caused by human telomerase reverse transcriptase inhibition by siRNA.

    Science.gov (United States)

    Miri-Moghaddam, Ebrahim; Deezagi, Abdolkhaleg; Soheili, Zahra Sohaila; Shariati, Parvin

    2010-01-01

    The close correlation between telomerase activity and human telomerase reverse transcriptase (hTERT) expression has made hTERT to be considered as a selective molecular target for human cancer therapy. In this study, the ability of short-interfering RNA (siRNA) to downregulate hTERT expression and its correlation with cell growth and apoptosis in the promyelocytic cell line HL-60 was evaluated. hTERT siRNA was designed and transfected to HL-60. hTERT mRNA expression, cell proliferation and apoptotic cells were measured. The results indicated that hTERT siRNA resulted in 97.2 ± 0.6% downregulation of the hTERT mRNA content; inhibition of the cell proliferation rate was about 52.8 ± 2.3% and the apoptotic index of cells was 30.5 ± 1.5%. hTERT plays an essential role in cell proliferation and control of the viability of leukemic cells, thus promising the development of drugs for leukemia. Copyright © 2010 S. Karger AG, Basel.

  10. Fluorescence detection of DNA, adenosine-5'-triphosphate (ATP), and telomerase activity by zinc(II)-protoporphyrin IX/G-quadruplex labels.

    Science.gov (United States)

    Zhang, Zhanxia; Sharon, Etery; Freeman, Ronit; Liu, Xiaoqing; Willner, Itamar

    2012-06-05

    The zinc(II)-protoporphyrin IX (ZnPPIX) fluorophore binds to G-quadruplexes, and this results in the enhanced fluorescence of the fluorophore. This property enabled the development of DNA sensors, aptasensors, and a sensor following telomerase activity. The DNA sensor is based on the design of a hairpin structure that includes a "caged" inactive G-quadruplex sequence. Upon opening the hairpin by the analyte DNA, the resulting fluorescence of the ZnPPIX/G-quadruplex provides the readout signal for the sensing event (detection limit 5 nM). Addition of Exonuclease III to the system allows the recycling of the analyte and its amplified analysis (detection limit, 200 pM). The association of the ZnPPIX to G-quadruplex aptamer-substrate complexes allowed the detection of adenosine-5'-triphosphate (ATP, detection limit 10 μM). Finally, the association of ZnPPIX to the G-quadruplex repeat units of telomers allowed the detection of telomerase activity originating from 380 ± 20 cancer 293T cell extract.

  11. Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite of extensive proliferation

    International Nuclear Information System (INIS)

    Abdallah, Basem M.; Haack-Sorensen, Mandana; Burns, Jorge S.; Elsnab, Birgitte; Jakob, Franz; Hokland, Peter; Kassem, Moustapha

    2005-01-01

    Human bone marrow mesenchymal stem cells (hMSC) represent a population of stem cells that are capable of differentiation into multiple lineages. However, these cells exhibit senescence-associated growth arrest and phenotypic changes during long-term in vitro culture. We have recently demonstrated that overexpression of human telomerase reverse transcriptase (hTERT) in hMSC reconstitutes telomerase activity and extends life span of the cells [Nat. Biotechnol. 20 (2002) 592]. In the present study, we have performed extensive characterization of three independent cell lines derived from the parental hMSC-TERT cell line based on different plating densities during expansion in culture: 1:2 (hMSC-TERT2), 1:4 (hMSC-TERT4), and 1:20 (hMSC-TERT20). The 3 cell lines exhibited differences in morphology and growth rates but they all maintained the characteristics of self-renewing stem cells and the ability to differentiate into multiple mesoderm-type cell lineages: osteoblasts, adipocytes, chondrocytes, and endothelial-like cells over a 3-year period in culture. Also, surface marker studies using flow cytometry showed a pattern similar to that known from normal hMSC. Thus, telomerization of hMSC by hTERT overexpression maintains the stem cell phenotype of hMSC and it may be a useful tool for obtaining enough number of cells with a stable phenotype for mechanistic studies of cell differentiation and for tissue engineering protocols

  12. Risk of progression of early cervical lesions is associated with integration and persistence of HPV-16 and expression of E6, Ki-67, and telomerase

    Directory of Open Access Journals (Sweden)

    Arianna Vega-Peña

    2013-01-01

    Full Text Available Background: Low-grade squamous intraepithelial lesions (LSIL are the earliest lesions of the uterine cervix, the persistence and integration of high-risk human papillomavirus (HR-HPV as type 16, which promotes the development of more aggressive lesions. Aim: To select more aggressive lesions with tendency to progress to invasive cervical cancer. Materials and Methods: A total of 75 cytological specimens in liquid base (Liqui-PREP were analyzed: 25 specimens were with no signs of SIL (NSIL and without HPV; 25 NSIL with HPV-16, and 25 with both LSIL and HPV-16. The expression of Ki-67, telomerase, and viral E6 was evaluated by immunocytochemistry; and the detection of viral DNA was done by polymerase chain reaction (PCR and restriction fragment length polymorphism (RFLPs for genotyping or sequencing of HPV-16. The physical state of HPV-16 was evaluated by in situ hybridization with amplification with tyramide. Results: Of the total group, 58.6% had LSIL associated with persistence and of these 59.3% was associated with integrated state of HPV as intense expression of E6, Ki-67 (P = 0.013, P = 0.055 has except for the expression of telomerase present a non-significant association (P<0.341. Conclusions: Overexpression of E6 and Ki-67 is associated with the integration of HPV-16, favoring viral persistence, and increasing the risk of progression in women with NSIL and LSIL.

  13. Search for the NIR counterpart to GRB130807A/SWIFTJ1759.2-2736 in quiescence

    NARCIS (Netherlands)

    Greiss, S.; Steeghs, D.; Jonker, P.G.; Maccarone, T.; Torres, M.A.P.; Heinke, C.; Wijnands, R.

    2013-01-01

    In order to search for the counterpart of the transient source SWIFTJ1759.2-2736 (Atel #5268), we investigated near-infrared (NIR) data of the Galactic Bulge region obtained as part of the VVV survey (Minniti et al. 2010, New Astronomy, Volume 15, 433). The observations took place while the source

  14. The second Herschel-ATLAS Data Release - III. Optical and near-infrared counterparts in the North Galactic Plane field

    Science.gov (United States)

    Furlanetto, C.; Dye, S.; Bourne, N.; Maddox, S.; Dunne, L.; Eales, S.; Valiante, E.; Smith, M. W.; Smith, D. J. B.; Ivison, R. J.; Ibar, E.

    2018-05-01

    This paper forms part of the second major public data release of the Herschel Astrophysical Terahertz Large Area Survey (H-ATLAS). In this work, we describe the identification of optical and near-infrared counterparts to the submillimetre detected sources in the 177 deg2 North Galactic Plane (NGP) field. We used the likelihood ratio method to identify counterparts in the Sloan Digital Sky Survey and in the United Kingdom InfraRed Telescope Imaging Deep Sky Survey within a search radius of 10 arcsec of the H-ATLAS sources with a 4σ detection at 250 μm. We obtained reliable (R ≥ 0.8) optical counterparts with r performance of the likelihood ratio method to identify optical and near-infrared counterparts taking into account the depth and area of both input catalogues. Using catalogues with the same surface density of objects in the overlapping ˜25 deg2 area, we obtained that the reliable fraction in the near-infrared (54.8 per cent) is significantly higher than in the optical (36.4 per cent). Finally, using deep radio data which covers a small region of the NGP field, we found that 80-90 per cent of our reliable identifications are correct.

  15. Aggression as a Motive for Gossip During Conflict : The Role of Power, Social Value Orientation, and Counterpart's Behavior

    NARCIS (Netherlands)

    Jeuken, E.; Beersma, B.; ten Velden, F.S.; Dijkstra, M.T.M.

    Not much is known about the motives behind the use of gossip in conflict situations. We report a laboratory experiment that examined the influence of social value orientation, counterpart's behavior, and power on the motive to use gossip for indirect aggression in a conflict situation. Results

  16. Aggression as a motive for gossip during conflict: The role of power, social value orientation, and counterpart's behavior

    NARCIS (Netherlands)

    Jeuken, A. E.; Beersma, B.; Ten Velden, F.S.; Dijkstra, M.T.M.

    2015-01-01

    Not much is known about the motives behind the use of gossip in conflict situations. We report a laboratory experiment that examined the influence of social value orientation, counterpart's behavior, and power on the motive to use gossip for indirect aggression in a conflict situation. Results

  17. THE SUB-mJy RADIO POPULATION OF THE E-CDFS: OPTICAL AND INFRARED COUNTERPART IDENTIFICATION

    Energy Technology Data Exchange (ETDEWEB)

    Bonzini, M.; Mainieri, V.; Padovani, P.; Rosati, P. [ESO, Karl-Schwarzschild-Strasse 2, D-85748 Garching (Germany); Kellermann, K. I. [National Radio Astronomy Observatory, 520 Edgemont Road, Charlottesville, VA 22903-2475 (United States); Miller, N. [Department of Astronomy, University of Maryland, College Park, MD 20742-2421 (United States); Tozzi, P.; Balestra, I. [INAF Osservatorio Astronomico di Trieste, via G.B. Tiepolo 11, I-34131, Trieste (Italy); Vattakunnel, S. [Dipartimento di Fisica Universit di Trieste, piazzale Europa 1, I-34127 Trieste (Italy); Brandt, W. N.; Luo, B. [Department of Astronomy and Astrophysics, Pennsylvania State University, University Park, PA 16802 (United States); Xue, Y. Q., E-mail: mbonzini@eso.org [Key Laboratory for Research in Galaxies and Cosmology, Department of Astronomy, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui 230026 (China)

    2012-11-15

    We study a sample of 883 sources detected in a deep Very Large Array survey at 1.4 GHz in the Extended Chandra Deep Field South. This paper focuses on the identification of their optical and infrared (IR) counterparts. We use a likelihood-ratio technique that is particularly useful when dealing with deep optical images to minimize the number of spurious associations. We find a reliable counterpart for 95% of our radio sources. Most of the counterparts (74%) are detected at optical wavelengths, but there is a significant fraction (21%) that are only detectable in the IR. Combining newly acquired optical spectra with data from the literature, we are able to assign a redshift to 81% of the identified radio sources (37% spectroscopic). We also investigate the X-ray properties of the radio sources using the Chandra 4 Ms and 250 ks observations. In particular, we use a stacking technique to derive the average properties of radio objects undetected in the Chandra images. The results of our analysis are collected in a new catalog containing the position of the optical/IR counterpart, the redshift information, and the X-ray fluxes. It is the deepest multi-wavelength catalog of radio sources, which will be used for future study of this galaxy population.

  18. The Effect of Counterpart Material on the Sliding Wear of TiAlN Coatings Deposited by Reactive Cathodic Pulverization

    Directory of Open Access Journals (Sweden)

    Michell Felipe Cano Ordoñez

    2015-11-01

    Full Text Available This work aims to study the effect of the counterpart materials (100Cr6, Al2O3 and WC-Co on the tribological properties of TiAlN thin films deposited on AISI H13 steel substrate by reactive magnetron co-sputtering. The structural characterization of the TiAlN films, performed by X-ray diffraction, showed (220 textured fcc crystalline structure. The values of hardness and elastic modulus obtained by nanoindentation were 27 GPa and 420 GPa, respectively, which resulted in films with a relatively high resistance to plastic deformation. Ball-on-disk sliding tests were performed using normal loads of 1 N and 3 N, and 0.10 m/s of tangential velocity. The wear coefficient of the films was determined by measuring the worn area using profilometry every 1000 cycles. The mechanical properties and the chemical stability of the counterpart material, debris formation and the contact stress influences the friction and the wear behavior of the studied tribosystems. Increasing the hardness of the counterpart decreases the coefficient of friction (COF due to lower counterpart material transference and tribofilm formation, which is able to support the contact pressure. High shear stress concentration at the coating/substrate interface was reported for higher load promoting failure of the film-substrate system for all tribopairs

  19. Post-test analysis of the ROSA/LSTF and PKL counterpart test

    Energy Technology Data Exchange (ETDEWEB)

    Carlos, S., E-mail: scarlos@iqn.upv.es [Departament d’Enginyeria Química i Nuclear, Universitat Politècnica de València, Camí de Vera, 14, València Spain (Spain); Querol, A., E-mail: anquevi@iqn.upv.es [Departament d’Enginyeria Química i Nuclear, Universitat Politècnica de València, Camí de Vera, 14, València Spain (Spain); Instituto de Seguridad Industrial, Radiofísica y Medioambiental, Universitat Politècnica de València, Camí de Vera, 14, València (Spain); Gallardo, S., E-mail: sergalbe@iqn.upv.es [Departament d’Enginyeria Química i Nuclear, Universitat Politècnica de València, Camí de Vera, 14, València Spain (Spain); Instituto de Seguridad Industrial, Radiofísica y Medioambiental, Universitat Politècnica de València, Camí de Vera, 14, València (Spain); Sanchez-Saez, F., E-mail: frasansa@etsii.upv.es [Departament d’Enginyeria Química i Nuclear, Universitat Politècnica de València, Camí de Vera, 14, València Spain (Spain); and others

    2016-02-15

    Highlights: • TRACE modelization for PKL and ROSA/LSTF installations. • Secondary-side depressurization as accident management action. • CET vs PCT relation. • Analysis of differences in the vessel models. - Abstract: Experimental facilities are scaled models of commercial nuclear power plants, and are of great importance to improve nuclear power plants safety. Thus, the results obtained in the experiments undertaken in such facilities are essential to develop and improve the models implemented in the thermal-hydraulic codes, which are used in safety analysis. The experiments and inter-comparisons of the simulated results are usually performed in the frame of international programmes in which different groups of several countries simulate the behaviour of the plant under the accidental conditions established, using different codes and models. The results obtained are compared and studied to improve the knowledge on codes performance and nuclear safety. Thus, the Nuclear Energy Agency (NEA), in the nuclear safety work area, auspices several programmes which involve experiments in different experimental facilities. Among the experiments proposed in NEA programmes, one on them consisted of performing a counterpart test between ROSA/LSTF and PKL facilities, with the main objective of determining the effectiveness of late accident management actions in a small break loss of coolant accident (SBLOCA). This study was proposed as a result of the conclusion obtained by the NEA Working Group on the Analysis and Management of Accidents, which analyzed different installations and observed differences in the measurements of core exit temperature (CET) and maximum peak cladding temperature (PCT). In particular, the transient consists of a small break loss of coolant accident (SBLOCA) in a hot leg with additional failure of safety systems but with accident management measures (AM), consisting of a fast secondary-side depressurization, activated by the CET. The paper

  20. Post-test analysis of the ROSA/LSTF and PKL counterpart test

    International Nuclear Information System (INIS)

    Carlos, S.; Querol, A.; Gallardo, S.; Sanchez-Saez, F.

    2016-01-01

    Highlights: • TRACE modelization for PKL and ROSA/LSTF installations. • Secondary-side depressurization as accident management action. • CET vs PCT relation. • Analysis of differences in the vessel models. - Abstract: Experimental facilities are scaled models of commercial nuclear power plants, and are of great importance to improve nuclear power plants safety. Thus, the results obtained in the experiments undertaken in such facilities are essential to develop and improve the models implemented in the thermal-hydraulic codes, which are used in safety analysis. The experiments and inter-comparisons of the simulated results are usually performed in the frame of international programmes in which different groups of several countries simulate the behaviour of the plant under the accidental conditions established, using different codes and models. The results obtained are compared and studied to improve the knowledge on codes performance and nuclear safety. Thus, the Nuclear Energy Agency (NEA), in the nuclear safety work area, auspices several programmes which involve experiments in different experimental facilities. Among the experiments proposed in NEA programmes, one on them consisted of performing a counterpart test between ROSA/LSTF and PKL facilities, with the main objective of determining the effectiveness of late accident management actions in a small break loss of coolant accident (SBLOCA). This study was proposed as a result of the conclusion obtained by the NEA Working Group on the Analysis and Management of Accidents, which analyzed different installations and observed differences in the measurements of core exit temperature (CET) and maximum peak cladding temperature (PCT). In particular, the transient consists of a small break loss of coolant accident (SBLOCA) in a hot leg with additional failure of safety systems but with accident management measures (AM), consisting of a fast secondary-side depressurization, activated by the CET. The paper

  1. Comparing the mental health of rural-to-urban migrant children and their counterparts in china: Protocol for a systematic review and meta-analysis.

    Science.gov (United States)

    Zhang, Jun-Hua; Yan, Li-Xia; Yuan, Yang

    2018-04-01

    In recent years, the issue of migrant children with peasant parents working in cities has attracted widespread attention in recent years because of the sheer number and the benefits bundled in China's household. The focus has gradually extended from early education opportunities to all aspects of physical and mental development, especially the social adaptation and mental health of migrant children. The negative impact of environment changes on migrant children' mental health is very worrying for parents and the society. Some studies have found that immigrant children's mental health is significantly lower than their peers, but there are also studies that hold the opposite view. Thus, the mental health status of migrant children is still a controversial issue, which may have a certain relationship with the potential differences in the specific problems of mental health, regions, comparison objects, and researchers. The objective of this protocol is to investigate whether mental health and subdimensions differ between rural-to-urban migrant children and their counterparts living in China and examine study characteristics that might result in differences among studies. We will search PubMed, Embase, OVID, ERIC, Web of Science, and Chinese databases including CNKI, Chongqing VIP, and Wan Fang data from start to April 2018. Cross-sectional studies with a comparison of migrant children and their counterparts will be included. The primary outcome will be the mean and standard deviation of mental health and its sub-dimensions. Standardized mean difference is used as the main effect value. Subgroup analyses will be carried out by the location of studies and school type of. Sensitivity analyses will be conducted to assess the robustness of the findings. Analyses will be performed with RevMan and Stata software. This systematic review and meta-analysis will compare the mental health status of rural-to-urban migrant children and their counterparts living in China. The results

  2. Autocatalytic caspase-3 driven by human telomerase reverse transcriptase promoter suppresses human ovarian carcinoma growth in vitro and in mice.

    Science.gov (United States)

    Song, Yue; Xia, Zhijun; Shen, Keng; Zhai, Xingyue

    2013-05-01

    To construct recombinant adenoviruses AdHT-rev-casp3 and Ad-rev-casp3, which express autocatalysis caspase-3 driven by human telomerase reverse transcriptase promoter and cytomegalovirus promoter, respectively; and to investigate their antitumor effects on ovarian cancer in vitro and in vivo. Cell viabilities were determined using the cell counting kit 8 and flow cytometry. Reverse transcriptase polymerase chain reaction and immunoblotting assays were used to detect cellular apoptotic activities after treatments. Tumor growth and survival of mice bearing AO cells were studied. AdHT-rev-casp3 significantly suppressed the survival of AO cells in a dose-dependent modality with a viability rate of 60.45% ± 7.8% at an multiplicity of infection (MOI) of 70 and 42.18 ± 5.3% at an MOI of 100, which was somewhat lower than that of the AO cells treated with Ad-rev-casp3 (32.28% ± 5.3% and 21.84% ± 3.4%, respectively). In contrast, AdHT-rev-casp3 induced little human umbilical vein epithelial cell (HUVEC) death with a viability rate of 98.52% ± 6.9% at an MOI of 70, whereas Ad-rev-casp3 induced significant cell death in HUVEC with a viability rate of 27.14% ± 5.4%. Additionally, AdHT-rev-casp3 (MOI = 70) caused significant apoptosis in AO cells with an apoptotic rate of 25.97%, whereas it caused undetectable apoptosis in HUVECs with the rate of only 1.75%. Ad-rev-casp3 (MOI = 70) caused strong apoptosis in both AO and HUVECs, with the rate of 35.82% and 38.12%, respectively. AdHT-rev-casp3 caused markedly higher levels of active caspase-3, causing no detectable active caspase-3 expression in HUVECs. The tumor growth suppression rate of AdHT-rev-casp3 was 54.94%, significantly higher than that of phosphate-buffered saline at the end point of the study. AdHT-rev-casp3 significantly improved the survival of mice receiving intraperitoneal inoculation of AO cells with little liver damage, with the mean survival of 177 ± 12 days. AdHT-rev-casp3 causes effective apoptosis

  3. Negative Ion Density Fronts

    International Nuclear Information System (INIS)

    Igor Kaganovich

    2000-01-01

    Negative ions tend to stratify in electronegative plasmas with hot electrons (electron temperature Te much larger than ion temperature Ti, Te > Ti ). The boundary separating a plasma containing negative ions, and a plasma, without negative ions, is usually thin, so that the negative ion density falls rapidly to zero-forming a negative ion density front. We review theoretical, experimental and numerical results giving the spatio-temporal evolution of negative ion density fronts during plasma ignition, the steady state, and extinction (afterglow). During plasma ignition, negative ion fronts are the result of the break of smooth plasma density profiles during nonlinear convection. In a steady-state plasma, the fronts are boundary layers with steepening of ion density profiles due to nonlinear convection also. But during plasma extinction, the ion fronts are of a completely different nature. Negative ions diffuse freely in the plasma core (no convection), whereas the negative ion front propagates towards the chamber walls with a nearly constant velocity. The concept of fronts turns out to be very effective in analysis of plasma density profile evolution in strongly non-isothermal plasmas

  4. THE SCUBA-2 COSMOLOGY LEGACY SURVEY: MULTIWAVELENGTH COUNTERPARTS TO 10{sup 3} SUBMILLIMETER GALAXIES IN THE UKIDSS-UDS FIELD

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Chian-Chou; Smail, Ian; Ma, Cheng-Jiun; Simpson, James M.; Swinbank, A. Mark [Centre for Extragalactic Astronomy, Department of Physics, Durham University, South Road, Durham DH1 3LE (United Kingdom); Ivison, Rob J.; Arumugam, Vinodiran; Mortlock, Alice; Dunlop, James S.; Michałowski, Michał J. [Institute for Astronomy, University of Edinburgh, Royal Observatory, Blackford Hill, Edinburgh EH9 3HJ (United Kingdom); Almaini, Omar; Conselice, Christopher J.; Hartley, Will G. [University of Nottingham, School of Physics and Astronomy, Nottingham, NG7 2RD (United Kingdom); Geach, James E. [Center for Astrophysics Research, Science and Technology Research Institute, University of Hertfordshire, Hatfield AL10 9AB (United Kingdom); Simpson, Chris [Astrophysics Research Institute, Liverpool John Moores University, Liverpool Science Park, 146 Brownlow Hill, Liverpool L3 5RF (United Kingdom); Aretxaga, Itziar [Instituto Nacional de Astrofísica, Óptica y Electrónica (INAOE), Luis Enrique Erro 1, Sta. Ma. Tonantzintla, Puebla (Mexico); Blain, Andrew [Physics and Astronomy, University of Leicester, Leicester, LE1 7RH (United Kingdom); Chapman, Scott C. [Department of Physics and Atmospheric Science, Dalhousie University, 6310 Coburg Road, Halifax, NS B3H 4R2 (Canada); Farrah, Duncan [Department of Physics, Virginia Tech, Blacksburg, VA 24061 (United States); Halpern, Mark [Department of Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC V6T 1Z1 (Canada); and others

    2016-04-01

    We present multiwavelength identifications for the counterparts of 1088 submillimeter sources detected at 850 μm in the SCUBA-2 Cosmology Legacy Survey study of the UKIRT Infrared Deep Sky Survey-Ultra-Deep Survey (UDS) field. By utilizing an Atacama Large Millimeter Array (ALMA) pilot study on a subset of our bright SCUBA-2 sample as a training set, along with the deep optical–near-infrared (OIR) data available in this field, we develop a novel technique, Optical–IR Triple Color (OIRTC), using z − K, K − [3.6], [3.6] − [4.5] colors to select the candidate submillimeter galaxy (SMG) counterparts. By combining radio identification and the OIRTC technique, we find counterpart candidates for 80% of the Class = 1 ≥ 4σ SCUBA-2 sample, defined as those that are covered by both radio and OIR imaging and the base sample for our scientific analyses. Based on the ALMA training set, we expect the accuracy of these identifications to be 82% ± 20%, with a completeness of 69% ± 16%, essentially as accurate as the traditional p-value technique but with higher completeness. We find that the fraction of SCUBA-2 sources having candidate counterparts is lower for fainter 850 μm sources, and we argue that for follow-up observations sensitive to SMGs with S{sub 850} ≳ 1 mJy across the whole ALMA beam, the fraction with multiple counterparts is likely to be >40% for SCUBA-2 sources at S{sub 850} ≳ 4 mJy. We find that the photometric redshift distribution for the SMGs is well fit by a lognormal distribution, with a median redshift of z = 2.3 ± 0.1. After accounting for the sources without any radio and/or OIRTC counterpart, we estimate the median redshift to be z = 2.6 ± 0.1 for SMGs with S{sub 850} > 1 mJy. We also use this new large sample to study the clustering of SMGs and the far-infrared properties of the unidentified submillimeter sources by stacking their Herschel SPIRE far-infrared emission.

  5. A Modality Called 'Negation'

    NARCIS (Netherlands)

    Berto, F.

    2015-01-01

    I propose a comprehensive account of negation as a modal operator, vindicating a moderate logical pluralism. Negation is taken as a quantifier on worlds, restricted by an accessibility relation encoding the basic concept of compatibility. This latter captures the core meaning of the operator. While

  6. Negative thermal expansion materials

    International Nuclear Information System (INIS)

    Evans, J.S.O.

    1997-01-01

    The recent discovery of negative thermal expansion over an unprecedented temperature range in ZrW 2 O 8 (which contracts continuously on warming from below 2 K to above 1000 K) has stimulated considerable interest in this unusual phenomenon. Negative and low thermal expansion materials have a number of important potential uses in ceramic, optical and electronic applications. We have now found negative thermal expansion in a large new family of materials with the general formula A 2 (MO 4 ) 3 . Chemical substitution dramatically influences the thermal expansion properties of these materials allowing the production of ceramics with negative, positive or zero coefficients of thermal expansion, with the potential to control other important materials properties such as refractive index and dielectric constant. The mechanism of negative thermal expansion and the phase transitions exhibited by this important new class of low-expansion materials will be discussed. (orig.)

  7. Comparison of Physical Fitness Parameters with EUROFIT Test Battery of Male Adolescent Soccer Players and Sedentary Counterparts

    Directory of Open Access Journals (Sweden)

    Özgür ERİKOĞLU

    2015-09-01

    Full Text Available The aim of this study was to compare physical fitness parameters of male adolescent soccer players and sedentary counterparts. A total of 26 male adolescents participated in this study voluntarily: Active soccer players (n: 3, age x : 13,00 ± 0,00 and sedentary counterparts (n: 13, age x :12,92 ± 0,75. The EUROFIT test battery was used to determine physical fitness. The test battery includes body height and weight measurements, touching the discs, flamingo balan ce, throwing health ball, vertical jumping, sit and reach, sit - up for 30 s, 20 meter sprint run, and 20 meter shuttle run tests. Data were analyzed by Mann Whitney U test. Significance was defined as p.05. In conclusion, children who do sports are more successful on most of the fitness parameters than sedentary children.

  8. THE NATURE OF THE BRIGHT ULX X-2 IN NGC 3921: A CHANDRA POSITION AND HST CANDIDATE COUNTERPART

    Energy Technology Data Exchange (ETDEWEB)

    Jonker, P. G.; Heida, M.; Torres, M. A. P.; Ratti, E. M. [SRON, Netherlands Institute for Space Research, Sorbonnelaan 2, 3584 CA Utrecht (Netherlands); Miller-Jones, J. C. A. [International Centre for Radio Astronomy Research, Curtin University, GPO Box U1987, Perth, WA 6845 (Australia); Fabian, A. C.; Walton, D. J. [Institute of Astronomy, Madingley Road, Cambridge CB3 0HA (United Kingdom); Miniutti, G. [Centro de Astrobiologia (CSIC-INTA), Departamento de Astrofisica, ESA, P.O. Box 78, E-28691 Villanueva de la Canada, Madrid (Spain); Roberts, T. P., E-mail: p.jonker@sron.nl [Department of Physics, Durham University, South Road, Durham DH1 3LE (United Kingdom)

    2012-10-10

    We report on Chandra observations of the bright ultraluminous X-ray (ULX) source in NGC 3921. Previous XMM-Newton observations reported in the literature show the presence of a bright ULX at a 0.5-10 keV luminosity of 2 Multiplication-Sign 10{sup 40} erg s{sup -1}. Our Chandra observation finds the source at a lower luminosity of Almost-Equal-To 8 Multiplication-Sign 10{sup 39} erg s{sup -1}; furthermore, we provide a Chandra position of the ULX accurate to 0.''7 at 90% confidence. The X-ray variability makes it unlikely that the high luminosity is caused by several separate X-ray sources. In three epochs of archival Hubble Space Telescope observations, we find a candidate counterpart to the ULX. There is direct evidence for variability between the two epochs of WFPC2 F814W observations with the observation obtained in 2000 showing a brighter source. Furthermore, converting the 1994 F336W and 2000 F300W WFPC2 and the 2010 F336W WFC3 observations to the Johnson U-band filter assuming a spectral type of O7I, we find evidence for a brightening of the U-band light in 2000. Using the higher resolution WFC3 observations, we resolve the candidate counterpart into two sources of similar color. We discuss the nature of the ULX and the probable association with the optical counterpart(s). Finally, we investigate a potential new explanation for some (bright) ULXs as the decaying stages of flares caused by the tidal disruption of a star by a recoiled supermassive black hole. However, we find that there should be at most only one of such systems within z = 0.08.

  9. Search for high confidence AGN candidates and its counterparts in the Fermi-LAT unassociated sample using machine learning

    Energy Technology Data Exchange (ETDEWEB)

    Einecke, Sabrina [Technical University Dortmund (Germany); Doert, Marlene [Ruhr-University Bochum (Germany)

    2016-07-01

    The third Fermi-LAT source catalog (3FGL) is the deepest all-sky survey in gamma-rays and comprises 3033 point sources. While for 2023 sources plausible associations have been found, 1010 remain unassociated. A search for active galactic nuclei (AGN) will help to reduce the number of unassociated sources, and will increase our knowledge of the population of gamma-ray emitting AGN. Several machine learning approaches applied to Fermi data have shown the capability of this method. The extension to multiwavelength data improves these studies, and at the same time offers the possibility to determine the most likely corresponding counterpart. As the 95% confidence region of the localization by the Fermi measurement is in the order of several arcminutes, generally multiple point sources at different wavelengths are located within this region and the association is ambiguous. To figure out the most likely counterpart, the associated sample is used to train machine learning classifiers as e.g. the random forest. Therefore, all possible combinations of the Fermi measurement and the measurements at a second wavelength are considered for a particular source. In this talk, the statistical model to obtain high confidence AGN counterpart candidates is described as well as the validation of the model to estimate the performance.

  10. Health and functional status and utilization of health care services among holocaust survivors and their counterparts in Israel.

    Science.gov (United States)

    Iecovich, Esther; Carmel, Sara

    2010-01-01

    To examine differences in health and functional status and in utilization of health services between holocaust survivors and their counterparts; and (b) to investigate if holocaust survivor status is a significant predictor of health status, functional status, and utilization of health services. The study included 1255 respondents of whom 272 were holocaust survivors. Interviews were conducted face-to-face at the respondents' homes. Participants were asked about their health (self-rated health and comorbidity) and functional (ADL and IADL) status, utilization of inpatient and outpatient health care services, age, gender, education, marital status, length of residence in Israel, and if they were holocaust survivors. Holocaust survivors, who were frailer and more chronically ill compared to their counterparts, visited their family physician and the nurse at the health care clinic more often than their counterparts did, and received more homecare services. Yet, there were no differences between them in the utilization of other health care services such as visits to specialists, emergency department, and hospitalizations. Holocaust survivors are more homebound due to more morbidity and functional limitations and therefore receive more health home care services that offset the utilization of other health services. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  11. Atomic negative ions

    International Nuclear Information System (INIS)

    Brage, T.

    1991-01-01

    We review some of the recent progress in the studies of alkaline-earth, negative ions. Computations of autodetachment rates, electron affinities and transition wavelengths are discussed and some new and improved results are given

  12. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumor types are associated with increased TERT expression and telomerase activation

    Science.gov (United States)

    Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun; Diplas, Bill H.; Yang, Rui; Killela, Patrick J.; Liang, Junbo; Meng, Qun; Ye, Zai-Yuan; Wang, Wei; Jiang, Xiao-Ting; Xu, Li; He, Xiang-Lei; Zhao, Zhong-Sheng; Xu, Wen-Juan; Wang, Hui-Ju; Ma, Ying-Yu; Xia, Ying-Jie; Li, Li; Zhang, Ru-Xuan; Jin, Tao; Zhao, Zhong-Kuo; Xu, Ji; Yu, Sheng; Wu, Fang; Wang, Si-Zhen; Jiao, Yu-Chen; Yan, Hai; Tao, Hou-Quan

    2015-01-01

    Background Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers. Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations. This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumor types and 799 tumor tissues from Chinese cancer patients. Thymic epithelial tumors, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by RT-qPCR, telomerase activity by the TRAP assay, and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in GIST, thymic epithelial tumors, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets. PMID:25843513

  13. A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC promoter in a patient with Paroxysmal Nocturnal Haemoglobinuria

    Directory of Open Access Journals (Sweden)

    Mason Philip J

    2004-06-01

    Full Text Available Abstract Background Mutations in the gene coding for the RNA component of telomerase, hTERC, have been found in autosomal dominant dyskeratosis congenita (DC and aplastic anemia. Paroxysmal nocturnal hemoglobinuria (PNH is a clonal blood disorder associated with aplastic anemia and characterized by the presence of one or more clones of blood cells lacking glycosylphosphatidylinositol (GPI anchored proteins due to a somatic mutation in the PIGA gene. Methods We searched for mutations in DNA extracted from PNH patients by amplification of the hTERC gene and denaturing high performance liquid chromatography (dHPLC. After a mutation was found in a potential transcription factor binding site in one patient electrophoretic mobility shift assays were used to detect binding of transcription factors to that site. The effect of the mutation on the function of the promoter was tested by transient transfection constructs in which the promoter is used to drive a reporter gene. Results Here we report the finding of a novel promoter mutation (-99C->G in the hTERC gene in a patient with PNH. The mutation disrupts an Sp1 binding site and destroys its ability to bind Sp1. Transient transfection assays show that mutations in this hTERC site including C-99G cause either up- or down-regulation of promoter activity and suggest that the site regulates core promoter activity in a context dependent manner in cancer cells. Conclusions These data are the first report of an hTERC promoter mutation from a patient sample which can modulate core promoter activity in vitro, raising the possibility that the mutation may affect the transcription of the gene in hematopoietic stem cells in vivo, and that dysregulation of telomerase may play a role in the development of bone marrow failure and the evolution of PNH clones.

  14. Dioxin exerts anti-estrogenic actions in a novel dioxin-responsive telomerase-immortalized epithelial cell line of the porcine oviduct (TERT-OPEC).

    Science.gov (United States)

    Hombach-Klonisch, Sabine; Pocar, Paola; Kauffold, Johannes; Klonisch, Thomas

    2006-04-01

    Oviduct epithelial cells are important for the nourishment and survival of ovulated oocytes and early embryos, and they respond to the steroid hormones estrogen and progesterone. Endocrine-disrupting polyhalogenated aromatic hydrocarbons (PHAH) are environmental toxins that act in part through the ligand-activated transcription factor arylhydrocarbon receptor (AhR; dioxin receptor), and exposure to PHAH has been shown to decrease fertility. To investigate effects of PHAHs on the oviduct epithelium as a potential target tissue of dioxin-type endocrine disruptors, we have established a novel telomerase-immortalized oviduct porcine epithelial cell line (TERT-OPEC). TERT-OPEC exhibited active telomerase and the immunoreactive epithelial marker cytokeratin but lacked the stromal marker vimentin. TERT-OPEC contained functional estrogen receptor (ER)-alpha and AhR, as determined by the detection of ER-alpha- and AhR-specific target molecules. Treatment of TERT-OPEC with the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a significant increase in the production of the cytochrome P-450 microsomal enzyme CYP1A1. Activated AhR caused a downregulation of ER nuclear protein fraction and significantly decreased ER-signaling in TERT-OPEC as determined by ERE-luciferase transient transfection assays. In summary, the TCDD-induced and AhR-mediated anti-estrogenic responses by TERT-OPEC suggest that PHAH affect the predominantly estrogen-dependent differentiation of the oviduct epithelium within the fallopian tube. This action then alters the local endocrine milieu, potentially resulting in a largely unexplored cause of impaired embryonic development and female infertility.

  15. miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an “ALT-like” phenotype in diffuse malignant peritoneal mesothelioma cells

    Directory of Open Access Journals (Sweden)

    Graziella Cimino-Reale

    2017-07-01

    Full Text Available Abstract Background Understanding the molecular/cellular underpinnings of diffuse malignant peritoneal mesothelioma (DMPM, a fatal malignancy with limited therapeutic options, is of utmost importance for the fruitful management of the disease. In this context, we previously found that telomerase activity (TA, which accounts for the limitless proliferative potential of cancer cells, is prognostic for disease relapse and cancer-related death in DMPM patients. Consequently, the identification of factors involved in telomerase activation/regulation may pave the way towards the development of novel therapeutic interventions for the disease. Here, the capability of miR-380-5p, a microRNA negligibly expressed in telomerase-positive DMPM clinical specimens, to interfere with telomerase-mediated telomere maintenance and, hence, with cancer cell growth was assessed on preclinical models of DMPM. Methods DMPM cells were transfected with a miR-380-5p synthetic precursor, and the effects of miRNA replacement were evaluated in terms of growing capability, induction of apoptosis and interference with TA. Reiterated weekly transfections were also performed in order to analyse the phenotype arising upon prolonged miR-380-5p reconstitution in DMPM cells. Results The ectopic expression of miR-380-5p elicited a remarkable inhibition of TA and resulted in DMPM cell growth impairment and apoptosis induction. In particular, we demonstrated for the first time that these effects were the result of a molecular circuitry converging on telomerase associated protein 1 (TEP1, where the miRNA was able to target the gene both directly in unconventional targeting modality and indirectly via p53 accumulation consequent to miRNA-mediated downregulation of testis-specific protein, Y-encoded-like 5 gene. Moreover, miR-380-5p did not cause telomere attrition and cell growth arrest in long-term DMPM transfectants, which in turn showed slightly elongated telomeres and molecular

  16. NEGATION AFFIXES IN ENGLISH

    Directory of Open Access Journals (Sweden)

    Dedy Subandowo -

    2017-02-01

    Full Text Available Abstract: This research entitled "Negation Affixes in English". This study is aimed to describe the various negation affixes in English, morphological process, morphophonemic and meaning. The research data were taken from various sources of English grammar book, morphology, research journal and the book which relatees to the research. English grammar books used in this study are written by Otto Jesperson, Marcella Frank, Greenbaum and Geoffrey Leech.  The method used in this research is the descriptive-qualitative method. While the data collection techniques are performed by using jot-down method. And the results of analysis are presented in tabular form and descriptive method. The result of the research shows that English has six types of negative affixes which are categorized by the intensity of its appearance, such as dis-, in-, non-, un-, anti- and -less. Based on the function, negation affixes are divided into several categories such as adjectives, nouns, verbs, and adverbs. The morphophonemic affix in- has four allomorphs, they are in-, im-, il- and ir- . While the analysis revealed that negation affixes have some basic meanings, such as ‘not’, ‘without’, and ‘anti’.

  17. [Construction of autocatalytic caspase-3 driven by amplified human telomerase reverse transcriptase promoter and its enhanced efficacy of inducing apoptosis in human ovarian carcinoma].

    Science.gov (United States)

    Song, Yue; Shen, Keng; He, Chun-Xia

    2007-09-01

    To construct recombinant adenoviral vector expressing autocatalysis caspase-3 driven by human telomerase reverse transcriptase promoter amplified by two-step transcription amplification (hTERTp-TSTA), and investigate its antitumor effect in ovarian cancer in vitro and in vivo. Recombinant adenoviruses expressing autocatalytic caspase-3 (rev-caspase-3) driven by hTERTp-TSTA were prepared, which were named as AdHTVP2G5-rev-casp3. AdHT-rev-casp3, Ad-rev-casp3 and AdHTVP2G5-EGEP, which express rev-caspase-3 driven by hTERTp, cytomegalovirus promoter (CMVp) and enhanced green fluorescent protein (EGFP), respectively, were used as controls. Western blot, cell counting kit (CCK-8), flow cytometry (FCM) and TdT-mediated dUTP-biotin nick end labeling (TUNEL) were used to detect the expression of p17, active subunit of caspase-3, and p85, and to measure cell survival rates, apoptotic rates and cell cycle distribution in ovarian cell line AO and normal human umbilical vein endothelial cell line HUVEC, following treatments of AdHTVP2G5-rev-casp3. subcutaneous tumor models and abdominally spread tumor models of human ovarian carcinoma using AO cells in BALB/c nude mice were established. Following treatments of AdHTVP2G5-rev-casp3, western blot was used to detect the expression of active caspase-3 in abdominally spread tumors and liver tissues, respectively, and the mouse survival rates and the volume of tumor nodules were measured, and the serum level of alanine transaminase (ALT) and aspartate transaminase (AST) were analyzed to monitor liver damages and HE staining was used to detect the histopathological changes of various organs. The levels of p17 expression in AdHTVP2G5-rev-casp3-treated AO cells were significantly higher than that in Ad-rev-casp3 or AdHT-rev-casp3 treated AO cells, while no expression was observed in AdHTVP2G5-rev-casp3-treated HUVEC. There was strong cell killing of AdHTVP2G5-rev-casp3 of hTERT positive AO cells, but not of the hTERT-negative HUVEC cells

  18. Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

    Science.gov (United States)

    Yano, Shuya; Takehara, Kiyoto; Miwa, Shinji; Kishimoto, Hiroyuki; Tazawa, Hiroshi; Urata, Yasuo; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

    2016-01-01

    We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative high-invasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)-light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model. PMID:27689331

  19. On Various Negative Translations

    Directory of Open Access Journals (Sweden)

    Gilda Ferreira

    2011-01-01

    Full Text Available Several proof translations of classical mathematics into intuitionistic mathematics have been proposed in the literature over the past century. These are normally referred to as negative translations or double-negation translations. Among those, the most commonly cited are translations due to Kolmogorov, Godel, Gentzen, Kuroda and Krivine (in chronological order. In this paper we propose a framework for explaining how these different translations are related to each other. More precisely, we define a notion of a (modular simplification starting from Kolmogorov translation, which leads to a partial order between different negative translations. In this derived ordering, Kuroda and Krivine are minimal elements. Two new minimal translations are introduced, with Godel and Gentzen translations sitting in between Kolmogorov and one of these new translations.

  20. Negative ion sourcery

    International Nuclear Information System (INIS)

    Os, C.F.A. van.

    1989-01-01

    The work described in this thesis is involved by current research programs in the field of nuclear-fusion. A brief introduction to fusion is given, anticipated problems related to current drive of the fusion plasma are pinpointed and probable suggestions to overcome these problems are described. One probable means for current drive is highlighted; Neutral Beam Injection (NBI). This is based on injecting a 1 MeV neutral hydrogen or deuterium beam into a fusion plasma. Negative ions are needed as primary particles because they can easily be neutralized at 1 MeV. The two current schemes for production of negative ions are described, volume production and negative surface ionization. The latter method is extensively studied in this thesis. (author). 171 refs.; 55 figs.; 7 tabs

  1. QUEST FOR COSMOS SUBMILLIMETER GALAXY COUNTERPARTS USING CARMA AND VLA: IDENTIFYING THREE HIGH-REDSHIFT STARBURST GALAXIES

    International Nuclear Information System (INIS)

    Smolčić, V.; Navarrete, F.; Bertoldi, F.; Aravena, M.; Sheth, K.; Ilbert, O.; Yun, M. S.; Salvato, M.; Finoguenov, A.; McCracken, H. J.; Diener, C.; Aretxaga, I.; Hughes, D.; Wilson, G.; Riechers, D. A.; Capak, P.; Scoville, N. Z.; Karim, A.; Schinnerer, E.

    2012-01-01

    We report on interferometric observations at 1.3 mm at 2''-3'' resolution using the Combined Array for Research in Millimeter-wave Astronomy. We identify multi-wavelength counterparts of three submillimeter galaxies (SMGs; F 1m > 5.5 mJy) in the COSMOS field, initially detected with MAMBO and AzTEC bolometers at low, ∼10''-30'', resolution. All three sources—AzTEC/C1, Cosbo-3, and Cosbo-8—are identified to coincide with positions of 20 cm radio sources. Cosbo-3, however, is not associated with the most likely radio counterpart, closest to the MAMBO source position, but with that farther away from it. This illustrates the need for intermediate-resolution (∼2'') mm-observations to identify the correct counterparts of single-dish-detected SMGs. All of our three sources become prominent only at NIR wavelengths, and their mm-to-radio flux based redshifts suggest that they lie at redshifts z ∼> 2. As a proof of concept, we show that photometric redshifts can be well determined for SMGs, and we find photometric redshifts of 5.6 ± 1.2, 1.9 +0.9 –0.5 , and ∼4 for AzTEC/C1, Cosbo-3, and Cosbo-8, respectively. Using these we infer that these galaxies have radio-based star formation rates of ∼> 1000 M ☉ yr –1 and IR luminosities of ∼10 13 L ☉ consistent with properties of high-redshift SMGs. In summary, our sources reflect a variety of SMG properties in terms of redshift and clustering, consistent with the framework that SMGs are progenitors of z ∼ 2 and today's passive galaxies.

  2. Comparison of nutritional value of transgenic peanut expressing bar and rcg3 genes with non-transgenic counterparts

    International Nuclear Information System (INIS)

    Robab, U.E.; )

    2014-01-01

    The transgenic peanut plants expressing bar and rcg3 genes were subjected to assessment of any change in nutritional value of the crop at various locations. The protein and fat contents of transgenic lines were compared with the non-transgenic parent varieties. Protein content in the transgenic lines was higher as compared to that in non-transgenic counterparts and differences among locations for fat and protein content were significant. No differences among fatty acids were recorded for genes, events and locations. Irrespective of small differences, all the values were in range described for this crop and transgenic lines appeared to be substantially equivalent to non-transgenic parent varieties. (author)

  3. Telomerase activity and telomere length in the colorectal polyp-carcinoma sequence Actividad de la telomerasa y longitud del telómero en la secuencia pólipo-carcinoma colorrectal

    Directory of Open Access Journals (Sweden)

    C. Valls Bautista

    2009-03-01

    Full Text Available Objective: the role of telomerase activity and telomere length in the adenoma-carcinoma sequence of colon carcinogenesis has not been well established. The objective of this study was to determine telomerase activity and telomere length patterns in patients with adenomatous polyps either associated or not with colorectal cancer, as well as the role of telomeric instability in the adenoma-carcinoma sequence. Patients and methods: we included in the study 14 patients who underwent surgery for colorectal cancer and/or polyps. In 6 of these patients fresh samples of tumor tissue, polyps, and normal mucosa were obtained; in the 8 remaining cases, we collected only polyps and normal mucosa. We used the fluorescent-telomeric repeat amplification protocol assay (TRAP-F to determine telomerase activity and telomere length using Southern-blot testing. Results: telomerase activity was detected in 86% of polyps and 50% of associated normal mucosa. Mean telomerase activity in polyp tissue was 5.85; in the normal mucosa it was 0.58 TPG. Mean telomere length was 6.78 Kbp and 7.78, respectively. Polyps in patients without synchronous cancer had a telomerase activity that was significantly higher (9.4 than in those with cancer (1.1. Conclusions: telomerase activity increases in the colorectal adenoma-carcinoma sequence, concurrently with a decrease in telomere length. The presence of synchronous cancer modifies telomerase activity in polyps.Objetivo: el papel de la actividad de la telomerasa y la longitud del telómero en la secuencia adenoma-carcinoma de la carcinogénesis colónica no ha sido bien establecido. El objetivo fue determinar el comportamiento de la actividad de la telomerasa y la longitud del telómero en pacientes con pólipos adenomatosos asociados o no a cáncer colorrectal y conocer el papel de la inestabilidad telomérica en la secuencia adenoma-carcinoma. Pacientes y métodos: se estudiaron 14 pacientes intervenidos de cáncer colorrectal y

  4. An Enhanced Method for Scheduling Observations of Large Sky Error Regions for Finding Optical Counterparts to Transients

    Energy Technology Data Exchange (ETDEWEB)

    Rana, Javed; Singhal, Akshat; Gadre, Bhooshan; Bhalerao, Varun; Bose, Sukanta, E-mail: javed@iucaa.in [Inter-University Centre for Astronomy and Astrophysics, Post Bag 4, Ganeshkhind, Pune 411 007 (India)

    2017-04-01

    The discovery and subsequent study of optical counterparts to transient sources is crucial for their complete astrophysical understanding. Various gamma-ray burst (GRB) detectors, and more notably the ground-based gravitational wave detectors, typically have large uncertainties in the sky positions of detected sources. Searching these large sky regions spanning hundreds of square degrees is a formidable challenge for most ground-based optical telescopes, which can usually image less than tens of square degrees of the sky in a single night. We present algorithms for better scheduling of such follow-up observations in order to maximize the probability of imaging the optical counterpart, based on the all-sky probability distribution of the source position. We incorporate realistic observing constraints such as the diurnal cycle, telescope pointing limitations, available observing time, and the rising/setting of the target at the observatory’s location. We use simulations to demonstrate that our proposed algorithms outperform the default greedy observing schedule used by many observatories. Our algorithms are applicable for follow-up of other transient sources with large positional uncertainties, such as Fermi -detected GRBs, and can easily be adapted for scheduling radio or space-based X-ray follow-up.

  5. In vitro transfection of the hepatitis B virus PreS2 gene into the human hepatocarcinoma cell line HepG2 induces upregulation of human telomerase reverse transcriptase

    International Nuclear Information System (INIS)

    Liu Hua; Luan Fang; Ju Ying; Shen Hongyu; Gao Lifen; Wang Xiaoyan; Liu Suxia; Zhang Lining; Sun Wensheng; Ma Chunhong

    2007-01-01

    The preS2 domain is the minimal functional unit of transcription activators that is encoded by the Hepatitis B virus (HBV) surface (S) gene. It is present in more than one-third of the HBV-integrates in HBV induced hepatocarcinoma (HCC). To further understand the functional role of PreS2 in hepatocytes, a PreS2 expression plasmid, pcS2, was constructed and stably transfected into HepG2 cells. We conducted growth curve and colony-forming assays to study the impact of PreS2 expression on cell proliferation. Cells transfected with PreS2 proliferated more rapidly and formed colonies in soft agar. PreS2 expressing cells also induced upregulation of human telomerase reverse transcriptase (hTERT) and telomerase activation by RT-PCR and the modified TRAP assay. Blocking expression of hTERT with antisense oligonuleotide reversed the growth rate in cells stably transfected with PreS2. Our data suggest that PreS2 may increase the malignant transformation of human HCC cell line HepG2 by upregulating hTERT and inducing telomerase activation

  6. In vitro transfection of the hepatitis B virus PreS2 gene into the human hepatocarcinoma cell line HepG2 induces upregulation of human telomerase reverse transcriptase

    Energy Technology Data Exchange (ETDEWEB)

    Hua, Liu [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Fang, Luan [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Ying, Ju [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Hongyu, Shen [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Lifen, Gao [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Xiaoyan, Wang [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Suxia, Liu [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Lining, Zhang [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Wensheng, Sun [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Chunhong, Ma [Institute of Immunology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan 250012 (China); Key Laboratory for Experimental Teratology, Ministry of Education (China)]. E-mail: machunhong@sdu.edu.cn

    2007-04-06

    The preS2 domain is the minimal functional unit of transcription activators that is encoded by the Hepatitis B virus (HBV) surface (S) gene. It is present in more than one-third of the HBV-integrates in HBV induced hepatocarcinoma (HCC). To further understand the functional role of PreS2 in hepatocytes, a PreS2 expression plasmid, pcS2, was constructed and stably transfected into HepG2 cells. We conducted growth curve and colony-forming assays to study the impact of PreS2 expression on cell proliferation. Cells transfected with PreS2 proliferated more rapidly and formed colonies in soft agar. PreS2 expressing cells also induced upregulation of human telomerase reverse transcriptase (hTERT) and telomerase activation by RT-PCR and the modified TRAP assay. Blocking expression of hTERT with antisense oligonuleotide reversed the growth rate in cells stably transfected with PreS2. Our data suggest that PreS2 may increase the malignant transformation of human HCC cell line HepG2 by upregulating hTERT and inducing telomerase activation.

  7. Dualising Intuitionictic Negation

    Directory of Open Access Journals (Sweden)

    Graham Priest

    2009-01-01

    Full Text Available One of Da Costa's motives when he constructed the paraconsistent logic Cw was to dualise the negation of intuitionistic logic. In this paper I explore a different way of going about this task. A logic is defined by taking the Kripke semantics for intuitionistic logic, and dualising the truth conditions for negation. Various properties of the logic are established, including its relation to CWo Tableau and natural deduction systems for the logic are produced, as are appropriate algebraic structures. The paper then investigates dualising the intuitionistic conditional in the same way. This establishes various connections between the logic, and a logic called in the literature 'Brouwerian logic' or 'closed-set logic'.

  8. Dualising Intuitionistic Negation

    Directory of Open Access Journals (Sweden)

    Graham Priest

    2009-08-01

    Full Text Available One of Da Costa’s motives when he constructed the paraconsistent logic C! was to dualise the negation of intuitionistic logic. In this paper I explore a different way of going about this task. A logic is defined by taking the Kripke semantics for intuitionistic logic, and dualising the truth conditions for negation. Various properties of the logic are established, including its relation to C!. Tableau and natural deduction systems for the logic are produced, as are appropriate algebraic structures. The paper then investigates dualising the intuitionistic conditional in the same way. This establishes various connections between the logic, and a logic called in the literature ‘Brouwerian logic’ or ‘closed-set logic’.

  9. Immortalization of Human Fetal Hepatocyte by Ectopic Expression of Human Telomerase Reverse Transcriptase, Human Papilloma Virus (E7) and Simian Virus 40 Large T (SV40 T) Antigen Towards Bioartificial Liver Support.

    Science.gov (United States)

    Giri, Shibashish; Bader, Augustinus

    2014-09-01

    Generation of genetically stable and non-tumoric immortalization cell line from primary cells would be enormously useful for research and therapeutic purposes, but progress towards this goal has so far been limited. It is now universal acceptance that immortalization of human fetal hepatocytes based on recent advances of telomerase biology and oncogene, lead to unlimited population doubling could be the possible source for bioartificial liver device. Immortalization of human fetal hepatocytes cell line by ectopic expression of human telomerase reverse transcriptase (hTERT), human papilloma virus gene (E7) and simian virus 40 large T (SV40 T) antigens is main goal of present study. We used an inducible system containing human telomerase and E7, both of which are cloned into responder constructs controlled by doxycycline transactivator. We characterized the immortalized human fetal hepatocyte cells by analysis of green fluorescent cells (GFP) positive cells using flow cytometry (FACs) cell sorting and morphology, proliferative rate and antigen expression by immunohistochemical analysis. In addition to we analysized lactate formation, glucose consumption, albumin secretion and urea production of immortalized human fetal hepatocyte cells. After 25 attempts for transfection of adult primary hepatocytes by human telomerase and E7 to immortalize them, none of the transfection systems resulted in the production of a stable, proliferating cell line. Although the transfection efficiency was more than 70% on the first day, the vast majority of the transfected hepatocytes lost their signal within the first 5-7 days. The remaining transfected hepatocytes persisted for 2-4 weeks and divided one or two times without forming a clone. After 10 attempts of transfection human fetal hepatocytes using the same transfection system, we obtained one stable human fetal hepatocytes cell line which was able albumin secretion urea production and glucose consumption. We established a

  10. Expression profile of senescence-associated beta-galactosidase and activation of telomerase in human ovarian surface epithelial cells undergoing immortalization.

    Science.gov (United States)

    Litaker, J R; Pan, J; Cheung, Y; Zhang, D K; Liu, Y; Wong, S C; Wan, T S; Tsao, S W

    1998-11-01

    Senescence is a specific physiological stage of cells characterized by long population doubling time. It accounts for the inability of normal somatic cells to undergo indefinite cell division. As the number of population doublings increase, cell cycle regulatory mechanisms come into play and signal cells to exit the cell cycle and become senescent. Senescence has been implicated in the aging process and may function as a tumor suppressor mechanism in human cells. The ability to measure the degree of cellular senescence is important in understanding the biological processes regulating cell aging and immortalization. Senescent cells exhibit an enzyme termed senescence-associated histochemical staining. Cells immortalized by viral oncogenes often enter a stage of crisis at the early phase of immortalization. The cells at crisis have a long population doubling time. Cells at the crisis stage resemble senescent cells and the expression of SA- beta-Gal may be used to monitor the process of immortalization. In this study the expression profile of SA-beta-Gal was examined in human ovarian surface epithelial cells (HOSE 6-3) undergoing immortalization by the human papilloma viral oncogene E6 and E7 (HPV E6 and E7). Our results showed a low percentage (12.0%) of HOSE 6-3 cells expressing SA-beta-Gal activity at the pre-crisis stage. The percentage of HOSE 6-3 cells expressing SA-beta-Gal activity was highest (39.2%) at the crisis stage. When HOSE 6-3 cells achieved immortalized status there was a sharp decrease in cells (1. 3%) expressing SA-beta-Gal activity. In addition, an inverse relationship between the expression of SA-beta-Gal activity and telomerase activity was noted in cells undergoing immortalization. The results confirm that the SA-beta-Gal enzyme is a good marker for monitoring the population of cells undergoing senescence at different stages of immortalization and that telomerase activation is a characteristic feature of post-crisis cells.

  11. Negative ion beam processes

    International Nuclear Information System (INIS)

    Hayward, T.D.; Lawrence, G.P.; Bentley, R.F.; Malanify, J.J.; Jackson, J.A.

    1975-06-01

    Los Alamos Scientific Laboratory fiscal year 1975 work on production of intense, very bright, negative hydrogen (H - ), ion beams and conversion of a high-energy (a few hundred MeV) negative beam into a neutral beam are described. The ion source work has used a cesium charge exchange source that has produced H - ion beams greater than or equal to 10 mA (about a factor of 10 greater than those available 1 yr ago) with a brightness of 1.4 x 10 9 A/m 2 -rad 2 (about 18 times brighter than before). The high-energy, neutral beam production investigations have included measurements of the 800-MeV H - -stripping cross section in hydrogen gas (sigma/sub -10/, tentatively 4 x 10 -19 cm 2 ), 3- to 6-MeV H - -stripping cross sections in a hydrogen plasma (sigma/sub -10/, tentatively 2 to 4 x 10 -16 cm 2 ), and the small-angle scattering that results from stripping an 800-MeV H - ion beam to a neutral (H 0 ) beam in hydrogen gas. These last measurements were interrupted by the Los Alamos Meson Physics Facility shutdown in December 1974, but should be completed early in fiscal year 1976 when the accelerator resumes operation. Small-angle scattering calculations have included hydrogen gas-stripping, plasma-stripping, and photodetachment. Calculations indicate that the root mean square angular spread of a 390-MeV negative triton (T - ) beam stripped in a plasma stripper may be as low as 0.7 μrad

  12. Differential production of proteolytic enzymes by normal human fibroblasts and their counterparts transformed by treatment with 60Co gamma rays

    International Nuclear Information System (INIS)

    Nishitani, Koji; Namba, Masayoshi; Ohkubo, Shigeki; Kimoto, Tetsuo

    1985-01-01

    Production of proteolytic enzymes by human fibroblasts in the process of transformation was investigated. The cells used were normal human fibroblasts (KSM-6) and their in vitro counterparts transformed by treatment with 60 Co gamma rays (KMST-6). Cells seeded by treatment with EDTA were cultured in a serum free medium. Proteolytic enzymes in the culture medium of cells were assayed using a synthetic substrate, N-α-(p-tosyl)-L-arginine ( 3 H) methyl ester hydrochloride. The transformed cells (KMST-6) produced a larger amount of enzymes than normal cells (KMS-6). The enzyme production in both cell lines was high in the exponential growth stage and then decreased as the cells reached confluency. The proteolytic enzymes produced by these cells were trypsin- and thrombin-like enzymes. Cell growth of KMST-6 or KMS-6 was not inhibited by the addition of protease inhibitors to the culture medium. (author)

  13. Distribution of apparent activation energy counterparts during thermo - And thermo-oxidative degradation of Aronia melanocarpa (black chokeberry).

    Science.gov (United States)

    Janković, Bojan; Marinović-Cincović, Milena; Janković, Marija

    2017-09-01

    Kinetics of degradation for Aronia melanocarpa fresh fruits in argon and air atmospheres were investigated. The investigation was based on probability distributions of apparent activation energy of counterparts (ε a ). Isoconversional analysis results indicated that the degradation process in an inert atmosphere was governed by decomposition reactions of esterified compounds. Also, based on same kinetics approach, it was assumed that in an air atmosphere, the primary compound in degradation pathways could be anthocyanins, which undergo rapid chemical reactions. A new model of reactivity demonstrated that, under inert atmospheres, expectation values for ε a occured at levels of statistical probability. These values corresponded to decomposition processes in which polyphenolic compounds might be involved. ε a values obeyed laws of binomial distribution. It was established that, for thermo-oxidative degradation, Poisson distribution represented a very successful approximation for ε a values where there was additional mechanistic complexity and the binomial distribution was no longer valid. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Comparative study of He bubble formation in nanostructured reduced activation steel and its coarsen-grained counterpart

    Science.gov (United States)

    Liu, W. B.; Zhang, J. H.; Ji, Y. Z.; Xia, L. D.; Liu, H. P.; Yun, D.; He, C. H.; Zhang, C.; Yang, Z. G.

    2018-03-01

    High temperature (550 °C) He ions irradiation was performed on nanostructured (NS) and coarsen-grained (CG) reduced activation steel to investigate the effects of GBs/interfaces on the formation of bubbles during irradiation. Experimental results showed that He bubbles were preferentially trapped at dislocations and/or grain boundaries (GBs) for both of the samples. Void denuded zones (VDZs) were observed in the CG samples, while VDZs near GBs were unobvious in NS sample. However, both the average bubble size and the bubble density in peak damage region of the CG sample were significantly larger than that observed in the NS sample, which indicated that GBs play an important role during the irradiation, and the NS steel had better irradiation resistance than its CG counterpart.

  15. RODOS - The domestic counterpart

    International Nuclear Information System (INIS)

    Vamanu, Dan V.

    1999-01-01

    One term of reference for validly teaming up with Project RODOS (Real-Time-On-Line Decision Support System for Nuclear Emergencies in Europe) is to institutionally - contribute research initiatives geared towards emulating the RODOS functions on novel conceptual pathways, expand system's coverage of issues that are relevant in a nuclear crisis management and bring in a domestic perspective on how the system may best perform in each and every national - i.e. legal, managerial, logistic and cultural environment. On this line, one reviews the approach taken in the IFIN-HH RODOS Group to address the challenge, as well a number of representative outputs. These include: i) A phase-one, pre-RODOS, period (1990 - 1994), involving topical field orientation, feasibility demonstrations and expertise acquisition by hands-on training in environmental radiology modeling and DSS code development, the resulting products - codes in the 'APUD' and 'ACA-IFA' family, including custom versions developed by appointment of the IAEA Safety Section and AECL-Research, Ontario, Canada - being favourably reviewed by the NEA/OECD Data Bank; ii) A phase-two, upgrading and consolidation period (1994 -1996), assisted by the IAEA fellowship system and the US Government via the Nuclear Regulatory Commission in Washington, D.C, having on record an effective participation in the development of the US NRC, EPA, and DOE's 'FRMAC Assessment Manual - The Federal manual for Assessing Environmental Data during a Radiological Emergency', and the 'RTM-95 International Technical Response Manual', and the research initiative of developing a software support for the manuals' implementation - the codes 'ROBOT' (Rule-Oriented Basic Operational Tool); iii) A phase-three period (1996 - ), evolving within the RODOS framework and featuring, inter alia: (a) the application of the ROBOT concept in the development of a standalone software platform, code-named NOTEPAD for DSS support in field operations, nuclear accident drills, expert service provision on issues such as siting and health and environmental impact assessment, mainly targeting the accident source near-field; (b) a likewise experiment in the summary assessment of the far-field consequences of an atmospheric release ('QuickFIX'); (c) a research initiative in modeling the dispersion in complex topography terrains, using linearized equations of the mesoscale meteorology and heuristic concepts; (d) the development, by appointment of the Swiss Federal Institute of Technology ETH-Zurich and under the joint guidance of Institut de protection et de surete nucleaire CEA-IPSN and Kernforschungszentrum Karlsruhe, of the technical specifications and working - prototypes of the 'CONTAINMENT' module in the software package 'STEPS' (Source Term Estimation based on Plant Status). (author)

  16. The Discovery of the Electromagnetic Counterpart of GW170817: Kilonova AT 2017gfo/DLT17ck

    International Nuclear Information System (INIS)

    Valenti, Stefano; Yang, Sheng; Tartaglia, Leonardo; Sand, David J.; Cappellaro, Enrico; Corsi, Alessandra; Jha, Saurabh W.; Reichart, Daniel E.; Haislip, Joshua; Kouprianov, Vladimir

    2017-01-01

    During the second observing run of the Laser Interferometer Gravitational-wave Observatory (LIGO) and Virgo Interferometer, a gravitational-wave signal consistent with a binary neutron star coalescence was detected on 2017 August 17th (GW170817), quickly followed by a coincident short gamma-ray burst trigger detected by the Fermi satellite. The Distance Less Than 40 (DLT40) Mpc supernova search performed pointed follow-up observations of a sample of galaxies regularly monitored by the survey that fell within the combined LIGO+Virgo localization region and the larger Fermi gamma-ray burst error box. Here we report the discovery of a new optical transient (DLT17ck, also known as SSS17a; it has also been registered as AT 2017gfo) spatially and temporally coincident with GW170817. The photometric and spectroscopic evolution of DLT17ck is unique, with an absolute peak magnitude of M _r = −15.8 ± 0.1 and an r -band decline rate of 1.1 mag day"−"1. This fast evolution is generically consistent with kilonova models, which have been predicted as the optical counterpart to binary neutron star coalescences. Analysis of archival DLT40 data does not show any sign of transient activity at the location of DLT17ck down to r ∼ 19 mag in the time period between 8 months and 21 days prior to GW170817. This discovery represents the beginning of a new era for multi-messenger astronomy, opening a new path by which to study and understand binary neutron star coalescences, short gamma-ray bursts, and their optical counterparts.

  17. Bimodal Long-lasting Components in Short Gamma-Ray Bursts: Promising Electromagnetic Counterparts to Neutron Star Binary Mergers

    Energy Technology Data Exchange (ETDEWEB)

    Kisaka, Shota; Sakamoto, Takanori [Department of Physics and Mathematics, Aoyama Gakuin University, Sagamihara, Kanagawa, 252-5258 (Japan); Ioka, Kunihito, E-mail: kisaka@phys.aoyama.ac.jp, E-mail: tsakamoto@phys.aoyama.ac.jp, E-mail: kunihito.ioka@yukawa.kyoto-u.ac.jp [Center for Gravitational Physics, Yukawa Institute for Theoretical Physics, Kyoto University, Kyoto 606-8502 (Japan)

    2017-09-10

    Long-lasting emission of short gamma-ray bursts (GRBs) is crucial to reveal the physical origin of the central engine as well as to detect electromagnetic (EM) counterparts to gravitational waves (GWs) from neutron star binary mergers. We investigate 65 X-ray light curves of short GRBs, which is six times more than previous studies, by combining both Swift /BAT and XRT data. The light curves are found to consist of two distinct components at >5 σ with bimodal distributions of luminosity and duration, i.e., extended (with a timescale of ≲10{sup 3} s) and plateau emission (with a timescale of ≳10{sup 3} s), which are likely the central engine activities, but not afterglows. The extended emission has an isotropic energy comparable to the prompt emission, while the plateau emission has ∼0.01–1 times this energy. Half (50%) of our sample has both components, while the other half is consistent with having both components. This leads us to conjecture that almost all short GRBs have both the extended and plateau emission. The long-lasting emission can be explained by the jets from black holes with fallback ejecta, and could power macronovae (or kilonovae) like GRB 130603B and GRB 160821B. Based on the observed properties, we quantify the detectability of EM counterparts to GWs, including the plateau emission scattered to the off-axis angle, with CALET /HXM, INTEGRAL /SPI-ACS, Fermi /GBM, MAXI /GSC, Swift /BAT, XRT, the future ISS-Lobster /WFI, Einstein Probe /WXT, and eROSITA .

  18. The Discovery of the Electromagnetic Counterpart of GW170817: Kilonova AT 2017gfo/DLT17ck

    Energy Technology Data Exchange (ETDEWEB)

    Valenti, Stefano; Yang, Sheng; Tartaglia, Leonardo [Department of Physics, University of California, 1 Shields Avenue, Davis, CA 95616-5270 (United States); Sand, David J. [Department of Astronomy/Steward Observatory, 933 North Cherry Avenue, Room N204, Tucson, AZ 85721-0065 (United States); Cappellaro, Enrico [INAF Osservatorio Astronomico di Padova, Vicolo dell’Osservatorio 5, I-35122 Padova (Italy); Corsi, Alessandra [Physics and Astronomy Department, Texas Tech University, Lubbock, TX 79409 (United States); Jha, Saurabh W. [Department of Physics and Astronomy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Reichart, Daniel E.; Haislip, Joshua; Kouprianov, Vladimir [Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)

    2017-10-20

    During the second observing run of the Laser Interferometer Gravitational-wave Observatory (LIGO) and Virgo Interferometer, a gravitational-wave signal consistent with a binary neutron star coalescence was detected on 2017 August 17th (GW170817), quickly followed by a coincident short gamma-ray burst trigger detected by the Fermi satellite. The Distance Less Than 40 (DLT40) Mpc supernova search performed pointed follow-up observations of a sample of galaxies regularly monitored by the survey that fell within the combined LIGO+Virgo localization region and the larger Fermi gamma-ray burst error box. Here we report the discovery of a new optical transient (DLT17ck, also known as SSS17a; it has also been registered as AT 2017gfo) spatially and temporally coincident with GW170817. The photometric and spectroscopic evolution of DLT17ck is unique, with an absolute peak magnitude of M {sub r} = −15.8 ± 0.1 and an r -band decline rate of 1.1 mag day{sup −1}. This fast evolution is generically consistent with kilonova models, which have been predicted as the optical counterpart to binary neutron star coalescences. Analysis of archival DLT40 data does not show any sign of transient activity at the location of DLT17ck down to r ∼ 19 mag in the time period between 8 months and 21 days prior to GW170817. This discovery represents the beginning of a new era for multi-messenger astronomy, opening a new path by which to study and understand binary neutron star coalescences, short gamma-ray bursts, and their optical counterparts.

  19. Nuclear counterparts of the cytoplasmic mitochondrial 12S rRNA gene: a problem of ancient DNA and molecular phylogenies.

    Science.gov (United States)

    van der Kuyl, A C; Kuiken, C L; Dekker, J T; Perizonius, W R; Goudsmit, J

    1995-06-01

    Monkey mummy bones and teeth originating from the North Saqqara Baboon Galleries (Egypt), soft tissue from a mummified baboon in a museum collection, and nineteenth/twentieth-century skin fragments from mangabeys were used for DNA extraction and PCR amplification of part of the mitochondrial 12S rRNA gene. Sequences aligning with the 12S rRNA gene were recovered but were only distantly related to contemporary monkey mitochondrial 12S rRNA sequences. However, many of these sequences were identical or closely related to human nuclear DNA sequences resembling mitochondrial 12S rRNA (isolated from a cell line depleted in mitochondria) and therefore have to be considered contamination. Subsequently in a separate study we were able to recover genuine mitochondrial 12S rRNA sequences from many extant species of nonhuman Old World primates and sequences closely resembling the human nuclear integrations. Analysis of all sequences by the neighbor-joining (NJ) method indicated that mitochondrial DNA sequences and their nuclear counterparts can be divided into two distinct clusters. One cluster contained all temporary cytoplasmic mitochondrial DNA sequences and approximately half of the monkey nuclear mitochondriallike sequences. A second cluster contained most human nuclear sequences and the other half of monkey nuclear sequences with a separate branch leading to human and gorilla mitochondrial and nuclear sequences. Sequences recovered from ancient materials were equally divided between the two clusters. These results constitute a warning for when working with ancient DNA or performing phylogenetic analysis using mitochondrial DNA as a target sequence: Nuclear counterparts of mitochondrial genes may lead to faulty interpretation of results.

  20. Negative leave balances

    CERN Multimedia

    Human Resources Department

    2005-01-01

    Members of the personnel entitled to annual leave and, where appropriate, saved leave and/or compensatory leave are requested to take note of the new arrangements described below, which were recommended by the Standing Concertation Committee (SCC) at its meeting on 1Â September 2005 and subsequently approved by the Director-General. The changes do not apply to members of the personnel participating in the Progressive Retirement Programme (PRP) or the Part-time Work as a pre-retirement measure, for whom the specific provisions communicated at the time of joining will continue to apply. Â Negative balances in annual leave, saved leave and/or compensatory leave accounts at the end of the leave year (30th September) and on the date on which bonuses are credited to the saved leave account (31st December): Where members of the personnel have a leave account with a negative balance on 30Â September and/or 31Â December, leave will automatically be transferred from one account to another on the relevant dates i...

  1. Negative leave balances

    CERN Multimedia

    Human Resources Department

    2005-01-01

    Members of the personnel entitled to annual leave and, where appropriate, saved leave and/or compensatory leave are requested to take note of the new arrangements described below, which were recommended by the Standing Concertation Committee (SCC) at its meeting on 1 September 2005 and subsequently approved by the Director-General. The changes do not apply to members of the personnel participating in the Progressive Retirement Programme (PRP) or the Part-time Work as a pre-retirement measure, for whom the specific provisions communicated at the time of joining will continue to apply.  Negative balances in annual leave, saved leave and/or compensatory leave accounts at the end of the leave year (30th September) and on the date on which bonuses are credited to the saved leave account (31st December): Where members of the personnel have a leave account with a negative balance on 30 September and/or 31 December, leave will automatically be transferred from one account to another on the relevant dates in or...

  2. Blatant Stereotype Threat and Women's Math Performance: Self-Handicapping as a Strategic Means To Cope with Obtrusive Negative Performance Expectations.

    Science.gov (United States)

    Keller, Johannes

    2002-01-01

    Examined the impact of increased salience of negative stereotypic expectations on math performance among high school students. Results indicated that female students in the condition of heightened salience of negative stereotypic expectations underperformed in comparison to their control group counterparts. The effect of blatant stereotype threat…

  3. Do `negative' temperatures exist?

    Science.gov (United States)

    Lavenda, B. H.

    1999-06-01

    A modification of the second law is required for a system with a bounded density of states and not the introduction of a `negative' temperature scale. The ascending and descending branches of the entropy versus energy curve describe particle and hole states, having thermal equations of state that are given by the Fermi and logistic distributions, respectively. Conservation of energy requires isentropic states to be isothermal. The effect of adiabatically reversing the field is entirely mechanical because the only difference between the two states is their energies. The laws of large and small numbers, leading to the normal and Poisson approximations, characterize statistically the states of infinite and zero temperatures, respectively. Since the heat capacity also vanishes in the state of maximum disorder, the third law can be generalized in systems with a bounded density of states: the entropy tends to a constant as the temperature tends to either zero or infinity.

  4. Guanidinylated 3-gluconamidopropyl methacrylamide-s-3-aminopropyl methacrylamide copolymer as siRNA carriers for inhibiting human telomerase reverse transcriptase expression.

    Science.gov (United States)

    Wu, Yang; Ji, Jinkai; Yang, Ran; Zhang, Xiaoqiang; Li, Yuanhui; Pu, Yuepu; Li, Xinsong

    2013-01-01

    In this report, a series of well-defined glucose- and guanidine-based cationic copolymers as gene carriers were developed to inhibit human telomerase reverse transcriptase (hTERT) gene expression. First of all, guandinylated 3-gluconamidopropyl methacrylamide-s-3-aminopropyl methacrylamide copolymers (guanidinylated GAPMA-s-APMA, abbreviated as GGA) were prepared via aqueous reversible addition--fragmentation chain transfer polymerization (RAFT). Then, three target hTERT siRNA TERT-1, TERT-2 and TERT-3 were designed and combined with GGA copolymers to form siRNA/GGA polyplexes. The polyplexes were examined by dynamic light scattering and agarose gel electrophoresis. The results indicated that GGA copolymers can condense siRNA effectively to form particles with the diameter from 157 nm to 411 nm and zeta potential values in the range from +3.7 to +15.8 mV at various charge ratios (N/P). The MTT assay data of siRNA/GGA polyplexes on human hepatocellular liver carcinoma cells (HepG2) indicated that GGA copolymer had better cell viabilities than polyethylenimine (PEI). Furthermore, the transfection of siRNA/GGA polyplexes was detected by real-time quantitative PCR (RT-qPCR) in HepG2. It was found that siRNA/GGA polyplexes could effectively silence hTERT mRNA expression in serum-free media (paminopropyl methacrylamide copolymers might be promise in gene delivery.

  5. Telomere length is short in PCOS and oral contraceptive does not affect the telomerase activity in granulosa cells of patients with PCOS.

    Science.gov (United States)

    Li, Ying; Deng, Bingbing; Ouyang, Nengyong; Yuan, Ping; Zheng, Lingyan; Wang, Wenjun

    2017-07-01

    Our study aimed to investigate the association of telomerase activity (TA) and telomere length (TL) in granulosa cells (GCs) with IVF outcomes of polycystic ovary syndrome (PCOS) patients, and the effects of oral contraceptive pill (OCP) pretreatment on these two parameters. One hundred sixty-three infertile women were enrolled and divided into a PCOS group (n = 65) and a non-PCOS group (n = 98). The PCOS group was further divided into an OCP pretreatment group (n = 35) and a non-OCP pretreatment group (n = 30), a TA PCOS group and 1.118 in non-PCOS group (P = 0.005). The patients with TL ≥1 accounted for 36.9% in PCOS group and 54.1% in non-PCOS group (P = 0.032). The average duration of infertility for PCOS patients was 5 years in TA PCOS patients. Shorter TL was found in PCOS patients. The TA levels did not change significantly in PCOS patients. PCOS patients with a lower TA level and shorter telomeres had an earlier onset of infertility symptoms. No predictive value was found for TA and TL in terms of embryo quality or IVF outcomes in PCOS patients, and no effect OCP pretreatment was observed on either TA and TL.

  6. The functional polymorphism rs73598374:G>A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length.

    Science.gov (United States)

    Concetti, Fabio; Carpi, Francesco M; Nabissi, Massimo; Picciolini, Matteo; Santoni, Giorgio; Napolioni, Valerio

    2015-02-01

    Recent evidence demonstrated a relevant role of adenosine deaminase (ADA) in replicative senescence of T cells through its capacity to modulate telomerase activity (TA). Herein, we tested the impact of the functional polymorphism ADA rs73598374:G>A (c.22G>A, p.Asp8Asn) on telomere biology, by measuring TA and leukocyte telomere length (LTL) in healthy subjects selected according to rs73598374 genotype. rs73598374-A carriers showed lower TA (P=0.019) and shorter LTL (P=0.003), respectively, compared to G/G carriers. rs73598374-A carriers showed a stronger cross-sectional age reduction of LTL (r=-0.314, P=0.005) compared to G/G carriers (r=-0.243, P=0.022). The reduced ADA activity associated to rs73598374-A variant predisposes those carriers to display higher levels of adenosine compared to G/G carriers. Consequently, it may lead to an accelerated process of replicative senescence, causing a stronger reduction of TA and in turn shorter LTL. In conclusion, the crucial role played by replicative senescence of the immune system in several human diseases and in the aging process underscores the relevance of the present findings and also spurs interest into the possible involvement of rs73598374 in shaping the susceptibility to several age-related diseases.

  7. Unique case of oligoastrocytoma with recurrence and grade progression: Exhibiting differential expression of high mobility group-A1 and human telomerase reverse transcriptase

    Science.gov (United States)

    Gandhi, Puneet; Khare, Richa; Niraj, Kavita; Garg, Nitin; Sorte, Sandeep K; Gulwani, Hanni

    2016-01-01

    Mixed gliomas, primarily oligoastrocytomas, account for about 5%-10% of all gliomas. Distinguishing oligoastrocytoma based on histological features alone has limitations in predicting the exact biological behavior, necessitating ancillary markers for greater specificity. In this case report, human telomerase reverse transcriptase (hTERT) and high mobility group-A1 (HMGA1); markers of proliferation and stemness, have been quantitatively analyzed in formalin-fixed paraffin-embedded tissue samples of a 34 years old patient with oligoastrocytoma. Customized florescence-based immunohistochemistry protocol with enhanced sensitivity and specificity is used in the study. The patient presented with a history of generalized seizures and his magnetic resonance imaging scans revealed infiltrative ill-defined mass lesion with calcified foci within the left frontal white matter, suggestive of glioma. He was surgically treated at our center for four consecutive clinical events. Histopathologically, the tumor was identified as oligoastrocytoma-grade II followed by two recurrence events and final progression to grade III. Overall survival of the patient without adjuvant therapy was more than 9 years. Glial fibrillary acidic protein, p53, Ki-67, nuclear atypia index, pre-operative neutrophil-lymphocyte ratio, are the other parameters assessed. Findings suggest that hTERT and HMGA1 are linked to tumor recurrence and progression. Established markers can assist in defining precise histopathological grade in conjuction with conventional markers in clinical setup. PMID:27672647

  8. Lithium alloy negative electrodes

    Science.gov (United States)

    Huggins, Robert A.

    The 1996 announcement by Fuji Photo Film of the development of lithium batteries containing convertible metal oxides has caused a great deal of renewed interest in lithium alloys as alternative materials for use in the negative electrode of rechargeable lithium cells. The earlier work on lithium alloys, both at elevated and ambient temperatures is briefly reviewed. Basic principles relating thermodynamics, phase diagrams and electrochemical properties under near-equilibrium conditions are discussed, with the Li-Sn system as an example. Second-phase nucleation, and its hindrance under dynamic conditions plays an important role in determining deviations from equilibrium behavior. Two general types of composite microstructure electrodes, those with a mixed-conducting matrix, and those with a solid electrolyte matrix, are discussed. The Li-Sn-Si system at elevated temperatures, and the Li-Sn-Cd at ambient temperatures are shown to be examples of mixed-conducting matrix microstructures. The convertible oxides are an example of the solid electrolyte matrix type. Although the reversible capacity can be very large in this case, the first cycle irreversible capacity required to convert the oxides to alloys may be a significant handicap.

  9. Microdosimetry of negative pions

    International Nuclear Information System (INIS)

    Amols, H.I.; Dicello, J.F.; Lane, T.F.

    1976-01-01

    The radiation quality of negative and positive pions of initial momentum 168MeV/c has been determined at eight different depths in a liquid phantom. The measurements were made with a 2.5cm diameter spherical proportional counter with Shonka A-150 neutron tissue equivalent plastic walls. The gas pressure in the sensitive volume was chosen to stimulate a diameter of 2μm in unit density material. Dose distributions as a function of lineal energy change slowly in the entrance and plateau regions with a dose mean lineal energy of 6-8keV/μm. Less than 3% of the dose is delivered in excess of 50keV/μm in this region. In the Bragg peak region the distributions change rapidly as a function of depth with the dose mean lineal energy increasing to 38keV/μm at the peak and to 57keV/μm just beyond the peak. On the basis of these microdosimetric data predictions of RBE and OER have been made with the use of both the theory of dual radiation action and also the delta ray theory of cell survival. The former has been used to predict biological response at low doses and the latter at high doses. A comparison is made between the two theories at intermediate doses. The results of these calculations are not inconsistant with recent biological data

  10. Negative legacy of obesity.

    Directory of Open Access Journals (Sweden)

    Kohsuke Shirakawa

    Full Text Available Obesity promotes excessive inflammation, which is associated with senescence-like changes in visceral adipose tissue (VAT and the development of type 2 diabetes (T2DM and cardiovascular diseases. We have reported that a unique population of CD44hi CD62Llo CD4+ T cells that constitutively express PD-1 and CD153 exhibit cellular senescence and cause VAT inflammation by producing large amounts of osteopontin. Weight loss improves glycemic control and reduces cardiovascular disease risk factors, but its long-term effects on cardiovascular events and longevity in obese individuals with T2DM are somewhat disappointing and not well understood. High-fat diet (HFD-fed obese mice were subjected to weight reduction through a switch to a control diet. They lost body weight and visceral fat mass, reaching the same levels as lean mice fed a control diet. However, the VAT of weight reduction mice exhibited denser infiltration of macrophages, which formed more crown-like structures compared to the VAT of obese mice kept on the HFD. Mechanistically, CD153+ PD-1+ CD4+ T cells are long-lived and not easily eliminated, even after weight reduction. Their continued presence maintains a self-sustaining chronic inflammatory loop via production of large amounts of osteopontin. Thus, we concluded that T-cell senescence is essentially a negative legacy effect of obesity.

  11. Positive Effects of Negative Publicity: When Negative Reviews Increase Sales

    OpenAIRE

    Jonah Berger; Alan T. Sorensen; Scott J. Rasmussen

    2010-01-01

    Can negative information about a product increase sales, and if so, when? Although popular wisdom suggests that "any publicity is good publicity," prior research has demonstrated only downsides to negative press. Negative reviews or word of mouth, for example, have been found to hurt product evaluation and sales. Using a combination of econometric analysis and experimental methods, we unify these perspectives to delineate contexts under which negative publicity about a product will have posit...

  12. NEW OPTICAL/ULTRAVIOLET COUNTERPARTS AND THE SPECTRAL ENERGY DISTRIBUTIONS OF NEARBY, THERMALLY EMITTING, ISOLATED NEUTRON STARS

    International Nuclear Information System (INIS)

    Kaplan, D. L.; Kamble, A.; Van Kerkwijk, M. H.; Ho, W. C. G.

    2011-01-01

    We present Hubble Space Telescope optical and ultraviolet photometry for five nearby, thermally emitting neutron stars. With these measurements, all seven such objects have confirmed optical and ultraviolet counterparts. Combining our data with archival space-based photometry, we present spectral energy distributions for all sources and measure the 'optical excess': the factor by which the measured photometry exceeds that extrapolated from X-ray spectra. We find that the majority have optical and ultraviolet fluxes that are inconsistent with that expected from thermal (Rayleigh-Jeans) emission, exhibiting more flux at longer wavelengths. We also find that most objects have optical excesses between 5 and 12, but that one object (RX J2143.0+0654) exceeds the X-ray extrapolation by a factor of more than 50 at 5000 A, and that this is robust to uncertainties in the X-ray spectra and absorption. We consider explanations for this ranging from atmospheric effects, magnetospheric emission, and resonant scattering, but find that none is satisfactory.

  13. TOWARD UNDERSTANDING THE B[e] PHENOMENON. III. PROPERTIES OF THE OPTICAL COUNTERPART OF IRAS 00470+6429

    International Nuclear Information System (INIS)

    Miroshnichenko, A. S.; Chentsov, E. L.; Klochkova, V. G.; Zharikov, S. V.; Grankin, K. N.; Kusakin, A. V.; Gandet, T. L.; Klingenberg, G.; Kildahl, S.; Rudy, R. J.; Lynch, D. K.; Venturini, C. C.; Mazuk, S.; Puetter, R. C.; Perry, R. B.; Carciofi, A. C.; Bjorkman, K. S.; Gray, R. O.; Bernabei, S.; Polcaro, V. F.

    2009-01-01

    FS CMa type stars are a group of Galactic objects with the B[e] phenomenon. They exhibit strong emission-line spectra and infrared excesses, which are most likely due to recently formed circumstellar dust. The group content and identification criteria were described in the first two papers of the series. In this paper we report our spectroscopic and photometric observations of the optical counterpart of IRAS 00470+6429 obtained in 2003-2008. The optical spectrum is dominated by emission lines, most of which have P Cyg type profiles. We detected significant brightness variations, which may include a regular component, and variable spectral line profiles in both shape and position. The presence of a weak Li I 6708 A line in the spectrum suggests that the object is most likely a binary system with a B2-B3 spectral-type primary companion of a luminosity log L/L sun = 3.9 ± 0.3 and a late-type secondary companion. We estimate a distance toward the object to be 2.0 ± 0.3 kpc from the Sun.

  14. Lysine residue 185 of Rad1 is a topological but not a functional counterpart of lysine residue 164 of PCNA.

    Directory of Open Access Journals (Sweden)

    Niek Wit

    Full Text Available Monoubiquitylation of the homotrimeric DNA sliding clamp PCNA at lysine residue 164 (PCNA(K164 is a highly conserved, DNA damage-inducible process that is mediated by the E2/E3 complex Rad6/Rad18. This ubiquitylation event recruits translesion synthesis (TLS polymerases capable of replicating across damaged DNA templates. Besides PCNA, the Rad6/Rad18 complex was recently shown in yeast to ubiquitylate also 9-1-1, a heterotrimeric DNA sliding clamp composed of Rad9, Rad1, and Hus1 in a DNA damage-inducible manner. Based on the highly similar crystal structures of PCNA and 9-1-1, K185 of Rad1 (Rad1(K185 was identified as the only topological equivalent of PCNA(K164. To investigate a potential role of posttranslational modifications of Rad1(K185 in DNA damage management, we here generated a mouse model with a conditional deletable Rad1(K185R allele. The Rad1(K185 residue was found to be dispensable for Chk1 activation, DNA damage survival, and class switch recombination of immunoglobulin genes as well as recruitment of TLS polymerases during somatic hypermutation of immunoglobulin genes. Our data indicate that Rad1(K185 is not a functional counterpart of PCNA(K164.

  15. Thermodynamic Stability of Ice II and Its Hydrogen-Disordered Counterpart: Role of Zero-Point Energy.

    Science.gov (United States)

    Nakamura, Tatsuya; Matsumoto, Masakazu; Yagasaki, Takuma; Tanaka, Hideki

    2016-03-03

    We investigate why no hydrogen-disordered form of ice II has been found in nature despite the fact that most of hydrogen-ordered ices have hydrogen-disordered counterparts. The thermodynamic stability of a set of hydrogen-ordered ice II variants relative to ice II is evaluated theoretically. It is found that ice II is more stable than the disordered variants so generated as to satisfy the simple ice rule due to the lower zero-point energy as well as the pair interaction energy. The residual entropy of the disordered ice II phase gradually compensates the unfavorable free energy with increasing temperature. The crossover, however, occurs at a high temperature well above the melting point of ice III. Consequently, the hydrogen-disordered phase does not exist in nature. The thermodynamic stability of partially hydrogen-disordered ices is also scrutinized by examining the free-energy components of several variants obtained by systematic inversion of OH directions in ice II. The potential energy of one variant is lower than that of the ice II structure, but its Gibbs free energy is slightly higher than that of ice II due to the zero-point energy. The slight difference in the thermodynamic stability leaves the possibility of the partial hydrogen-disorder in real ice II.

  16. A Dark Energy Camera Search for an Optical Counterpart to the First Advanced LIGO Gravitational Wave Event GW150914

    Science.gov (United States)

    Soares-Santos, M.; Kessler, R.; Burger, E.; Annis, J.; Brout, D.; Buckley-Geer, E.; Chen, H.; Cowperthwaite, P. S.; Diehl, H.T.; Doctor, Z.; hide

    2016-01-01

    We report the results of a deep search for an optical counterpart to the gravitational wave (GW) event GW150914, the first trigger from the Advanced LIGO GW detectors. We used the Dark Energy Camera (DECam) to image a 102 deg(exp 2) area, corresponding to 38% of the initial trigger high-probability sky region and to 11% of the revised high-probability region. We observed in the i and z bands at 4-5, 7, and 24 days after the trigger. The median 5(sigma) point-source limiting magnitudes of our search images are i = 22.5 and z = 21.8 mag. We processed the images through a difference-imaging pipeline using templates from pre-existing Dark Energy Survey data and publicly available DECam data. Due to missing template observations and other losses, our effective search area subtends 40 deg(exp 2), corresponding to a 12% total probability in the initial map and 3% in the final map. In this area, we search for objects that decline significantly between days 4-5 and day 7, and are undetectable by day 24, finding none to typical magnitude limits of i = 21.5, 21.1, 20.1 for object colors (i-z)= 1, 0, -1, respectively. Our search demonstrates the feasibility of a dedicated search program with DECam and bodes well for future research in this emerging field.

  17. CYGNUS X-3: ITS LITTLE FRIEND’S COUNTERPART, THE DISTANCE TO CYGNUS X-3, AND OUTFLOWS/JETS

    Energy Technology Data Exchange (ETDEWEB)

    McCollough, M. L.; Dunham, M. M. [Smithsonian Astrophysical Observatory, 60 Garden Street, Cambridge, MA 02138 (United States); Corrales, L., E-mail: mmccollough@cfa.harvard.edu [Kavli Institute for Astrophysics and Space Research, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States)

    2016-10-20

    Chandra observations have revealed a feature within 16″ of Cygnus X-3 that varied in phase with Cygnus X-3. This feature was shown to be a Bok globule that is along the line of sight to Cygnus X-3. We report on observations made with the Submillimeter Array to search for molecular emission from this globule, also known as Cygnus X-3's “Little Friend.” We have found a counterpart in both {sup 12}CO (2-1) and {sup 13}CO (2-1) emission. From the velocity shift of the molecular lines we are able to find two probable distances based on the Bayesian model of Milky Way kinematics of Reid et al. For the LF velocity of −47.5 km s{sup −1}, we find distances of 6.1 ± 0.6 kpc (62% probability) and 7.8 ± 0.6 kpc (38% probability). This yields distances to Cyg X-3 of 7.4 ± 1.1 kpc and 10.2 ± 1.2 kpc, respectively. Based on the probabilities entailed, we take 7.4 ± 1.1 kpc as the preferred distance to Cyg X-3. We also report the discovery of bipolar molecular outflow, suggesting that there is active star formation occurring within the Little Friend.

  18. UNVEILING THE NATURE OF THE UNIDENTIFIED GAMMA-RAY SOURCES. III. GAMMA-RAY BLAZAR-LIKE COUNTERPARTS AT LOW RADIO FREQUENCIES

    Energy Technology Data Exchange (ETDEWEB)

    Massaro, F.; Funk, S. [SLAC National Laboratory and Kavli Institute for Particle Astrophysics and Cosmology, 2575 Sand Hill Road, Menlo Park, CA 94025 (United States); D' Abrusco, R.; Paggi, A. [Harvard-Smithsonian Astrophysical Observatory, 60 Garden Street, Cambridge, MA 02138 (United States); Giroletti, M. [INAF Istituto di Radioastronomia, via Gobetti 101, I-40129 Bologna (Italy); Masetti, N. [INAF-Istituto di Astrofisica Spaziale e Fisica Cosmica di Bologna, via Gobetti 101, I-40129 Bologna (Italy); Tosti, G. [Dipartimento di Fisica, Universita degli Studi di Perugia, I-06123 Perugia (Italy); Nori, M. [Department of Physics and Astronomy, University of Bologna, viale Berti Pichat 6/2, I-40127 Bologna (Italy)

    2013-07-01

    About one-third of the {gamma}-ray sources listed in the second Fermi Large Area Telescope catalog (2FGL) have no firmly established counterpart at lower energies and so are classified as unidentified gamma-ray sources (UGSs). Here, we propose a new approach to find candidate counterparts for the UGSs based on the 325 MHz radio survey performed with the Westerbork Synthesis Radio Telescope in the northern hemisphere. First, we investigate the low-frequency radio properties of blazars, the largest known population of {gamma}-ray sources; then we search for sources with similar radio properties combining the information derived from the Westerbork Northern Sky Survey (WENSS) with those of the NRAO Very Large Array Sky Survey. We present a list of candidate counterparts for 32 UGSs with at least one counterpart in the WENSS. We also performed an extensive research in the literature to look for infrared and optical counterparts of the {gamma}-ray blazar candidates selected using the low-frequency radio observations to confirm their nature. On the basis of our multifrequency research, we identify 23 new {gamma}-ray blazar candidates out of the 32 UGSs investigated. Compa