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Sample records for human lymphoblastoid tk6

  1. Investigation of the apoptotic way induced by digallic acid in human lymphoblastoid TK6 cells

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    Bhouri Wissem

    2012-06-01

    Full Text Available Abstract Background The digallic acid (DGA purified from Pistacia lentiscus. L fruits was investigated for its antiproliferative and apoptotic activities on human lymphoblastoid TK6 cells. Methods We attempt to characterize the apoptotic pathway activated by DGA. Apoptosis was detected by DNA fragmentation, PARP cleavage and by evaluating caspase activities. Results The inhibition of lymphoblastoid cell proliferation was noted from 8.5 μg/ml of DGA. The induction of apoptosis was confirmed by DNA fragmentation and PARP cleavage. We have demonstrated that DGA induces apoptosis by activating the caspase-8 extrinsic pathway. Caspase-3 was also activated in a dose dependent manner. Conclusion In summary, DGA exhibited an apoptosis inductor effect in TK6 cells revealing thus its potential as a cancer-preventive agent.

  2. The food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine activates S-phase checkpoint and apoptosis, and induces gene mutation in human lymphoblastoid TK6 cells.

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    Zhu, H; Boobis, A R; Gooderham, N J

    2000-03-01

    The mutagenic heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-blpyridine (PhIP) is formed at parts per billion levels when meat is cooked. It is efficiently absorbed from cooked food and extensively activated to its genotoxic N-hydroxy derivative by human cytochrome P4501A enzymes. It is also a rodent carcinogen. To better understand the genetic toxicity of PhIP, we have examined its effect on the cell cycle and gene mutation frequency using human lymphoblastoid cells (TK6) as a model. Because TK6 cells are unable to activate PhIP, we have cultured the cells in the presence of irradiated Chinese hamster XEMh1A2-MZ cells that have been genetically engineered to express human CYP1A2. Asynchronized TK6 cells were harvested at various times after treatment with PhIP (1.25-10 microg/ml), fixed and stained with propidium iodide for the examination of cell cycle by fluorescence-activated flow cytometry. After 20 h of PhIP treatment, a slight S-phase delay of the cell cycle was observed. Normal cell cycle recovered after the cells were washed and further cultured in the absence of PhIP for 5 days. However, PhIP treatment for 40 h induced a more pronounced S-phase arrest that was accompanied by a decrease in the level of cyclin A, an S-phase cyclin. This was followed by the appearance of a sub-G1 population (indicative of apoptotic cell death), range from 13 to 54% with PhIP concentrations from 1.25 to 10 microg/ml, compared with 5% in the vehicle control. A concomitant increase of mutation frequency at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus, assessed by colony formation assay in the presence of 6-thioguanine, was detected after 40 h-range, 16 to 45 x 10(-6) compared with 12 x 10(-6) in cultures without PhIP. In G1-enriched cell populations (synchronized culture), although PhIP induced S-phase delay, the induction of sub-G1 cells was substantially decreased. Our studies show that in TK6 cells, PhIP activates S-phase checkpoint, yet eludes

  3. Poly(ADP-ribosyl)ation enhances H-RAS protein stability and causes abnormal cell cycle progression in human TK6 lymphoblastoid cells treated with hydroquinone.

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    Liu, Linhua; Ling, Xiaoxuan; Tang, Huanwen; Chen, Jialong; Wen, Qiaosheng; Zou, Fei

    2015-08-05

    Hydroquinone (HQ), one of the most important benzene-derived metabolites, can induce aberrant cell cycle progression; however, the mechanism of this induction remains unclear. Poly(ADP-ribosyl)ation (PARylation), which is catalysed primarily by poly(ADP-ribose) polymerase-1 (PARP-1), participates in various biological processes, including cell cycle control. The results of the present study show an accumulation in G1 phase versus S phase of TK6 human lymphoblast cells treated with HQ for 48h compared with PBS-treated cells; after 72h of HQ treatment, the cells transitioned from G1 arrest to S phase arrest. We examined the expression of six genes related to the cell cycle or leukaemia to further explore the reason for this phenomenon. Among these genes, H-RAS was found to be associated with this phenomenon because its mRNA and protein expression decreased at 48h and increased at 72h. Experiments for PARP activity induction and inhibition revealed that the observed PARylation was positively associated with H-RAS expression. Moreover, in cells treated with HQ in conjunction with PARP-1 knockdown, expression of the H-RAS protein decreased and the number of cells in G1 phase increased. The degree of poly(ADP-ribosyl) modification of the H-RAS protein increased in cells treated with HQ for 72h, further supporting that changes in PARylation contributed to the rapid alteration of H-RAS protein expression, followed by abnormal progression of the cell cycle. Co-immunoprecipitation (co-IP) assays were employed to determine whether protein complexes were formed by PARP-1 and H-RAS proteins, and the direct interaction between these proteins indicated that PARylation regulated H-RAS expression. As detected by confocal microscopy, the H-RAS protein was found in the nucleus and cytoplasm. To our knowledge, this study is the first to reveal that H-RAS protein can be modified by PARylation. Copyright © 2015. Published by Elsevier Ireland Ltd.

  4. Characterization of a TK6-Bcl-xL gly-159-ala Human Lymphoblast Clone

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    Chyall, L.: Gauny, S.; Kronenberg, A.

    2006-01-01

    TK6 cells are a well-characterized human B-lymphoblast cell line derived from WIL-2 cells. A derivative of the TK6 cell line that was stably transfected to express a mutated form of the anti-apoptotic protein Bcl-xL (TK6-Bcl-xL gly-159- ala clone #38) is compared with the parent cell line. Four parameters were evaluated for each cell line: growth under normal conditions, plating efficiency, and frequency of spontaneous mutation to 6‑thioguanine resistance (hypoxanthine phosphoribosyl transferase locus) or trifluorothymidine resistance (thymidine kinase locus). We conclude that the mutated Bcl-xL protein did not affect growth under normal conditions, plating efficiency or spontaneous mutation frequencies at the thymidine kinase (TK) locus. Results at the hypoxanthine phosphoribosyl transferase (HPRT) locus were inconclusive. A mutant fraction for TK6‑Bcl-xL gly-159-ala clone #38 cells exposed to 150cGy of 160kVp x-rays was also calculated. Exposure to x-irradiation increased the mutant fraction of TK6‑Bcl-xL gly-159-ala clone #38 cells.

  5. Effect of chemical mutagens and carcinogens on gene expression profiles in human TK6 cells.

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    Lode Godderis

    Full Text Available Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes, we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose-response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti- apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control.

  6. Flavonoids products from Nitraria retusa leaves promote lymphoblastoid cells apoptosis.

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    Jihed, Boubaker; Bhouri, Wissem; Ben Sghaier, Mohammed; Bouhlel, Ines; Kriffi, Mounira; Skandrani, Ines; Dijoux, Franca Marie Genviève; Ghedira, Kamel; Chekir-Ghedira, Leila

    2012-01-01

    In this report, the ethyl acetate extract and its major constituent, isorhamnetin 3-o-robinobioside (I3-O-Rob), from Nitraria retusa (N. Retusa) leaf extracts were evaluated for their ability to induce apoptosis in human lymphoblastoid cells (TK6). Apoptosis of TK6 cell line was carried out using DNA fragmentation, poly ADP-ribose polymerase (PARP) cleavage with reference to caspase-3 activity. These tested products, from N. Retusa, enhanced the apoptosis effects in the tested cancer cell line. This result was confirmed by DNA fragmentation and PARP cleavage indicating a release of caspase-3 level. Our results indicate that the original ethyl acetate extract and the I3-O-Rob have a great antiproliferative effect on human lymphoblastoid cells (TK6), which may be due to their involvement in the apoptotic pathway.

  7. Chromosome loss caused by DNA fragmentation induced in main nuclei and micronuclei of human lymphoblastoid cells treated with colcemid.

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    Yamamoto, Mika; Wakata, Akihiro; Aoki, Yoshinobu; Miyamae, Yoichi; Kodama, Seiji

    2014-04-01

    Aneuploidy, a change in the number of chromosomes, plays an essential role in tumorigenesis. Our previous study demonstrated that a loss of a whole chromosome is induced in human lymphocytes by colcemid, a well-known aneugen. Here, to clarify the mechanism for colcemid-induced chromosome loss, we investigated the relationship between chromosome loss and DNA fragmentation in human lymphoblastoid cells treated with colcemid (an aneugen) compared with methyl methanesulfonate (MMS; a clastogen). We analyzed the number of fluorescence in situ hybridization (FISH) signals targeted for a whole chromosome 2 in cytokinesis-blocked binucleated TK6 cells and WTK-1 cells treated with colcemid and MMS, and concurrently detected DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results revealed that DNA fragmentation occurred in 60% of all binucleated TK6 cells harboring colcemid-induced chromosome loss (30% of micronuclei and 30% of main nuclei). DNA fragmentation was observed in colcemid-induced micronuclei containing a whole chromosome but not in MMS-induced micronuclei containing chromosome fragments. In contrast, colcemid-induced nondisjunction had no effect on induction of DNA fragmentation, suggesting that DNA fragmentation was triggered by micronuclei containing a whole chromosome but not by micronuclei containing chromosome fragments or nondisjunction. In addition, the frequency of binucleated cells harboring chromosome loss with DNA fragmentation in micronuclei or main nuclei was higher in wild-type p53 TK6 cells than in mutated-p53 WTK-1 cells treated with colcemid. Taken together, these present and previous results suggest that colcemid-induced chromosome loss is caused by DNA fragmentation, which is triggered by a micronucleus with a whole chromosome and controlled by the p53-dependent pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Effects of Simulated Microgravity on the Expression Profile of Microrna in Human Lymphoblastoid Cells

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    Zhang, Ye; Wu, Honglu; Ramesh, Govindarajan; Rohde, Larry; Story, Michael; Mangala, Lingegowda

    2012-07-01

    EFFECTS OF SIMULATED MICROGRAVITY ON THE EXPRESSION PROFILE OF MICRORNA IN HUMAN LYMPHOBLASTOID CELLS Lingegowda S. Mangala1,2, Ye Zhang1,3, Zhenhua He2, Kamal Emami1, Govindarajan T. Ramesh4, Michael Story 5, Larry H. Rohde2, and Honglu Wu1 1 NASA Johnson Space Center, Houston, Texas, USA 2 University of Houston Clear Lake, Houston, Texas, USA 3 Wyle Integrated Science and Engineering Group, Houston, Texas, USA 4 Norfolk State University, Norfolk, VA, USA 5 University of Texas, Southwestern Medical Center, Dallas, Texas, USA This study explores the changes in expression of microRNA (miRNA) and related genes under simulated microgravity conditions. In comparison to static 1g, microgravity has been shown to alter global gene expression patterns and protein levels in cultured cells or animals. miRNA has recently emerged as an important regulator of gene expression, possibly regulating as many as one-third of all human genes. However, very little is known about the effect of altered gravity on miRNA expression. To test the hypothesis that the miRNA expression profile would be altered in zero gravity resulting in altered regulation of gene expression leading to metabolic or functional changes in cells, we cultured TK6 human lymphoblastoid cells in a High Aspect Ratio Vessel (HARV; bioreactor) for 72 h either in the rotating condition to model microgravity in space or in the static condition as a control. Expression of several miRNA was changed significantly in the simulated microgravity condition including miR-150, miR-34a, miR-423-5p, miR-22 and miR-141, miR-618 and miR-222. To confirm whether this altered miRNA expression correlates with gene expression and functional changes of the cells, we performed DNA microarray and validated the related genes using q-RT PCR. Network and pathway analysis of gene and miRNA expression profiles indicates that the regulation of cell communication and catalytic activities, as well as pathways involved in immune response_IL-15

  9. Effects of Modeled Microgravity on Expression Profiles of Micro RNA in Human Lymphoblastoid Cells

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    Mangala, Lingegowda S.; Emami, Kamal; Story, Michael; Ramesh, Govindarajan; Rohde, Larry; Wu, Honglu

    2010-01-01

    Among space radiation and other environmental factors, microgravity or an altered gravity is undoubtedly the most significant stress experienced by living organisms during flight. In comparison to the static 1g, microgravity has been shown to alter global gene expression patterns and protein levels in cultured cells or animals. Micro RNA (miRNA) has recently emerged as an important regulator of gene expression, possibly regulating as many as one-third of all human genes. miRNA represents a class of single-stranded noncoding regulatory RNA molecules ( 22 nt) that control gene expressions by inhibiting the translation of mRNA to proteins. However, very little is known on the effect of altered gravity on miRNA expression. We hypothesized that the miRNA expression profile will be altered in zero gravity resulting in regulation of the gene expression and functional changes of the cells. To test this hypothesis, we cultured TK6 human lymphoblastoid cells in Synthecon s Rotary cell culture system (bioreactors) for 72 h either in the rotating (10 rpm) to model the microgravity in space or in the static condition. The cell viability was determined before and after culturing the cells in the bioreactor using both trypan blue and guava via count. Expressions of a panel of 352 human miRNA were analyzed using the miRNA PCRarray. Out of 352 miRNAs, expressions of 75 were significantly altered by a change of greater than 1.5 folds and seven miRNAs were altered by a fold change greater than 2 under the rotating culture condition. Among these seven, miR-545 and miR-517a were down regulated by 2 folds, whereas miR-150, miR-302a, miR-139-3p, miR-515-3p and miR-564 were up regulated by 2 to 8 folds. To confirm whether this altered miRNA expression correlates with gene expression and functional changes of the cells, we performed DNA Illumina Microarray Analysis and validated the related genes using q-RT PCR.

  10. Molecular Mechanisms of Radiation-Induced Genomic Instability in Human Cells

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    Howard L. Liber; Jeffrey L. Schwartz

    2005-10-31

    There are many different model systems that have been used to study chromosome instability. What is clear from all these studies is that conclusions concerning chromosome instability depend greatly on the model system and instability endpoint that is studied. The model system for our studies was the human B-lymphoblastoid cell line TK6. TK6 was isolated from a spontaneously immortalized lymphoblast culture. Thus there was no outside genetic manipulation used to immortalize them. TK6 is a relatively stable p53-normal immortal cell line (37). It shows low gene and chromosome mutation frequencies (19;28;31). Our general approach to studying instability in TK6 cells has been to isolate individual clones and analyze gene and chromosome mutation frequencies in each. This approach maximizes the possibility of detecting low frequency events that might be selected against in mass cultures.

  11. Non-random distribution of instability-associated chromosomal rearrangement breakpoints in human lymphoblastoid cells

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    Moore, Stephen R. [Environmental Toxicology Graduate Program, Department of Cell Biology and Neuroscience, University of California, Riverside, CA (United States); Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire (United Kingdom); Papworth, David [Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire (United Kingdom); Grosovsky, Andrew J. [Environmental Toxicology Graduate Program, Department of Cell Biology and Neuroscience, University of California, Riverside, CA (United States)]. E-mail: Grosovsky@ucr.edu

    2006-08-30

    Genomic instability is observed in tumors and in a large fraction of the progeny surviving irradiation. One of the best-characterized phenotypic manifestations of genomic instability is delayed chromosome aberrations. Our working hypothesis for the current study was that if genomic instability is in part attributable to cis mechanisms, we should observe a non-random distribution of chromosomes or sites involved in instability-associated rearrangements, regardless of radiation quality, dose, or trans factor expression. We report here the karyotypic examination of 296 instability-associated chromosomal rearrangement breaksites (IACRB) from 118 unstable TK6 human B lymphoblast, and isogenic derivative, clones. When we tested whether IACRB were distributed across the chromosomes based on target size, a significant non-random distribution was evident (p < 0.00001), and three IACRB hotspots (chromosomes 11, 12, and 22) and one IACRB coldspot (chromosome 2) were identified. Statistical analysis at the chromosomal band-level identified four IACRB hotspots accounting for 20% of all instability-associated breaks, two of which account for over 14% of all IACRB. Further, analysis of independent clones provided evidence within 14 individual clones of IACRB clustering at the chromosomal band level, suggesting a predisposition for further breaks after an initial break at some chromosomal bands. All of these events, independently, or when taken together, were highly unlikely to have occurred by chance (p < 0.000001). These IACRB band-level cluster hotspots were observed independent of radiation quality, dose, or cellular p53 status. The non-random distribution of instability-associated chromosomal rearrangements described here significantly differs from the distribution that was observed in a first-division post-irradiation metaphase analysis (p = 0.0004). Taken together, these results suggest that genomic instability may be in part driven by chromosomal cis mechanisms.

  12. Involvement of recombination in x-ray mutagenesis of human cells

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    Amundson, S.A. (Los Alamos National Lab., NM (United States)); Xia, F.; Liber, H.L. (Harvard School of Public Health, Boston, MA (United States))

    1993-01-01

    Closely related human lymphoblastoid cell lines derived from WI-L2 differ greatly in their responses to X-irradiation. Compared with TK6 (ATCC CRL 8015), WI-L2-NS (ATCC CRL 8155) has an enhanced X-ray survival. The induction of mutation by X-rays is also markedly different. The hemizygous hprt locus is slightly more mutable in WI-L2-NS than in TK6, and the dose response fits best to a linear-quadratic curve rather than the linear fit of TK6X-ray induced mutation at the autosomal tk locus in heterozygotes derived from WI-L2-NS is 20-50 fold higher than in heterozygotes derived from TK6. A larger proportion of WI-L2-NS mutants had lost heterozygosity compared with mutants of TK6. , Fluorescence in situ hybridization indicated that loss of heterozygosity was due almost uniformly to deletion of an allele in mutants of TK6, and to recombination or gene conversion in mutants of WI-L2-NS. These results indicate that recombinational repair contributes to both cell survival and mutation following exposure to ionizing radiation.

  13. Involvement of recombination in x-ray mutagenesis of human cells

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    Amundson, S.A. [Los Alamos National Lab., NM (United States); Xia, F.; Liber, H.L. [Harvard School of Public Health, Boston, MA (United States)

    1993-06-01

    Closely related human lymphoblastoid cell lines derived from WI-L2 differ greatly in their responses to X-irradiation. Compared with TK6 (ATCC CRL 8015), WI-L2-NS (ATCC CRL 8155) has an enhanced X-ray survival. The induction of mutation by X-rays is also markedly different. The hemizygous hprt locus is slightly more mutable in WI-L2-NS than in TK6, and the dose response fits best to a linear-quadratic curve rather than the linear fit of TK6X-ray induced mutation at the autosomal tk locus in heterozygotes derived from WI-L2-NS is 20-50 fold higher than in heterozygotes derived from TK6. A larger proportion of WI-L2-NS mutants had lost heterozygosity compared with mutants of TK6. , Fluorescence in situ hybridization indicated that loss of heterozygosity was due almost uniformly to deletion of an allele in mutants of TK6, and to recombination or gene conversion in mutants of WI-L2-NS. These results indicate that recombinational repair contributes to both cell survival and mutation following exposure to ionizing radiation.

  14. P53 alters the cytotoxicity and genotoxicity for oxidized graphene in human B-lymphoblastoid cells

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    Petibone, Dayton Matthew

    Widespread use of oxidized graphene nanomaterials in industry, medicine, and consumer products raises concern about potential adverse impacts on human health. The p53 tumor suppressor protein is crucial to maintaining cellular and genetic stability to prevent carcinogenesis. Here, we show that oxygen functionalized graphene (f-G) absorption and p53 functional status correlate with cytotoxicity and genotoxicity in human B-lymphoblastoid cells. Trends in f-G absorption by were dose-dependent. Cells with functional p53 exposed to f-G arrested in G0/G1 phase of the cell cycle, suppressed f-G induced reactive oxygen species (ROS), and had elevated apoptosis. While compared to p53 competent cells, the p53 deficient cells exposed to f-G accumulated in S-phase of the cell cycle, had elevated ROS levels, and evaded apoptosis. The f-G genotoxicity was evident as increased loss-of-heterozygosity mutants independent of p53 status, and structural chromosome damage in p53 deficient cells. These findings have broad implications for the safety and efficacy of oxidized graphene nanomaterials in industrial, consumer products and biomedical applications.

  15. Stable human lymphoblastoid cell lines constitutively expressing hepatitis C virus proteins.

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    Wölk, Benno; Gremion, Christel; Ivashkina, Natalia; Engler, Olivier B; Grabscheid, Benno; Bieck, Elke; Blum, Hubert E; Cerny, Andreas; Moradpour, Darius

    2005-06-01

    The cellular immune response plays a central role in virus clearance and pathogenesis of liver disease in hepatitis C. The study of hepatitis C virus (HCV)-specific immune responses is limited by currently available cell-culture systems. Here, the establishment and characterization of stable human HLA-A2-positive B-lymphoblastoid x T hybrid cell lines constitutively expressing either the NS3-4A complex or the entire HCV polyprotein are reported. These cell lines, termed T1/NS3-4A and T1/HCVcon, respectively, were maintained in continuous culture for more than 1 year with stable characteristics. HCV structural and non-structural proteins were processed accurately, indicating that the cellular and viral proteolytic machineries are functional in these cell lines. Viral proteins were found in the cytoplasm in dot-like structures when expressed in the context of the HCV polyprotein or in a perinuclear fringe when the NS3-4A complex was expressed alone. T1/NS3-4A and T1/HCVcon cells were lysed efficiently by HCV-specific cytotoxic T lymphocytes from patients with hepatitis C and from human HLA-A2.1 transgenic mice immunized with a liposomal HCV vaccine, indicating that viral proteins are processed endogenously and presented efficiently via the major histocompatibility complex class I pathway. In conclusion, these cell lines represent a unique tool to study the cellular immune response, as well as to evaluate novel vaccine and immunotherapeutic strategies against HCV.

  16. Differences in the incorporation of bromodeoxyuridine by human lymphoblastoid cell lines

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    Henderson, E.E.; Strauss, B.

    1975-08-01

    Long term human lymphoblastoid lines differ in their ability to grow in medium containing bromodeoxyuridine (BrdU) and to incorporate analog into their DNA. Eight Burkitts' lymphoma cell lines divided at least twice in BrdU-containing medium and made DNA in which over 90 percent of the thymidine residues were substituted with analog in both strands. Three infectious mononucleosis-derived lines and 24 lines transformed in vitro were inhibited by BrdU after one cell division and made only hybrid DNA in which one strand was substituted with analog. One out of eight normal individuals from whom long term lines were prepared gave cell lines which divided at least twice in BrdU and gave DNA in which both strands were substituted with analog. It would appear that intrinsic cellular factors regulate the response to BrdU and that Burkitt's tumor lines are characterized by their ability to make stable doubly substituted DNA containing a high proportion of halogenated analog.

  17. The translocated c-myc oncogene of Raji Burkitt lymphoma cells is not expressed in human lymphoblastoid cells.

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    Nishikura, K; Erikson, J; ar-Rushdi, A; Huebner, K; Croce, C M

    1985-01-01

    We hybridized Raji Burkitt lymphoma cells, which carry a t(8;14) chromosome translocation, with human lymphoblastoid cells to study the expression of the translocated cellular myc oncogene (c-myc) in the hybrid cells. In Raji cells the c-myc oncogene is translocated to a switch region of the gamma heavy chain locus (S gamma). Because of sequence alterations in the 5' exon of the translocated c-myc oncogene in this cell line, it is possible to distinguish the transcripts of the translocated c-myc gene and of the normal c-myc gene. S1 nuclease protection experiments with a c-myc first exon probe indicate that Raji cells express predominantly the translocated c-myc gene, while the level of expression of the normal c-myc gene is less than 2% of that of the translocated c-myc gene. Somatic cell hybrids between Raji and human lymphoblastoid cells retain the lymphoblastoid phenotype and express only the normal c-myc oncogene. This result indicates that the activation of a c-myc oncogene translocated to a S region depends on the stage of B-cell differentiation of the cells harboring the translocated c-myc gene and not on alterations in the structure of the translocated c-myc oncogene. Images PMID:3857623

  18. Integration sites of Epstein-Barr virus genome on chromosomes of human lymphoblastoid cell lines

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    Wuu, K.D.; Chen, Y.J.; Wang-Wuu, S. [Institute of Genetics, Taipei (Taiwan, Province of China)

    1994-09-01

    Epstein-Barr virus (EBV) is the pathogen of infectious mononucleosis. The viral genome is present in more than 95% of the African cases of Burkitt lymphoma and it is usually maintained in episomal form in the tumor cells. Viral integration has been described only for Nanalwa which is a Burkitt lymphoma cell line lacking episomes. In order to examine the role of EBV in the immortalization of human Blymphocytes, we investigated whether the EBV integration into the human genome is essential. If the integration does occur, we would like to know whether the integration is randomly distributed or whether the viral DNA integrates preferentially at certain sites. Fourteen in vitro immortalized human lymphoblastoid cell lines (LCLs) were examined by fluorescence in situ hybridization (FISH) with a biotinylated EBV BamHI w DNA fragment as probe. The episomal form of EBV DNA was found in all cells of these cell lines, while only about 65% of the cells have the integrated viral DNA. This might suggest that integration is not a pre-requisite for cell immortalization. Although all chromosomes, except Y, have been found with integrated viral genome, chromsomes 1 and 5 are the most frequent EBV DNA carrier (p<0.05). Nine chromosome bands, namely, 1p31, 1q31, 2q32, 3q13, 3q26, 5q14, 6q24, 7q31 and 12q21, are preferential targets for EBV integration (p<0.001). Eighty percent of the total 938 EBV hybridization signals were found to be at G-band-positive area. This suggests that the mechanism of EBV integration might be different from that of the retroviruses, which specifically integrate to G-band-negative areas. Thus, we conclude that the integration of EBV to host genome is non-random and it may have something to do with the structure of chromosome and DNA sequences.

  19. Arsenite-induced autophagy is associated with proteotoxicity in human lymphoblastoid cells

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    Bolt, Alicia M.; Zhao, Fei; Pacheco, Samantha; Klimecki, Walter T., E-mail: klimecki@pharmacy.arizona.edu

    2012-10-15

    Epidemiological studies of arsenic-exposed populations have provided evidence that arsenic exposure in humans is associated with immunosuppression. Previously, we have reported that arsenite-induced toxicity is associated with the induction of autophagy in human lymphoblastoid cell lines (LCL). Autophagy is a cellular process that functions in the degradation of damaged cellular components, including protein aggregates formed by misfolded or damaged proteins. Accumulation of misfolded or damaged proteins in the endoplasmic reticulum (ER) lumen causes ER stress and activates the unfolded protein response (UPR). In an effort to investigate the mechanism of autophagy induction by arsenite in the LCL model, we examined the potential contribution of ER stress and activation of the UPR. LCL exposed to sodium arsenite for 8-days induced expression of UPR-activated genes, including CHOP and GRP78, at the RNA and the protein level. Evidence for activation of the three arms of the UPR was observed. The arsenite-induced activation of the UPR was associated with an accumulation of protein aggregates containing p62 and LC3, proteins with established roles in the sequestration and autophagic clearance of protein aggregates. Taken together, these data provide evidence that arsenite-induced autophagy is associated with the generation of ER stress, activation of the UPR, and formation of protein aggregates that may be targeted to the lysosome for degradation. -- Highlights: ► Arsenite induces endoplasmic reticulum stress and the unfolded protein response. ► Arsenite induces the formation of protein aggregates that contain p62 and LC3-II. ► Time-course data suggests that arsenite-induced autophagy precedes ER stress.

  20. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines.

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    Edwin Choy

    2008-11-01

    Full Text Available Lymphoblastoid cell lines (LCLs, originally collected as renewable sources of DNA, are now being used as a model system to study genotype-phenotype relationships in human cells, including searches for QTLs influencing levels of individual mRNAs and responses to drugs and radiation. In the course of attempting to map genes for drug response using 269 LCLs from the International HapMap Project, we evaluated the extent to which biological noise and non-genetic confounders contribute to trait variability in LCLs. While drug responses could be technically well measured on a given day, we observed significant day-to-day variability and substantial correlation to non-genetic confounders, such as baseline growth rates and metabolic state in culture. After correcting for these confounders, we were unable to detect any QTLs with genome-wide significance for drug response. A much higher proportion of variance in mRNA levels may be attributed to non-genetic factors (intra-individual variance--i.e., biological noise, levels of the EBV virus used to transform the cells, ATP levels than to detectable eQTLs. Finally, in an attempt to improve power, we focused analysis on those genes that had both detectable eQTLs and correlation to drug response; we were unable to detect evidence that eQTL SNPs are convincingly associated with drug response in the model. While LCLs are a promising model for pharmacogenetic experiments, biological noise and in vitro artifacts may reduce power and have the potential to create spurious association due to confounding.

  1. Effects of soluble and particulate Cr(VI) on genome-wide DNA methylation in human B lymphoblastoid cells.

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    Lou, Jianlin; Wang, Yu; Chen, Junqiang; Ju, Li; Yu, Min; Jiang, Zhaoqiang; Feng, Lingfang; Jin, Lingzhi; Zhang, Xing

    2015-10-01

    Several previous studies highlighted the potential epigenetic effects of Cr(VI), especially DNA methylation. However, few studies have compared the effects of Cr(VI) on DNA methylation profiles between soluble and particulate chromate in vitro. Accordingly, Illumina Infinium Human Methylation 450K BeadChip array was used to analyze DNA methylation profiles of human B lymphoblastoid cells exposed to potassium dichromate or lead chromate, and the cell viability was also studied. Array based DNA methylation analysis showed that the impacts of Cr(VI) on DNA methylation were limited, only about 40 differentially methylated CpG sites, with an overlap of 15CpG sites, were induced by both potassium dichromate and lead chromate. The results of mRNA expression showed that after Cr(VI) treatment, mRNA expression changes of four genes (TBL1Y, FZD5, IKZF2, and KIAA1949) were consistent with their DNA methylation alteration, but DNA methylation changes of other six genes did not correlate with mRNA expression. In conclusion, both of soluble and particulate Cr(VI) could induce a small amount of differentially methylated sites in human B lymphoblastoid cells, and the correlations between DNA methylation changes and mRNA expression varied between different genes. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Spontaneous chromosomal aberrations in Fanconi anaemia, ataxia telangiectasia fibroblast and Bloom's syndrome lymphoblastoid cell lines as detected by conventional cytogenetic analysis and fluorescence in situ hybridisation (FISH) technique.

    Science.gov (United States)

    Sakamoto Hojo, E T; van Diemen, P C; Darroudi, F; Natarajan, A T

    1995-02-01

    Several primary and transformed human cell lines derived from cancer prone patients are employed routinely for biochemical and DNA repair studies. Since transformation leads to some chromosomal instability a cytogenetic analysis of spontaneous chromosome aberrations in fibroblast cell lines derived from patients with Fanconi anaemia (FA), ataxia telangiectasia (AT), and in lymphoblastoid cell lines derived from patients with Bloom's syndrome (BS), was undertaken. Unstable aberrations were analysed in Giemsa stained preparations and the chromosome painting technique was used for evaluating the frequencies of stable aberrations (translocations). In addition, the frequency of sister-chromatid exchanges (SCEs) was determined in differentially stained metaphases. The SV40-transformed fibroblasts from these cell lines have higher frequencies of unstable aberrations than the primary fibroblasts. In the four lymphoblastoid cell lines derived from BS patients higher frequencies of spontaneously occurring chromosomal aberrations in comparison to normal TK6wt cells were also evident. The frequency of spontaneously occurring chromosome translocations was determined with fluorescence in situ hybridisation (FISH) and using DNA libraries specific for chromosomes 1, 2, 3, 4, 7, 8, 11, 14, 19, 20 and X. The translocation levels were found to be elevated for primary FA fibroblasts and lymphoblastoid cells derived from BS patients in comparison with control cell lines, hetero- and homozygote BS cell lines not differing in this respect. The SV40-transformed cell lines showed very high frequencies of translocations independent of their origin and almost every cell contained at least one translocation. In addition, clonal translocations were found in transformed control TK6wt and AT cell lines for chromosomes 20 and 14, respectively. The spontaneous frequencies of SCEs were similar in transformed fibroblasts derived from normal individuals and AT patients, whereas in SV40-transformed FA

  3. Generation of human scFvs antibodies recognizing a prion protein epitope expressed on the surface of human lymphoblastoid cells

    Directory of Open Access Journals (Sweden)

    Imperiale Valentina

    2007-07-01

    Full Text Available Abstract Background A hallmark of prion disease is the transformation of normal cellular prion protein (PrPc into an infectious disease-associated isoform, (PrPsc. Anti-prion protein monoclonal antibodies are invaluable for structure-function studies of PrP molecules. Furthermore recent in vitro and in vivo studies indicate that anti-PrP monoclonal antibodies can prevent the incorporation of PrPc into propagating prions. In the present article, we show two new human phage antibodies, isolated on recombinant hamster prion protein (rHaPrP. Results We adopted an antibody phage display strategy to isolate specific human antibodies directed towards rHaPrP which has been used as a bait for panning the synthetic ETH-2 antibody phage library. Two phage antibodies clones named MA3.B4 and MA3.G3 were isolated and characterized under genetic biochemical and immunocytochemical aspects. The clones were found to recognize the prion protein in ELISA studies. In flow-cytometry studies, these human single chain Fragment variable (scFv phage-antibodies show a well defined pattern of reactivity on human lymphoblastoid and myeloid cells. Conclusion Sequence analysis of the gene encoding for the antibody fragments and antigen recognition patterns determined by flow-cytometry analysis indicate that the isolated scFvs recognize novel epitopes in the PrPc molecule. These new anti PrPc human antibodies are unique reagents for prion protein detection and may represent a biologic platform to develop new reagents to treat PrPsc associated disease.

  4. Complete genome sequence of Hydrogenobacter thermophilus type strain (TK-6T)

    Energy Technology Data Exchange (ETDEWEB)

    Zeytun, Ahmet [Los Alamos National Laboratory (LANL); Sikorski, Johannes [DSMZ - German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, Germany; Nolan, Matt [Joint Genome Institute, Walnut Creek, California; Lapidus, Alla L. [Joint Genome Institute, Walnut Creek, California; Lucas, Susan [Joint Genome Institute, Walnut Creek, California; Han, James [Joint Genome Institute; Tice, Hope [Joint Genome Institute, Walnut Creek, California; Cheng, Jan-Fang [Joint Genome Institute, Walnut Creek, California; Tapia, Roxanne [Los Alamos National Laboratory (LANL); Goodwin, Lynne A. [Los Alamos National Laboratory (LANL); Pitluck, Sam [Joint Genome Institute, Walnut Creek, California; Liolios, Konstantinos [Joint Genome Institute, Walnut Creek, California; Ivanova, N [U.S. Department of Energy, Joint Genome Institute; Mavromatis, K [U.S. Department of Energy, Joint Genome Institute; Mikhailova, Natalia [U.S. Department of Energy, Joint Genome Institute; Ovchinnikova, Galina [U.S. Department of Energy, Joint Genome Institute; Pati, Amrita [U.S. Department of Energy, Joint Genome Institute; Chen, Amy [Joint Genome Institute, Walnut Creek, California; Palaniappan, Krishna [Joint Genome Institute, Walnut Creek, California; Ngatchou, Olivier Duplex [HZI - Helmholtz Centre for Infection Research, Braunschweig, Germany; Land, Miriam L [ORNL; Hauser, Loren John [ORNL; Chang, Yun-Juan [ORNL; Jeffries, Cynthia [Oak Ridge National Laboratory (ORNL); Han, Cliff [Los Alamos National Laboratory (LANL); Detter, J. Chris [Joint Genome Institute, Walnut Creek, California; Ubler, Susanne [Universitat Regensburg, Regensburg, Germany; Rohde, Manfred [HZI - Helmholtz Centre for Infection Research, Braunschweig, Germany; Tindall, Brian [DSMZ - German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, Germany; Wirth, Reinhard [Universitat Regensburg, Regensburg, Germany; Woyke, Tanja [Joint Genome Institute, Walnut Creek, California; Bristow, James [Joint Genome Institute, Walnut Creek, California; Eisen, Jonathan [Joint Genome Institute, Walnut Creek, California; Markowitz, Victor [Joint Genome Institute, Walnut Creek, California; Hugenholtz, Philip [U.S. Department of Energy, Joint Genome Institute; Klenk, Hans-Peter [DSMZ - German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, Germany; Kyrpides, Nikos C [Joint Genome Institute, Walnut Creek, California

    2011-01-01

    Hydrogenobacter thermophilus Kawasumi et al. 1984 is the type species of the genus Hydrogenobacter. H. thermophilus was the first obligate autotrophic organism reported among aerobic hydrogen-oxidizing bacteria. Strain TK-6T is of interest because of the unusually efficient hydrogen-oxidizing ability of this strain, which results in a faster generation time compared to other autotrophs. It is also able to grow anaerobically using nitrate as an electron acceptor when molecular hydrogen is used as the energy source, and able to aerobically fix CO2 via the reductive tricarboxylic acid cycle. This is the fifth completed genome sequence in the family Aquificaceae, and the second genome sequence determined from a strain derived from the original isolate. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 1,742,932 bp long genome with its 1,899 protein-coding and 49 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.

  5. Inhibition of human antigen-induced lymphoblastoid B-cell function by an in vivo-induced suppressor T cell.

    Science.gov (United States)

    Brieva, J A; Stevens, R H

    1983-04-01

    Lymphoblastoid (LB) B cells which spontaneously produce antitetanus toxoid IgG antibodies (Tet-IgG) in short-term cultures (3 days) appear in the circulation 5-7 days after immunization with tetanus toxoid. Addition of pokeweed mitogen (PWM), normally a stimulator of antibody production, caused instead a reduction in the in vitro synthesis of Tet-IgG by the LB cells. In order for this inhibition of antibody production to occur, T cells had to be present, and the inhibition was proportional to the number of T cells added to the culture, demonstrating the existence of PWM-inducible suppressor cells. The cells mediating the suppression had the OKT8 phenotype and also exhibited the following characteristics: (1) a PWM pretreatment period as little as 14 hr was enough to complete activation; (2) conventional inhibitors of suppressor T cells as hydrocortisone and cyclosporin A only partially reversed its effect; and (3) DNA synthesis was not required. The T-suppressor activity was detectable in the circulation before immunization, increased two- to fourfold by 5-12 days after boosting, and waned after 3 weeks. The mechanism of action of this suppression does not appear to involve conventional cytotoxic T cells as (1) the suppression was mediated across allogeneic barriers and (2) the suppression could not be reversed by inclusion of anti-Leu-2a antibodies in the culture. These results suggest that this suppressor T-cell subset may be important in the normal regulation of activated stages of human B lymphocytes.

  6. Spectra of spontaneous and X-ray-induced mutations at the hprt locus in related human lymphoblast cell lines that express wild-type or mutant p53

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, E.N.; Xia, F.; Kelsey, K.T.; Liber, H.L. [Harvard School of Public Health, Boston, MA (United States)

    1995-09-01

    Previous work showed that WTK1 human lymphoblastoid cells are radioresistant but more sensitive to X-ray-induced mutation than the closely related line TK6. In addition, WTK1 cells contain a mutant p53 while in TK6 cells p53 is wild-type. In this work, we examined the spectra of 68 X-ray-induced and 56 spontaneous mutants at the hemizygous hprt locus in WTK1 cells. The induced spectra were classified by Southern blot and multiplex polymerase chain reaction (PCR); there were 19 point mutations (28%) with an unaltered Southern blot or PCR pattern, 26 (38%) partial deletions or rearrangements and 23 (34%) complete gene deletions. The spontaneous spectrum included 25 (45%) point mutations, 22 (39%) partial deletions and 9 (16%) complete gene deletions. These spectra of mutations were compared to those of TK6 cells. Although distinct differences in the spectra of mutations at the tk locus were reported previously, overall there is no significant difference in the spectra of X-ray-induced or spontaneous mutations at the hprt locus in these two cell lines. While there was an increase in the proportion of large-scale changes that occurred at tk after X irradiation, the spectrum of mutations at the hprt locus shows all classes of mutations increasing proportionately in WTK1 cells. However, the proportion of internal partial deletion mutations at the hprt locus was about 2 times more frequent in WTK1 than in TK6 cells. 39 refs., 2 figs., 2 tabs.

  7. NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells

    Science.gov (United States)

    Zhang, Ying; Lim, Chang U K.; Williams, Eli S.; Zhou, Junqing; Zhang, Qinming; Fox, Michael H.; Bailey, Susan M.; Liber, Howard L.

    2005-01-01

    Hypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation-induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (gamma-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation-induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation-induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.

  8. Analysis of mutant frequencies and mutation spectra in hMTH1 knockdown TK6 cells exposed to UV radiation

    Energy Technology Data Exchange (ETDEWEB)

    Fotouhi, Asal [Center for Radiation Protection Research, Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University (Sweden); Hagos, Winta Woldai [Department of Toxicogenetics, Leiden University Medical Center, Leiden (Netherlands); Ilic, Marina; Wojcik, Andrzej; Harms-Ringdahl, Mats [Center for Radiation Protection Research, Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University (Sweden); Gruijl, Frank de [Department of Dermatology, Leiden University Medical Center, Leiden (Netherlands); Mullenders, Leon; Jansen, Jacob G. [Department of Toxicogenetics, Leiden University Medical Center, Leiden (Netherlands); Haghdoost, Siamak, E-mail: Siamak.Haghdoost@su.se [Center for Radiation Protection Research, Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University (Sweden)

    2013-11-15

    Highlights: • hMTH1 protects cells from mutagenesis induced by UVA and UVB, but not UVC. • No protective role of hMTH1 in cell survival post UVB and UVC irradiation. • hMTH1 prevents induction of transition-type mutations at AT and GC post UVA irradiation. • 2-OH-dATP rather than 8-oxo-dGTP in the nucleotide pool likely contributes in UVA-induced mutations. - Abstract: Ultraviolet radiation is a highly mutagenic agent that damages the DNA by the formation of mutagenic photoproducts at dipyrimidine sites and by oxidative DNA damages via reactive oxygen species (ROS). ROS can also give rise to mutations via oxidation of dNTPs in the nucleotide pool, e.g. 8-oxo-dGTP and 2-OH-dATP and subsequent incorporation during DNA replication. Here we show that expression of human MutT homolog 1 (hMTH1) which sanitizes the nucleotide pool by dephosphorylating oxidized dNTPs, protects against mutagenesis induced by long wave UVA light and by UVB light but not by short wave UVC light. Mutational spectra analyses of UVA-induced mutations at the endogenous Thymidine kinase gene in human lymphoblastoid cells revealed that hMTH1 mainly protects cells from transitions at GC and AT base pairs.

  9. Studying the protein expression in human B lymphoblastoid cells exposed to 1.8-GHz (GSM) radiofrequency radiation (RFR) with protein microarray.

    Science.gov (United States)

    Zhijian, Chen; Xiaoxue, Li; Wei, Zheng; Yezhen, Lu; Jianlin, Lou; Deqiang, Lu; Shijie, Chen; Lifen, Jin; Jiliang, He

    2013-03-29

    In the present study, the protein microarray was used to investigate the protein expression in human B-cell lymphoblastoid cells intermittently exposed to 1.8-GHz GSM radiofrequency radiation (RFR) at the specific absorption rate (SAR) of 2.0 W/kg for 24 h. The differential expression of 27 proteins was found, which were related to DNA damage repair, apoptosis, oncogenesis, cell cycle and proliferation (ratio >1.5-fold, P<0.05). The results validated with Western blot assay indicated that the expression of RPA32 was significantly down-regulated (P<0.05) while the expression of p73 was significantly up-regulated in RFR exposure group (P<0.05). Because of the crucial roles of those proteins in DNA repair and cell apoptosis, the results of present investigation may explain the biological effects of RFR on DNA damage/repair and cell apoptosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Isolation of a human lymphoblastoid line heterozygous at the thymidine kinase locus: possibility for a rapid human cell mutation assay

    Energy Technology Data Exchange (ETDEWEB)

    Skopek, T.R.; Liber, H.L.; Penman, B.W.; Thilly, W.G.

    1978-09-29

    A thymidine kinase heterozygote designated H2BT has been isolated from the human lymphoblast line HH4. Significant increase in the trifluorothymidine-resistant fraction was observed in the new cell line following treatment with the mutagens ICR-191 and butylmethansulfonate. Phenotypic expression was complete forty-eight hours after treatment.

  11. Low Dose Radiation Response Curves, Networks and Pathways in Human Lymphoblastoid Cells Exposed from 1 to 10 cGy of Acute Gamma Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.; Furtado, M. R.; Bhattacharya, M. S.; Marchetti, F.; Coleman, M.A.

    2011-04-18

    We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, molecule transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.

  12. Abrogation of radiation-inducible telomerase upregulation in HPV16 E6 transfectants of human lymphoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Neuhof, D.; Auberger, F.; Ruess, A.; Weber, K.J. [Radiobiology Research Lab., Dept. of Clinical Radiology, Univ. of Heidelberg (Germany); Wenz, F. [Section for Radiation Oncology, Univ. Clinic Mannheim (Germany)

    2004-01-01

    Background: telomerase activity in a human lymphoblastoid cell line with wild-type p53 status (TK6) was previously shown to be rapidly induced by ionizing radiation doses as low as 10 cgy. Since this low-dose response was absent in a closely related cell line overexpressing a mutant form of p53 (WTK1), the putative involvement of p53 was further investigated using stable human papillomavirus 16 (HPV16) E6 transfectants of these cell lines. The E6 product mediates rapid degradation of wild-type p53, but has also been found to upregulate telomerase. Material and methods: telomerase activity in HPV16 E6 transfectants of the human lymphoblastoid cell lines TK6 and WTK1 was measured by PCR/ELISA and was quantified using internal standards (titration by cell number) run within each separate assay. Mean telomere length was determined by southern hybridization of terminal restriction fragments with a biotin-labeled telomeric DNA probe. Results: the TK6E6 and the WTK1E6 cells exhibited higher baseline telomerase activities than the parental cells. This was also accompanied by increased telomere lengths. Radiation exposure (up to 10 gy) was unable to significantly further enhance telomerase activities, although the dynamic range of the assay would have allowed to record higher signals. Conclusion: the lacking radiation induction of telomerase activities in the E6 transfectants could reflect saturation, if E6 and radiation would share a common pathway of telomerase upregulation. Present evidence from the literature, however, suggests that E6 mediates telomerase reverse transcriptase (TERT) subunit transcriptional activation, whereas radiation signals to posttranscriptional/posttranslational control of telomerase activity. Therefore, the present data enforce the previous hypothesis of a p53 dependence of telomerase upregulation by low doses of radiation and its abrogation, likely due to p53 degradation, in E6-expressing cells. (orig.)

  13. Effects of cell cycle position on ionizing radiation mutagenesis. I. Quantitative assays of two genetic loci in a human lymphoblastoid cell line

    Energy Technology Data Exchange (ETDEWEB)

    Chuang, Yao-Yu; Liber, H.L. [Harvard School of Public Health, Boston, MA (United States)

    1996-11-01

    Relatively little work has been done on the influence of the position of the cell in the cell cycle on ionizing radiation-induced mutagenesis. We synchronized WTK1 human lymphoblastoid cells with 200 {mu}M lovastatin for 48 h; under these conditions more than 80% of the cells were arrested in G{sub 1} phase. Upon release, there was a 12-15-h lag followed by movement of a large fraction into S phase. We irradiated cells with either 1.5 Gy X rays at 1, 15, 18, 21 or 24 h or 1.5 Gy {gamma} rays at 1, 5, 10, 15 or 24 h after release from lovastatin. We showed that WTK1 cells were most sensitive to ionizing radiation-induced toxicity in G{sub 1} and into S phase, and more resistant in mid to late S and G{sub 2}/M phase. Somewhat surprisingly, we found that the two different gene loci had different sensitivities to radiation-induced mutation through the cell cycle. Cells in late G{sub 1} through mid-S phase were most sensitive to radiation-induced mutations at the autosomal thymidine kinase (TK) locus, whereas G{sub 1} phase was the most sensitive phase at the X-linked hypoxanthine guanine phosphoribosyl transferase (HPRT) locus. 29 refs., 6 figs., 1 tab.

  14. Analysis of negative historical control group data from the in vitro micronucleus assay using TK6 cells.

    Science.gov (United States)

    Lovell, David P; Fellows, Mick; Marchetti, Francesco; Christiansen, Joan; Elhajouji, Azeddine; Hashimoto, Kiyohiro; Kasamoto, Sawako; Li, Yan; Masayasu, Ozaki; Moore, Martha M; Schuler, Maik; Smith, Robert; Stankowski, Leon F; Tanaka, Jin; Tanir, Jennifer Y; Thybaud, Veronique; Van Goethem, Freddy; Whitwell, James

    2018-01-01

    The recent revisions of the Organisation for Economic Co-operation and Development (OECD) genetic toxicology test guidelines emphasize the importance of historical negative controls both for data quality and interpretation. The goal of a HESI Genetic Toxicology Technical Committee (GTTC) workgroup was to collect data from participating laboratories and to conduct a statistical analysis to understand and publish the range of values that are normally seen in experienced laboratories using TK6 cells to conduct the in vitro micronucleus assay. Data from negative control samples from in vitro micronucleus assays using TK6 cells from 13 laboratories were collected using a standard collection form. Although in some cases statistically significant differences can be seen within laboratories for different test conditions, they were very small. The mean incidence of micronucleated cells/1000 cells ranged from 3.2/1000 to 13.8/1000. These almost four-fold differences in micronucleus levels cannot be explained by differences in scoring method, presence or absence of exogenous metabolic activation (S9), length of treatment, presence or absence of cytochalasin B or different solvents used as vehicles. The range of means from the four laboratories using flow cytometry methods (3.7-fold: 3.5-12.9 micronucleated cells/1000 cells) was similar to that from the nine laboratories using other scoring methods (4.3-fold: 3.2-13.8 micronucleated cells/1000 cells). No laboratory could be identified as an outlier or as showing unacceptably high variability. Quality Control (QC) methods applied to analyse the intra-laboratory variability showed that there was evidence of inter-experimental variability greater than would be expected by chance (i.e. over-dispersion). However, in general, this was low. This study demonstrates the value of QC methods in helping to analyse the reproducibility of results, building up a 'normal' range of values, and as an aid to identify variability within a

  15. A Study of Alterations in DNA Epigenetic Modifications (5mC and 5hmC) and Gene Expression Influenced by Simulated Microgravity in Human Lymphoblastoid Cells.

    Science.gov (United States)

    Chowdhury, Basudev; Seetharam, Arun; Wang, Zhiping; Liu, Yunlong; Lossie, Amy C; Thimmapuram, Jyothi; Irudayaraj, Joseph

    2016-01-01

    Cells alter their gene expression in response to exposure to various environmental changes. Epigenetic mechanisms such as DNA methylation are believed to regulate the alterations in gene expression patterns. In vitro and in vivo studies have documented changes in cellular proliferation, cytoskeletal remodeling, signal transduction, bone mineralization and immune deficiency under the influence of microgravity conditions experienced in space. However microgravity induced changes in the epigenome have not been well characterized. In this study we have used Next-generation Sequencing (NGS) to profile ground-based "simulated" microgravity induced changes on DNA methylation (5-methylcytosine or 5mC), hydroxymethylation (5-hydroxymethylcytosine or 5hmC), and simultaneous gene expression in cultured human lymphoblastoid cells. Our results indicate that simulated microgravity induced alterations in the methylome (~60% of the differentially methylated regions or DMRs are hypomethylated and ~92% of the differentially hydroxymethylated regions or DHMRs are hyperhydroxymethylated). Simulated microgravity also induced differential expression in 370 transcripts that were associated with crucial biological processes such as oxidative stress response, carbohydrate metabolism and regulation of transcription. While we were not able to obtain any global trend correlating the changes of methylation/ hydroxylation with gene expression, we have been able to profile the simulated microgravity induced changes of 5mC over some of the differentially expressed genes that includes five genes undergoing differential methylation over their promoters and twenty five genes undergoing differential methylation over their gene-bodies. To the best of our knowledge, this is the first NGS-based study to profile epigenomic patterns induced by short time exposure of simulated microgravity and we believe that our findings can be a valuable resource for future explorations.

  16. A Study of Alterations in DNA Epigenetic Modifications (5mC and 5hmC and Gene Expression Influenced by Simulated Microgravity in Human Lymphoblastoid Cells.

    Directory of Open Access Journals (Sweden)

    Basudev Chowdhury

    Full Text Available Cells alter their gene expression in response to exposure to various environmental changes. Epigenetic mechanisms such as DNA methylation are believed to regulate the alterations in gene expression patterns. In vitro and in vivo studies have documented changes in cellular proliferation, cytoskeletal remodeling, signal transduction, bone mineralization and immune deficiency under the influence of microgravity conditions experienced in space. However microgravity induced changes in the epigenome have not been well characterized. In this study we have used Next-generation Sequencing (NGS to profile ground-based "simulated" microgravity induced changes on DNA methylation (5-methylcytosine or 5mC, hydroxymethylation (5-hydroxymethylcytosine or 5hmC, and simultaneous gene expression in cultured human lymphoblastoid cells. Our results indicate that simulated microgravity induced alterations in the methylome (~60% of the differentially methylated regions or DMRs are hypomethylated and ~92% of the differentially hydroxymethylated regions or DHMRs are hyperhydroxymethylated. Simulated microgravity also induced differential expression in 370 transcripts that were associated with crucial biological processes such as oxidative stress response, carbohydrate metabolism and regulation of transcription. While we were not able to obtain any global trend correlating the changes of methylation/ hydroxylation with gene expression, we have been able to profile the simulated microgravity induced changes of 5mC over some of the differentially expressed genes that includes five genes undergoing differential methylation over their promoters and twenty five genes undergoing differential methylation over their gene-bodies. To the best of our knowledge, this is the first NGS-based study to profile epigenomic patterns induced by short time exposure of simulated microgravity and we believe that our findings can be a valuable resource for future explorations.

  17. Effects of Vitamin K3 and K5 on Daunorubicin-resistant Human T Lymphoblastoid Leukemia Cells.

    Science.gov (United States)

    Nakaoka, Eri; Tanaka, Sachiko; Onda, Kenji; Sugiyama, Kentaro; Hirano, Toshihiko

    2015-11-01

    Anticancer efficacy of vitamin K derivatives on multidrug-resistant cancer cells has been scarcely investigated. The effects of vitamins K3 and K5 on proliferation of human leukemia MOLT-4 cells and on daunorubicin-resistant MOLT-4/DNR cells were estimated by a WST assay. Apoptotic cells were detected by Annexin V and propidium iodide staining, followed by flow cytometry. Vitamins K3 and K5 significantly inhibited proliferation of leukemic cells at 10 and 100 μM (pVitamin K3 induced cell apoptosis at 10 and 100 μM in both MOLT-4 and MOLT-4/DNR cells (pVitamin K5 also increased apoptotic cells, while rather inducing necrotic cell death. Vitamins K3 and K5 suppress MOLT-4 and MOLT-4/DNR cell-proliferation partially through induction of apoptosis, and these vitamin derivatives can overcome drug resistance due to P-glycoprotein expression. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Mutagenicity and clastogenicity of extracts of Helicobacter pylori detected by the Ames test and in the micronucleus test using human lymphoblastoid cells.

    Science.gov (United States)

    Arimoto-Kobayashi, Sakae; Ohta, Kaori; Yuhara, Yuta; Ayabe, Yuka; Negishi, Tomoe; Okamoto, Keinosuke; Nakajima, Yoshihiro; Ishikawa, Takeshi; Oguma, Keiji; Otsuka, Takanao

    2015-07-01

    Epidemiological studies have demonstrated a close association between infection with Helicobacter pylori (H.pylori) and the development of gastric carcinoma. Chronic H.pylori infection increases the frequency of mutation in gastric epithelial cells. However, the mechanism by which infection of H.pylori leads to mutation in gastric epithelial cells is unclear. We suspected that components in H.pylori may be related to the mutagenic response associated with DNA alkylation, and could be detected with the Ames test using a more sensitive strain for alkylating agents. Our investigation revealed that an extract of H.pylori was mutagenic in the Ames test with Salmonella typhimurium YG7108, which is deficient in the DNA repair of O(6)-methylguanine. The extract of H.pylori may contain methylating or alkylating agents, which might induce O (6)-alkylguanine in DNA. Mutagenicity of the alkylating agents N-methyl-N-nitrosourea (MNU) and N-methyl-N'-nitro-N-nitrosoguanidine in the Ames test with S.typhimurium TA1535 was enhanced significantly in the presence of the extract of H.pylori. The tested extracts of H.pylori resulted in a significant induction of micronuclei in human-derived lymphoblastoid cells. Heat instability and dialysis resistance of the extracts of H.pylori suggest that the mutagenic component in the extracts of H.pylori is a heat-unstable large molecule or a heat-labile small molecule strongly attached or adsorbed to a large molecule. Proteins in the extracts of H.pylori were subsequently fractionated using ammonium sulphate precipitation. However, all fractions expressed enhancing effects toward MNU mutagenicity. These results suggest the mutagenic component is a small molecule that is absorbed into proteins in the extract of H.pylori, which resist dialysis. Continuous and chronic exposure of gastric epithelial cells to the alkylative mutagenic component from H.pylori chronically infected in the stomach might be a causal factor in the gastric carcinogenesis

  19. Mutagenic adaptive response to high-LET radiation in human lymphoblastoid cells exposed to low doses of heavy-ion radiation

    Energy Technology Data Exchange (ETDEWEB)

    Vares, Guillaume, E-mail: vares@nirs.go.jp [Radiation Risk Reduction Research Program, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555 (Japan); Wang, Bing, E-mail: jp2813km@nirs.go.jp [Radiation Risk Reduction Research Program, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555 (Japan); Tanaka, Kaoru; Kakimoto, Ayana; Eguchi-Kasai, Kyomi; Nenoi, Mitsuru [Radiation Risk Reduction Research Program, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555 (Japan)

    2011-07-01

    Adaptive response (AR) and bystander effect are two important phenomena involved in biological responses to low doses of ionizing radiation (IR). Furthermore, there is a strong interest in better understanding the biological effects of high-LET radiation. We previously demonstrated the ability of low doses of X-rays to induce an AR to challenging heavy-ion radiation . In this study, we assessed in vitro the ability of priming low doses (0.01 Gy) of heavy-ion radiation to induce a similar AR to a subsequent challenging dose (1-4 Gy) of high-LET IR (carbon-ion: 20 and 40 keV/{mu}m, neon-ion: 150 keV/{mu}m) in TK6, AHH-1 and NH32 cells. Our results showed that low doses of high-LET radiation can induce an AR characterized by lower mutation frequencies at hypoxanthine-guanine phosphoribosyl transferase locus and faster DNA repair kinetics, in cells expressing p53.

  20. Metformin pharmacogenomics: a genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines.

    Science.gov (United States)

    Niu, Nifang; Liu, Tongzheng; Cairns, Junmei; Ly, Reynold C; Tan, Xianglin; Deng, Min; Fridley, Brooke L; Kalari, Krishna R; Abo, Ryan P; Jenkins, Gregory; Batzler, Anthony; Carlson, Erin E; Barman, Poulami; Moran, Sebastian; Heyn, Holger; Esteller, Manel; Wang, Liewei

    2016-11-01

    Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genome-wide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s). Top candidate genes were functionally validated using siRNA screening, followed by MTS assay in breast cancer cell lines. Further study of one top candidate, STUB1, was performed to elucidate the mechanisms by which STUB1 might contribute to metformin action. GWA analyses in LCLs identified 198 mRNA expression probe sets, 12 SNP loci, and 5 DNA methylation loci associated with metformin IC50 with P-values breast cancer cell lines. Mechanistic studies revealed that the E3 ubiquitin ligase, STUB1, could influence metformin response by facilitating proteasome-mediated degradation of cyclin A. GWAS using a genomic data-enriched LCL model system, together with functional and mechanistic studies using cancer cell lines, help us to identify novel genetic and epigenetic biomarkers involved in metformin anticancer response.

  1. Comparative mutagenesis of human cells in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Thilly, W.G.

    1992-05-01

    This report discusses measuring methods of point mutations; high density cell cultures for low dose studies; measurement and sequence determination of mutations in DNA; the mutational spectra of styrene oxide and ethlyene oxide in TK-6 cells; mutational spectrum of Cr in human lymphoblast cells; mutational spectra of radon in TK-6 cells; and the mutational spectra of smokeless tobacco. (CBS)

  2. Integrity of genome-wide genotype data from low passage lymphoblastoid cell lines

    Directory of Open Access Journals (Sweden)

    Nina S. McCarthy

    2016-09-01

    Full Text Available We compared genotype data from the HumanExomeCore Array in peripheral blood mononuclear cells and low passage lymphoblastoid cell lines from the same 24 individuals to test for genotypic errors caused by the Epstein–Barr Virus transformation process. Genotype concordance across the 24 comparisons was 99.57% for unfiltered genotype data, and 99.63% following standard genotype quality control filters. Mendelian error rates and levels of heterozygosity were not significantly different between lymphoblastoid cell lines and their parent peripheral blood mononuclear cells. These results show that at low passage numbers, genotype discrepancies are minimal even before stringent quality control, and extend current evidence qualifying the use of low-passage lymphoblastoid cell lines as a reliable DNA source for genotype analysis.

  3. Genotoxicity testing of PLGA-PEO nanoparticles in TK6 cells by the comet assay and the cytokinesis-block micronucleus assay.

    Science.gov (United States)

    Kazimirova, Alena; Magdolenova, Zuzana; Barancokova, Magdalena; Staruchova, Marta; Volkovova, Katarina; Dusinska, Maria

    2012-10-09

    The in vitro genotoxicity of PLGA-PEO (poly-lactic-co-glycolic acid-polyethylene oxide copolymer) nanoparticles was assessed in TK6 cells using the comet assay as well as cytokinesis-block micronucleus (CBMN) assay. The cells were exposed to 0.12-75μg/cm² of PLGA-PEO nanoparticles during 2 and 24h for analysis in the comet assay, and to 3-75μg/cm² of these nanoparticles during 4, 24, 48 and 72h, respectively, for analysis in the CBMN assay. Two different protocols for treatment with cytochalasin B were used. We found that PLGA-PEO was neither cytotoxic (measured by relative cell growth activity and cytokinesis-block proliferation index (CBPI)), nor did it induce DNA strand-breaks (detected by the comet assay) or oxidative DNA lesions (measured by the comet assay modified with lesion-specific enzyme formamidopyrimidine-DNA-glycosylase). There were no statistically significant differences in the frequencies of micronucleated binucleated cells (MNBNCs) between untreated and treated cells in either of the conditions used. This suggests that PLGA-PEO did not have potential genotoxicity. However, using two experimental protocols of the micronucleus assay, PLGA-PEO nanoparticles showed a weak but significant increase in the level of MN in mononucleated cells, in cells treated for 48h with PLGA-PEO nanoparticles when cytochalasin B was added for the last 24h (1st protocol), and in cells treated for 24h with PLGA-PEO nanoparticles followed by washing of NPs and addition of cytochalasin B for another 24h (2nd protocol). It remains unclear whether the increase of MNMNC after treatment with PLGA-PEO nanoparticles is the effect of a possible, weak aneugenic potential or early effect of these particles, or due to another reason. These results suggest that aneugenicity in addition to clastogenicity may be considered as an important biomarker when assessing the genotoxic potential of polymeric nanoparticles. © 2012 Elsevier B.V. All rights reserved.

  4. Different toxic effects of YTX in tumor K-562 and lymphoblastoid cell lines

    Directory of Open Access Journals (Sweden)

    Andrea Fernández Araújo

    2015-06-01

    Full Text Available Yessotoxin (YTX modulates cellular phosphodiesterases (PDEs. In this regard, opposite effects had been described in the tumor model K-562 cell line and fresh human lymphocytes in terms of cell viability, cyclic adenosine 3´,5´-cyclic monophosphate (cAMP production and protein expression after YTX treatment. Studies in depth of the pathways activated by YTX in K-562 cell line, have demonstrated the activation of two different cell death types, apoptosis and autophagy after 24 and 48 hours of treatment, respectively. Furthermore, the key role of type 4A PDE (PDE4A in both pathways activated by YTX was demonstrated. Therefore, taking into account the differences between cellular lines and fresh cells, a study of cell death pathways activated by YTX in a non-tumor cell line with mitotic activity, was performed. The cellular model used was the lymphoblastoid cell line that represents a non-tumor model with normal apoptotic and mitotic machinery. In this context, cell viability and cell proliferation, expression of proteins involved in cell death activated by YTX and mitochondrial mass, were studied after the incubation with the toxin. Opposite to the tumor model, no cell death activation was observed in lymphoblastoid cell line in the presence of YTX. In this sense, variations in apoptosis hallmarks were not detected in the lymphoblastoid cell line after YTX incubation, whereas this type I of programmed cell death was observed in K-526 cells. On the other hand, autophagy cell death was triggered in this cellular line, while other autophagic process is suggested in lymphoblastoid cells. These YTX effects are related to PDE4A in both cellular lines. In addition, while cell death is triggered in K-526 cells after YTX treatment, in lymphoblastoid cells the toxin stops cellular proliferation. These results point to YTX as a specific toxic compound of tumor cells, since in the non-tumor lymphoblastoid cell line, no cell death hallmarks are observed.

  5. Potassium bromate treatment predominantly causes large deletions, but not GC > TA transversion in human cells

    Energy Technology Data Exchange (ETDEWEB)

    Luan, Yang [Div. of Cellular and Gene Therapy Products, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)]|[Div. of Genetics and Mutagenesis, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)]|[Center for Drug Safety Evaluation, Shanghai Inst. of Materia Medica, Chinese Academy of Sciences, 294 Tai-Yuan Road, Shanghai 200031 (China); Suzuki, Takayoshi [Div. of Cellular and Gene Therapy Products, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan); Palanisamy, Rajaguru [Div. of Cellular and Gene Therapy Products, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)]|[Department of Biotechnology, School of Engineering and Technology, Bharathidasan Univ., Palkalaiperur, Tiruchirappalli 620024 (India); Takashima, Yoshio; Sakamoto, Hiroko; Sakuraba, Mayumi; Koizumi, Tomoko; Hayashi, Makoto [Div. of Genetics and Mutagenesis, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan); Saito, Mika [Div. of Genetics and Mutagenesis, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)]|[Dept. of Food Science and Technology, College of Bioresource Sciences, Nihon Univ., 1866 Kameino, Fujisawa-shi, Kanagawa 252-8510 (Japan); Matsufuji, Hiroshi; Yamagata, Kazuo [Dept. of Food Science and Technology, College of Bioresource Sciences, Nihon Univ., 1866 Kameino, Fujisawa-shi, Kanagawa 252-8510 (Japan); Yamaguchi, Teruhide [Div. of Cellular and Gene Therapy Products, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan); Honma, Masamitsu [Div. of Genetics and Mutagenesis, National Inst. of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)]. E-mail: honma@nihs.go.jp

    2007-06-01

    Potassium bromate (KBrO{sub 3}) is strongly carcinogenic in rodents and mutagenic in bacteria and mammalian cells in vitro. The proposed genotoxic mechanism for KBrO{sub 3} is oxidative DNA damage. KBrO{sub 3} can generate high yields of 8-hydroxydeoxyguanosine (8OHdG) DNA adducts, which cause GC > TA transversions in cell-free systems. In this study, we investigated the in vitro genotoxicity of KBrO{sub 3} in human lymphoblastoid TK6 cells using the comet (COM) assay, the micronucleus (MN) test, and the thymidine kinase (TK) gene mutation assay. After a 4 h treatment, the alkaline and neutral COM assay demonstrated that KBrO{sub 3} directly yielded DNA damages including DNA double strand breaks (DSBs). KBrO{sub 3} also induced MN and TK mutations concentration-dependently. At the highest concentration (5 mM), KBrO{sub 3} induced MN and TK mutation frequencies that were over 30 times the background level. Molecular analysis revealed that 90% of the induced mutations were large deletions that involved loss of heterozygosity (LOH) at the TK locus. Ionizing-irradiation exhibited similar mutational spectrum in our system. These results indicate that the major genotoxicity of KBrO{sub 3} may be due to DSBs that lead to large deletions rather than to 8OHdG adducts that lead to GC > TA transversions, as is commonly believed. To better understand the genotoxic mechanism of KBrO{sub 3}, we analyzed gene expression profiles of TK6 cells using Affymetrix Genechip. Some genes involved in stress, apoptosis, and DNA repair were up-regulated by the treatment of KBrO{sub 3}. However, we could not observe the similarity of gene expression profile in the treatment of KBrO{sub 3} to ionizing-irradiation as well as oxidative damage inducers.

  6. Production of vesicular stomatitis virus by antigen- or mitogen-stimulated lymphocytes and continuous lymphoblastoid lines

    Energy Technology Data Exchange (ETDEWEB)

    Nowakowski, M.; Feldman, J.D.; Kano, S.; Bloom, B.R.

    1973-04-01

    The purpose of this study is to explore at the ultrastructural level the nature of the cells engaged in the production of vesicular stomatitis virus (VSV) in different lymphoid cell populations, particularly after stimulation with several different agents. Specifically, we have examined (a) lymph node cells from guinea pigs with delayed hypersensitivity activated by specific antigen, (b) murine spleen cells activated by selective B cell and T cell mitogens, and (c) cells of human and murine continuous lymphoblastoid or lymphoma lines.

  7. File list: Oth.Bld.10.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: His.Bld.50.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  1. File list: Pol.Bld.05.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  3. File list: Unc.Bld.50.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  4. File list: Pol.Bld.10.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  5. File list: His.Bld.20.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  10. File list: Unc.Bld.10.AllAg.Lymphoblastoid_cell_line [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. Assay for mutagenesis in heterozygous diploid human lymphoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Skopek, Thomas R. (Somerville, MA); Liber, Howard L. (Brookline, MA); Penman, Bruce W. (Cambridge, MA); Thilly, William G. (Cambridge, MA); Hoppe, IV, Henry (Arlington, MA)

    1981-01-01

    An assay is disclosed for determining mutagenic damage caused by the administration of a known or suspected mutagen to diploid human lymphoblastoid cell lines. The gene locus employed for this assay is the gene for thymidine kinase, uridine kinase, or cytidine deaminase. Since human lymphoblastoid cells contain two genes for these enzymes, heterozygotes of human lymphoblastoid cells are used in this assay.

  12. Assay for mutagenesis in heterozygous diploid human lymphoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Skopek, T.R.; Liber, H.L.; Penman, B.W.; Thilly, W.G.; Hoppe, H. IV.

    1981-11-24

    An assay is disclosed for determining mutagenic damage caused by the administration of a known or suspected mutagen to diploid human lymphoblastoid cell lines. The gene locus employed for this assay is the gene for thymidine kinase, uridine kinase, or cytidine deaminase. Since human lymphoblastoid cells contain two genes for these enzymes, heterozygotes of human lymphoblastoid cells are used in this assay. 7 figs.

  13. Suitability of human and mammalian cells of different origin for the assessment of genotoxicity of metal and polymeric engineered nanoparticles.

    Science.gov (United States)

    Cowie, Hilary; Magdolenova, Zuzana; Saunders, Margaret; Drlickova, Martina; Correia Carreira, Sara; Halamoda Kenzaoi, Blanka; Gombau, Lourdes; Guadagnini, Rina; Lorenzo, Yolanda; Walker, Laura; Fjellsbø, Lise Marie; Huk, Anna; Rinna, Alessandra; Tran, Lang; Volkovova, Katarina; Boland, Sonja; Juillerat-Jeanneret, Lucienne; Marano, Francelyne; Collins, Andrew R; Dusinska, Maria

    2015-05-01

    Nanogenotoxicity is a crucial endpoint in safety testing of nanomaterials as it addresses potential mutagenicity, which has implications for risks of both genetic disease and carcinogenesis. Within the NanoTEST project, we investigated the genotoxic potential of well-characterised nanoparticles (NPs): titanium dioxide (TiO2) NPs of nominal size 20 nm, iron oxide (8 nm) both uncoated (U-Fe3O4) and oleic acid coated (OC-Fe3O4), rhodamine-labelled amorphous silica 25 (Fl-25 SiO2) and 50 nm (Fl-50 SiO) and polylactic glycolic acid polyethylene oxide polymeric NPs - as well as Endorem® as a negative control for detection of strand breaks and oxidised DNA lesions with the alkaline comet assay. Using primary cells and cell lines derived from blood (human lymphocytes and lymphoblastoid TK6 cells), vascular/central nervous system (human endothelial human cerebral endothelial cells), liver (rat hepatocytes and Kupffer cells), kidney (monkey Cos-1 and human HEK293 cells), lung (human bronchial 16HBE14o cells) and placenta (human BeWo b30), we were interested in which in vitro cell model is sufficient to detect positive (genotoxic) and negative (non-genotoxic) responses. All in vitro studies were harmonized, i.e. NPs from the same batch, and identical dispersion protocols (for TiO2 NPs, two dispersions were used), exposure time, concentration range, culture conditions and time-courses were used. The results from the statistical evaluation show that OC-Fe3O4 and TiO2 NPs are genotoxic in the experimental conditions used. When all NPs were included in the analysis, no differences were seen among cell lines - demonstrating the usefulness of the assay in all cells to identify genotoxic and non-genotoxic NPs. The TK6 cells, human lymphocytes, BeWo b30 and kidney cells seem to be the most reliable for detecting a dose-response.

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  1. Ultraviolet hypersensitivity of Cockayne syndrome lymphoblastoid lines - the effects of exogenous. beta. -nicotinamide adenine dinucleotide

    Energy Technology Data Exchange (ETDEWEB)

    Otsuka, Fujio; Kukita, Atsushi

    1986-12-01

    Four Cockayne Syndrome (CS) lymphoblastoid lines were tested for the lethal effects of UV radiation (254 nm) with or without addition of exogenous ..beta..-nicotinamide adenine dinucleotide (..beta..-NAD/sup +/) to their culture medium. Two of them exhibited a small but significantly increased resistance to UV radiation when ..beta..-NAD/sup +/ was added to the culture. However, their UV sensitivity after ..beta..-NAD+ addition was still much greater than that of normal control lines. Normal control lymphoblastoid lines and those from complementation group A and group C of xeroderma pigmentosum (XP) did not reveal any differences in post-UV sensitivity after the addition of exogenous ..beta..-NAD/sup +/. Thus the abnormal response to the lethal effects of UV radiation of CS lymphoblastoid lines could not be rectified by ..beta..-NAD/sup +/ addition. However, ..beta..-NAD/sup +/ does appear to play some partial role in reducing the high UV sensitivity of some CS lymphoblastoid lines.

  2. Molecular signatures in response to Isoliquiritigenin in lymphoblastoid cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae-Eun; Hong, Eun-Jung; Nam, Hye-Young [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Hwang, Meeyul [Research Center for Biomedical Resource of Oriental Medicine, Daegu Haany University (Korea, Republic of); Kim, Ji-Hyun [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Han, Bok-Ghee, E-mail: bokghee@nih.go.kr [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of); Jeon, Jae-Pil, E-mail: jpjeon@cdc.go.kr [National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention (Korea, Republic of)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer We identified the inhibitory effect of ISL on cell proliferation of LCLs. Black-Right-Pointing-Pointer We found ISL-induced genes and miRNAs through microarray approach. Black-Right-Pointing-Pointer ISL-treated LCLs represented gene expression changes in cell cycle and p53 pathway. Black-Right-Pointing-Pointer We revealed 12 putative mRNA-miRNA functional pairs associated with ISL effect. -- Abstract: Isoliquiritigenin (ISL) has been known to induce cell cycle arrest and apoptosis of various cancer cells. However, genetic factors regulating ISL effects remain unclear. The aim of this study was to identify the molecular signatures involved in ISL-induced cell death of EBV-transformed lymphoblastoid cell lines (LCLs) using microarray analyses. For gene expression and microRNA (miRNA) microarray experiments, each of 12 LCL strains was independently treated with ISL or DMSO as a vehicle control for a day prior to total RNA extraction. ISL treatment inhibited cell proliferation of LCLs in a dose-dependent manner. Microarray analysis showed that ISL-treated LCLs represented gene expression changes in cell cycle and p53 signaling pathway, having a potential as regulators in LCL survival and sensitivity to ISL-induced cytotoxicity. In addition, 36 miRNAs including five miRNAs with unknown functions were differentially expressed in ISL-treated LCLs. The integrative analysis of miRNA and gene expression profiles revealed 12 putative mRNA-miRNA functional pairs. Among them, miR-1207-5p and miR-575 were negatively correlated with p53 pathway- and cell cycle-associated genes, respectively. In conclusion, our study suggests that miRNAs play an important role in ISL-induced cytotoxicity in LCLs by targeting signaling pathways including p53 pathway and cell cycle.

  3. Cold Atmospheric Plasma Induces Apoptosis and Oxidative Stress Pathway Regulation in T-Lymphoblastoid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Eleonora Turrini

    2017-01-01

    Full Text Available Cold atmospheric plasma (CAP has shown its antitumor activity in both in vitro and in vivo systems. However, the mechanisms at the basis of CAP-cell interaction are not yet completely understood. The aim of this study is to investigate CAP proapoptotic effect and identify some of the molecular mechanisms triggered by CAP in human T-lymphoblastoid leukemia cells. CAP treatment was performed by means of a wand electrode DBD source driven by nanosecond high-voltage pulses under different operating conditions. The biological endpoints were assessed through flow cytometry and real-time PCR. CAP caused apoptosis in Jurkat cells mediated by p53 upregulation. To test the involvement of intrinsic and/or extrinsic pathway, the expression of Bax/Bcl-2 and caspase-8 was analyzed. The activation of caspase-8 and the upregulation of Bax and Bcl-2 were observed. Moreover, CAP treatment increased ROS intracellular level. The situation reverts after a longer time of treatment. This is probably due to compensatory cellular mechanisms such as the posttranscriptional upregulation of SOD1, CAT, and GSR2. According to ROS increase, CAP induced a significant increase in DNA damage at all treatment conditions. In conclusion, our results provide a deeper understanding of CAP potential in the oncological field and pose the basis for the evaluation of its toxicological profile.

  4. Characterization of the microDNA through the response to chemotherapeutics in lymphoblastoid cell lines.

    Directory of Open Access Journals (Sweden)

    Pamela Mehanna

    Full Text Available Recently, a new class of extrachromosomal circular DNA, called microDNA, was identified. They are on average 100 to 400 bp long and are derived from unique non-repetitive genomic regions with high gene density. MicroDNAs are thought to arise from DNA breaks associated with RNA metabolism or replication slippage. Given the paucity of information on this entirely novel phenomenon, we aimed to get an additional insight into microDNA features by performing the microDNA analysis in 20 independent human lymphoblastoid cell lines (LCLs prior and after treatment with chemotherapeutic drugs. The results showed non-random genesis of microDNA clusters from the active regions of the genome. The size periodicity of 190 bp was observed, which matches DNA fragmentation typical for apoptotic cells. The chemotherapeutic drug-induced apoptosis of LCLs increased both number and size of clusters further suggesting that part of microDNAs could result from the programmed cell death. Interestingly, proportion of identified microDNA sequences has common loci of origin when compared between cell line experiments. While compatible with the original observation that microDNAs originate from a normal physiological process, obtained results imply complementary source of its production. Furthermore, non-random genesis of microDNAs depicted by redundancy between samples makes these entities possible candidates for new biomarker generation.

  5. Polyphenolic Profile and Targeted Bioactivity of Methanolic Extracts from Mediterranean Ethnomedicinal Plants on Human Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Antonino Pollio

    2016-03-01

    Full Text Available The methanol extracts of the aerial part of four ethnomedicinal plants of Mediterranean region, two non-seed vascular plants, Equisetum hyemale L. and Phyllitis scolopendrium (L. Newman, and two Spermatophyta, Juniperus communis L. (J. communis and Cotinus coggygria Scop. (C. coggygria, were screened against four human cells lines (A549, MCF7, TK6 and U937. Only the extracts of J. communis and C. coggygria showed marked cytotoxic effects, affecting both cell morphology and growth. A dose-dependent effect of these two extracts was also observed on the cell cycle distribution. Incubation of all the cell lines in a medium containing J. communis extract determined a remarkable accumulation of cells in the G2/M phase, whereas the C. coggygria extract induced a significant increase in the percentage of G1 cells. The novelty of our findings stands on the observation that the two extracts, consistently, elicited coherent effects on the cell cycle in four cell lines, independently from their phenotype, as two of them have epithelial origin and grow adherent and two are lymphoblastoid and grow in suspension. Even the expression profiles of several proteins regulating cell cycle progression and cell death were affected by both extracts. LC-MS investigation of methanol extract of C. coggygria led to the identification of twelve flavonoids (compounds 1–11, 19 and eight polyphenols derivatives (12–18, 20, while in J. communis extract, eight flavonoids (21–28, a α-ionone glycoside (29 and a lignin (30 were found. Although many of these compounds have interesting individual biological activities, their natural blends seem to exert specific effects on the proliferation of cell lines either growing adherent or in suspension, suggesting potential use in fighting cancer.

  6. Use of lymphoblastoid cell lines to evaluate the hypersensitivity to ultraviolet radiation in Cockayne syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Otsuka, F.; Tarone, R.E.; Cayeux, S.; Robbins, J.H.

    1984-05-01

    Cockayne syndrome (CS) is a rare autosomal recessive disease characterized by acute sun sensitivity, cachectic dwarfism, and neurologic and skeletal abnormalities. Cultured skin fibroblasts from patients with this disease are known to be hypersensitive to the lethal effects of 254-nm UV radiation. The authors have studied the sensitivity of 254-nm UV radiation of lymphoblastoid lines derived from 3 typical CS patients, 1 atypical CS patient who had a very late age of onset of clinical manifestations, 2 patients who had both xeroderma pigmentosum (XP) and typical CS, and 3 heterozygous parents of these patients. Post-UV survival was determined by the trypan-blue dye-exclusion method. The lymphoblastoid lines from the 3 typical CS patients, the atypical CS patient, and the 2 patients with both CS and XP had decreased post-UV viability in comparison with lines from normal donors. Lines from the heterozygous parents had normal post-UV viability. The post-UV viability of the typical CS lines was similar to that of a XP complementation group C line. The relative post-UV viability of lymphoblastoid lines from the typical CS patients was similar to the relative post-UV survival of their fibroblast lines. The lymphoblastoid line from the atypical CS patient had a post-UV viability similar to that of the typical CS patients. Thus, the relative hypersensitivity of CS patients cells in vitro does not reflect the severity or age of onset of the patients clinical manifestations. The lymphoblastoid lines from the 2 patients who had both CS and XP were significantly more sensitive to the UV radiation than those from patients with only CS. Our studies demonstrate that lymphoblastoid lines from patients with CS are appropriate and useful cell lines for the study of the inherited hypersensitivity to UV radiation.

  7. Utilization of Lymphoblastoid Cell Lines as a System for the Molecular Modeling of Autism

    Science.gov (United States)

    Baron, Colin A.; Liu, Stephenie Y.; Hicks, Chindo; Gregg, Jeffrey P.

    2006-01-01

    In order to provide an alternative approach for understanding the biology and genetics of autism, we performed statistical analysis of gene expression profiles of lymphoblastoid cell lines derived from children with autism and their families. The goal was to assess the feasibility of using this model in identifying autism-associated genes.…

  8. Mechanisms of mutagenesis in human cells exposed to 55 MeV protons

    Science.gov (United States)

    Gauny, S.; Wiese, C.; Kronenberg, A.

    2001-01-01

    Protons represent the major type of charged particle radiation in spaceflight environments. The purpose of this study was to assess mutations arising in human lymphoid cells exposed to protons. Mutations were quantitated at the thymidine kinase (TK1) locus in cell lines derived from the same donor: TK6 cells (wt TP53) and WTK1 cells (mutant TP53). WTK1 cells were much more susceptible to mutagenesis following proton exposure than TK6 cells. Intragenic deletions were observed among early-arising TK1 mutants in TK6 cells, but not in WTK1 cells where all of the mutants arose by LOH. Deletion was the predominant mode of LOH in TK6 cells, while allelic recombination was the major mode of LOH in WTK1 cells. Deletions were of variable lengths, from recombination often extended to the telomere. In summary, proton exposures elicited many types of mutations at an autosomal locus in human cells. Most involved large scale loss of genetic information, either through deletion or by recombination.

  9. Genotoxic effects of high-energy iron particles in human lymphoblasts differing in radiation sensitivity

    Science.gov (United States)

    Evans, H. H.; Horng, M. F.; Evans, T. E.; Jordan, R.; Schwartz, J. L.

    2001-01-01

    The effects of (56)Fe particles and (137)Cs gamma radiation were compared in TK6 and WTK1 human lymphoblasts, two related cell lines which differ in TP53 status and in the ability to rejoin DNA double-strand breaks. Both cell lines were more sensitive to the cytotoxic and clastogenic effects of (56)Fe particles than to those of gamma rays. However, the mutagenicity of (56)Fe particles and gamma rays at the TK locus was the same per unit dose and was higher for gamma rays than for (56)Fe particles at isotoxic doses. The respective RBEs for TK6 and WTK1 cells were 1.5 and 1.9 for cytotoxicity and 2.5 and 1.9 for clastogenicity, but only 1 for mutagenicity. The results indicate that complex lesions induced by (56)Fe particles are repaired less efficiently than gamma-ray-induced lesions, leading to fewer colony-forming cells, a slightly higher proportion of aberrant cells at the first division, and a lower frequency of viable mutants at isotoxic doses. WTK1 cells (mutant TP53) were more resistant to the cytotoxic effects of both gamma rays and (56)Fe particles, but showed greater cytogenetic and mutagenic damage than TK6 cells (TP53(+)). A deficiency in the number of damaged TK6 cells (a) reaching the first mitosis after exposure and (b) forming viable mutants can explain these results.

  10. Abnormal segregation of alleles in CEPH pedigree DNAs arising from allele loss in lymphoblastoid DNA.

    Science.gov (United States)

    Royle, N J; Armour, J A; Crosier, M; Jeffreys, A J

    1993-01-01

    Somatic events that result in the reduction to hemi- or homozygosity at all loci affected by the event have been identified in lymphoblastoid DNA from mothers of two CEPH families. Using suitably informative probes, the allele deficiencies were detected by the abnormal transmission of alleles from grandparents to grandchildren, with the apparent absence of the alleles from the parent. Undetected somatic deficiencies in family DNAs could result in misscoring of recombination events and consequently introduce errors into linkage analysis.

  11. Abnormal segregation of alleles in CEPH pedigree DNAs arising from allele loss in lymphoblastoid DNA

    Energy Technology Data Exchange (ETDEWEB)

    Royle, N.J.; Armour, J.A.L.; Crosier, M.; Jeffreys, A.J. (Univ. of Leicester (United Kingdom))

    1993-01-01

    Somatic events that result in the reduction to hemior homozygosity at all loci affected by the event have been identified in lymphoblastoid DNA from mothers of two CEPH families. Using suitably informative probes, the allele deficiencies were detected by the abnormal transmission of alleles from grandparents to grandchildren, with the apparent absence of the alleles from the parent. Undetected somatic deficiencies in family DNAs could result in misscoring of recombination events and consequently introduce errors into linkage analysis. 15 refs., 2 figs.

  12. Malignant transformation of Bloom syndrome B-lymphoblastoid cell lines by carcinogens.

    OpenAIRE

    Shiraishi, Y; Yosida, T. H.; Sandberg, A. A.

    1985-01-01

    Three types of Bloom syndrome B-lymphoblastoid cell lines, as well as one derived from a normal person, treated with 4-nitroquinoline-N-oxide and N-methyl-N'-nitro-N-nitrosoguanidine (0.3 micrograms/ml for 24 hr), were studied for tumorigenicity in nude mice, colony formation in soft agar, cytogenetic changes, and immunoglobulin markers. When normal and Bloom syndrome cells with normal sister chromatid exchange (SCE) levels and karyotypes (type I) were treated with carcinogens, no significant...

  13. Protection against bovine leukosis virus infection in sheep with the BL 20 bovine lymphoblastoid cell line.

    Science.gov (United States)

    Roberts, D H; Lucas, M H; Sands, J; Wibberley, G

    1982-11-01

    The bovine lymphoblastoid BL 20 cell line derived from a case of sporadic bovine leukosis when inoculated into sheep did not induce an antibody response directed against bovine leukosis virus (BLV) structural proteins. Sheep were inoculated twice with the BL 20 cell line and then challenged with BLV infected lymphocytes. Three out of four sheep challenged four weeks after BL 20 inoculation did not develop BLV antibodies. Of the 12 sheep challenged later, three sheep did not develop BLV antibodies. BLV was isolated from all the seropositive animals and from none of the seronegative animals.

  14. Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.

    Science.gov (United States)

    Mandage, Rajendra; Telford, Marco; Rodríguez, Juan Antonio; Farré, Xavier; Layouni, Hafid; Marigorta, Urko M; Cundiff, Caitlin; Heredia-Genestar, Jose Maria; Navarro, Arcadi; Santpere, Gabriel

    2017-01-01

    Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection. To test this hypothesis, we retrieved whole-genome sequenced EBV-mapping reads from 1,753 LCL samples derived from 19 populations worldwide that were sequenced within the context of the 1000 Genomes Project. An in silico methodology was developed to estimate the number of EBV copy number in LCLs and validated these estimations by real-time PCR. After experimentally confirming that EBV relative copy number remains stable over cell passages, we performed a genome wide association analysis (GWAS) to try detecting genetic variants of the host that may be associated with EBV copy number. Our GWAS has yielded several genomic regions suggestively associated with the number of EBV genomes per cell in LCLs, unraveling promising candidate genes such as CAND1, a known inhibitor of EBV replication. While this GWAS does not unequivocally establish the degree to which genetic makeup of individuals determine viral levels within their derived LCLs, for which a larger sample size will be needed, it potentially highlighted human genes affecting EBV-related processes, which constitute interesting candidates to follow up in the context of EBV related pathologies.

  15. New alleles at microsatellite loci in CEPH families mainly arise from somatic mutations in the lymphoblastoid cell lines.

    Science.gov (United States)

    Banchs, I; Bosch, A; Guimerà, J; Lázaro, C; Puig, A; Estivill, X

    1994-01-01

    In the analysis of 40 CEPH families, under the EUROGEM project, with a total of 29 microsatellites (26 CA-repeats, a TCTA-repeat within the vWFII-3 gene, a TTA-repeat within the PLA-2 gene, and an AAAT-repeat intragenic to the NF1 gene) from human chromosomes 12, 17, and 21, we have detected 21 cases of abnormal segregation of alleles in 16 pedigrees for a total of 14 markers (48%). In 11 cases, the abnormal transmissions were of somatic origin, 10 of which (91%) occurred in the lymphoblastoid cell lines. In 9 other cases, it was not possible to determine if the origin of the new alleles was somatic or germline, and in one case hemizygosity in several family members was observed, so its origin was germline. The 20 new mutations detected in the 22,852 meioses analysed represent a mutation frequency of 8.7 x 10(-4) per locus per allele. The germline mutation rate could be as high as 3.9 x 10(-4) per locus per gamete (from 0 to 3.9 x 10(-4)), but the rate of somatic mutations detected in the study was much higher (4.8 x 10(-4) to 8.7 x 10(-4) per locus per allele). Individual mutation rates ranged from 0 to 3.8 x 10(-3). Among the markers analysed, all three that were tri- or tetranucleotide repeats showed one or two new alleles, compared to only 10 of the 26 (38%) CA-repeats showing mutations. Three CEPH families (102, 45 and 1333) each had several mutational events, and one individual (10210) had somatic mutations for two microsatellites from different chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system

    Directory of Open Access Journals (Sweden)

    Jing eJiang

    2013-08-01

    Full Text Available The mammalian target of rapamycin (mTOR inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA analyses involving single nucleotide polymorphisms (SNPs, mRNA and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs. Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. 127 and 100 SNPs had P<10-4, while 8 and 10 SNPs had P<10-5 with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.

  17. Molecular signatures of cardiac defects in Down syndrome lymphoblastoid cell lines suggest altered ciliome and Hedgehog pathways.

    Directory of Open Access Journals (Sweden)

    Clémentine Ripoll

    Full Text Available Forty percent of people with Down syndrome exhibit heart defects, most often an atrioventricular septal defect (AVSD and less frequently a ventricular septal defect (VSD or atrial septal defect (ASD. Lymphoblastoid cell lines (LCLs were established from lymphocytes of individuals with trisomy 21, the chromosomal abnormality causing Down syndrome. Gene expression profiles generated from DNA microarrays of LCLs from individuals without heart defects (CHD(-; n = 22 were compared with those of LCLs from patients with cardiac malformations (CHD(+; n = 21. After quantile normalization, principal component analysis revealed that AVSD carriers could be distinguished from a combined group of ASD or VSD (ASD+VSD carriers. From 9,758 expressed genes, we identified 889 and 1,016 genes differentially expressed between CHD(- and AVSD and CHD(- and ASD+VSD, respectively, with only 119 genes in common. A specific chromosomal enrichment was found in each group of affected genes. Among the differentially expressed genes, more than 65% are expressed in human or mouse fetal heart tissues (GEO dataset. Additional LCLs from new groups of AVSD and ASD+VSD patients were analyzed by quantitative PCR; observed expression ratios were similar to microarray results. Analysis of GO categories revealed enrichment of genes from pathways regulating clathrin-mediated endocytosis in patients with AVSD and of genes involved in semaphorin-plexin-driven cardiogenesis and the formation of cytoplasmic microtubules in patients with ASD-VSD. A pathway-oriented search revealed enrichment in the ciliome for both groups and a specific enrichment in Hedgehog and Jak-stat pathways among ASD+VSD patients. These genes or related pathways are therefore potentially involved in normal cardiogenesis as well as in cardiac malformations observed in individuals with trisomy 21.

  18. Molecular Signatures of Cardiac Defects in Down Syndrome Lymphoblastoid Cell Lines Suggest Altered Ciliome and Hedgehog Pathways

    Science.gov (United States)

    Ripoll, Clémentine; Rivals, Isabelle; Ait Yahya-Graison, Emilie; Dauphinot, Luce; Paly, Evelyne; Mircher, Clothilde; Ravel, Aimé; Grattau, Yann; Bléhaut, Henri; Mégarbane, André; Dembour, Guy; de Fréminville, Bénédicte; Touraine, Renaud; Créau, Nicole; Potier, Marie Claude; Delabar, Jean Maurice

    2012-01-01

    Forty percent of people with Down syndrome exhibit heart defects, most often an atrioventricular septal defect (AVSD) and less frequently a ventricular septal defect (VSD) or atrial septal defect (ASD). Lymphoblastoid cell lines (LCLs) were established from lymphocytes of individuals with trisomy 21, the chromosomal abnormality causing Down syndrome. Gene expression profiles generated from DNA microarrays of LCLs from individuals without heart defects (CHD−; n = 22) were compared with those of LCLs from patients with cardiac malformations (CHD+; n = 21). After quantile normalization, principal component analysis revealed that AVSD carriers could be distinguished from a combined group of ASD or VSD (ASD+VSD) carriers. From 9,758 expressed genes, we identified 889 and 1,016 genes differentially expressed between CHD− and AVSD and CHD− and ASD+VSD, respectively, with only 119 genes in common. A specific chromosomal enrichment was found in each group of affected genes. Among the differentially expressed genes, more than 65% are expressed in human or mouse fetal heart tissues (GEO dataset). Additional LCLs from new groups of AVSD and ASD+VSD patients were analyzed by quantitative PCR; observed expression ratios were similar to microarray results. Analysis of GO categories revealed enrichment of genes from pathways regulating clathrin-mediated endocytosis in patients with AVSD and of genes involved in semaphorin-plexin-driven cardiogenesis and the formation of cytoplasmic microtubules in patients with ASD-VSD. A pathway-oriented search revealed enrichment in the ciliome for both groups and a specific enrichment in Hedgehog and Jak-stat pathways among ASD+VSD patients. These genes or related pathways are therefore potentially involved in normal cardiogenesis as well as in cardiac malformations observed in individuals with trisomy 21. PMID:22912673

  19. All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder.

    Science.gov (United States)

    Riebold, Mathias; Mankuta, David; Lerer, Elad; Israel, Salomon; Zhong, Songfa; Nemanov, Luba; Monakhov, Mikhail V; Levi, Shlomit; Yirmiya, Nurit; Yaari, Maya; Malavasi, Fabio; Ebstein, Richard P

    2011-01-01

    Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.

  20. Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Lanemo Myhrinder, Anna; Hellqvist, Eva; Bergh, Ann-Charlotte

    2013-01-01

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface...... membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here...... a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA...

  1. Malignant transformation of Bloom syndrome B-lymphoblastoid cell lines by carcinogens.

    Science.gov (United States)

    Shiraishi, Y; Yosida, T H; Sandberg, A A

    1985-08-01

    Three types of Bloom syndrome B-lymphoblastoid cell lines, as well as one derived from a normal person, treated with 4-nitroquinoline-N-oxide and N-methyl-N'-nitro-N-nitrosoguanidine (0.3 micrograms/ml for 24 hr), were studied for tumorigenicity in nude mice, colony formation in soft agar, cytogenetic changes, and immunoglobulin markers. When normal and Bloom syndrome cells with normal sister chromatid exchange (SCE) levels and karyotypes (type I) were treated with carcinogens, no significant changes occurred in the immunoglobulin profile and karyotype, only rare colony formation was seen, and no tumors were produced. In contrast, when Bloom syndrome cells with high SCE levels (type II with normal karyotype and type III with an abnormal karyotype) were treated with carcinogens, tumors were produced in 22 of 53 nude mice injected; a high rate of colony formation in soft agar was seen; the cells exhibited virtual loss of immunoglobulin markers; and structural changes in chromosomes 1, 2, 3, 4, 5, 7, 11, 14, and 15 were found in the tumors in addition to the original chromosome abnormalities present in the injected cells. It appears that Bloom syndrome B-lymphoblastoid cell lines with high levels of SCE are highly susceptible to the action of carcinogens, as evidenced by tumor formation in nude mice and colony formation in agar. Apparently, the carcinogens were capable of transforming only those cells that had a critical level of SCE (approximately 140 per cell) and not those with only mildly increased levels (approximately 13 per cell).

  2. Epstein-Barr virus genetic variation in lymphoblastoid cell lines derived from Kenyan pediatric population.

    Science.gov (United States)

    Simbiri, Kenneth O; Smith, Nicholas A; Otieno, Richard; Wohlford, Eric E M; Daud, Ibrahim I; Odada, Sumba P; Middleton, Frank; Rochford, Rosemary

    2015-01-01

    Epstein-Barr virus (EBV) is associated with Burkitt's lymphoma (BL), and in regions of sub-Saharan Africa where endemic BL is common, both the EBV Type 1 (EBV-1) and EBV Type 2 strains (EBV-2) are found. Little is known about genetic variation of EBV strains in areas of sub-Saharan Africa. In the present study, spontaneous lymphoblastoid cell lines (LCLs) were generated from samples obtained from Kenya. Polymerase chain reaction (PCR) amplification of the EBV genome was done using multiple primers and sequenced by next-generation sequencing (NGS). Phylogenetic analyses against the published EBV-1 and EBV-2 strains indicated that one sample, LCL10 was closely related to EBV-2, while the remaining 3 LCL samples were more closely related to EBV-1. Moreover, single nucleotide polymorphism (SNP) analyses showed clustering of LCL variants. We further show by analysis of EBNA-1, BLLF1, BPLF1, and BRRF2 that latent genes are less conserved than lytic genes in these LCLs from a single geographic region. In this study we have shown that NGS is highly useful for deciphering detailed inter and intra-variations in EBV genomes and that within a geographic region different EBV genetic variations can co-exist, the implications of which warrant further investigation. The findings will enhance our understanding of potential pathogenic variants critical to the development and maintenance of EBV-associated malignancies.

  3. Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines.

    Science.gov (United States)

    Breen, M S; White, C H; Shekhtman, T; Lin, K; Looney, D; Woelk, C H; Kelsoe, J R

    2016-10-01

    Lithium (Li) is the mainstay mood stabilizer for the treatment of bipolar disorder (BD), although its mode of action is not yet fully understood nor is it effective in every patient. We sought to elucidate the mechanism of action of Li and to identify surrogate outcome markers that can be used to better understand its therapeutic effects in BD patients classified as good (responders) and poor responders (nonresponders) to Li treatment. To accomplish these goals, RNA-sequencing gene expression profiles of lymphoblastoid cell lines (LCLs) were compared between BD Li responders and nonresponders with healthy controls before and after treatment. Several Li-responsive gene coexpression networks were discovered indicating widespread effects of Li on diverse cellular signaling systems including apoptosis and defense response pathways, protein processing and response to endoplasmic reticulum stress. Individual gene markers were also identified, differing in response to Li between BD responders and nonresponders, involved in processes of cell cycle and nucleotide excision repair that may explain part of the heterogeneity in clinical response to treatment. Results further indicated a Li gene expression signature similar to that observed with clonidine treatment, an α2-adrenoceptor agonist. These findings provide a detailed mechanism of Li in LCLs and highlight putative surrogate outcome markers that may permit for advanced treatment decisions to be made and for facilitating recovery in BD patients.

  4. Different Mechanisms of Regulation of the Warburg Effect in Lymphoblastoid and Burkitt Lymphoma Cells.

    Science.gov (United States)

    Mushtaq, Muhammad; Darekar, Suhas; Klein, George; Kashuba, Elena

    2015-01-01

    The Warburg effect is one of the hallmarks of cancer and rapidly proliferating cells. It is known that the hypoxia-inducible factor 1-alpha (HIF1A) and MYC proteins cooperatively regulate expression of the HK2 and PDK1 genes, respectively, in the Burkitt lymphoma (BL) cell line P493-6, carrying an inducible MYC gene repression system. However, the mechanism of aerobic glycolysis in BL cells has not yet been fully understood. Western blot analysis showed that the HIF1A protein was highly expressed in Epstein-Barr virus (EBV)-positive BL cell lines. Using biochemical assays and quantitative PCR (Q-PCR), we found that-unlike in lymphoblastoid cell lines (LCLs)-the MYC protein was the master regulator of the Warburg effect in these BL cell lines. Inhibition of the transactivation ability of MYC had no influence on aerobic glycolysis in LCLs, but it led to decreased expression of MYC-dependent genes and lactate dehydrogenase A (LDHA) activity in BL cells. Our data suggest that aerobic glycolysis, or the Warburg effect, in BL cells is regulated by MYC expressed at high levels, whereas in LCLs, HIF1A is responsible for this phenomenon.

  5. Proteomic analysis of lymphoblastoid cells derived from monozygotic twins discordant for bipolar disorder: a preliminary study.

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    An-a Kazuno

    Full Text Available Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. In bipolar disorder, family and twin studies suggest contributions from genetic and environmental factors; however, the detailed molecular pathogenesis is yet unknown. Thus, identification of biomarkers may contribute to the clinical diagnosis of bipolar disorder. Monozygotic twins discordant for bipolar disorder are relatively rare but have been reported. Here we performed a comparative proteomic analysis of whole cell lysate derived from lymphoblastoid cells of monozygotic twins discordant for bipolar disorder by using two-dimensional differential in-gel electrophoresis (2D-DIGE. We found approximately 200 protein spots to be significantly differentially expressed between the patient and the co-twin (t test, p<0.05. Some of the proteins were subsequently identified by liquid chromatography tandem mass spectrometry and included proteins involved in cell death and glycolysis. To examine whether these proteins could serve as biomarkers of bipolar disorder, we performed Western blot analysis using case-control samples. Expression of phosphoglycerate mutase 1 (PGAM1, which is involved in glycolysis, was significantly up-regulated in patients with bipolar disorder (t test, p<0.05. Although PGAM1 cannot be regarded as a qualified biomarker of bipolar disorder from this preliminary finding, it could be one of the candidates for further study to identify biomarkers of bipolar disorder.

  6. Control of cell respiration by nitric oxide in Ataxia Telangiectasia lymphoblastoid cells.

    Science.gov (United States)

    Masci, Alessandra; Mastronicola, Daniela; Arese, Marzia; Piane, Maria; De Amicis, Andrea; Blanck, Thomas J J; Chessa, Luciana; Sarti, Paolo

    2008-01-01

    Ataxia Telangiectasia (AT) patients are particularly sensitive to oxidative-nitrosative stress. Nitric oxide (NO) controls mitochondrial respiration via the reversible inhibition of complex IV. The mitochondrial response to NO of AT lymphoblastoid cells was investigated. Cells isolated from three patients and three intrafamilial healthy controls were selected showing within each group a normal diploid karyotype and homogeneous telomere length. Different complex IV NO-inhibition patterns were induced by varying the electron flux through the respiratory chain, using exogenous cell membrane permeable electron donors. Under conditions of high electron flux the mitochondrial NO inhibition of respiration was greater in AT than in control cells (P< or =0.05). This property appears peculiar to AT, and correlates well to the higher concentration of cytochrome c detected in the AT cells. This finding is discussed on the basis of the proposed mechanism of reaction of NO with complex IV. It is suggested that the peculiar response of AT mitochondria to NO stress may be relevant to the mitochondrial metabolism of AT patients.

  7. Differences between the genomes of lymphoblastoid cell lines and blood-derived samples

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    Joesch-Cohen LM

    2017-02-01

    Full Text Available Lena M Joesch-Cohen, Gustavo Glusman Institute for Systems Biology, Seattle, WA, USA Abstract: Lymphoblastoid cell lines (LCLs represent a convenient research tool for expanding the amount of biologic material available from an individual. LCLs are commonly used as reference materials, most notably from the Genome in a Bottle Consortium. However, the question remains how faithfully LCL-derived genome assemblies represent the germline genome of the donor individual as compared to the genome assemblies derived from peripheral blood mononuclear cells. We present an in-depth comparison of a large collection of LCL- and peripheral blood mononuclear cell-derived genomes in terms of distributions of coverage and copy number alterations. We found significant differences in the depth of coverage and copy number calls, which may be driven by differential replication timing. Importantly, these copy number changes preferentially affect regions closer to genes and with higher GC content. This suggests that genomic studies based on LCLs may display locus-specific biases, and that conclusions based on analysis of depth of coverage and copy number variation may require further scrutiny. Keywords: genomics, whole-genome sequencing, viral transformation, copy number changes, bioinformatics

  8. Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder.

    Science.gov (United States)

    Fries, Gabriel R; Colpo, Gabriela D; Monroy-Jaramillo, Nancy; Zhao, Junfei; Zhao, Zhongming; Arnold, Jodi G; Bowden, Charles L; Walss-Bass, Consuelo

    2017-11-01

    Lithium is the most commonly prescribed medication for the treatment of bipolar disorder (BD), yet the mechanisms underlying its beneficial effects are still unclear. We aimed to compare the effects of lithium treatment in lymphoblastoid cell lines (LCLs) from BD patients and controls. LCLs were generated from sixty-two BD patients (based on DSM-IV) and seventeen healthy controls matched for age, sex, and ethnicity. Patients were recruited from outpatient clinics from February 2012 to October 2014. LCLs were treated with 1mM lithium for 7 days followed by microarray gene expression assay and validation by real-time quantitative PCR. Baseline differences between groups, as well as differences between vehicle- and lithium-treated cells within each group were analyzed. The biological significance of differentially expressed genes was examined by pathway enrichment analysis. No significant differences in baseline gene expression (adjusted p-value Lithium treatment of LCLs from controls did not lead to any significant differences. However, lithium altered the expression of 236 genes in LCLs from patients; those genes were enriched for signaling pathways related to apoptosis. Among those genes, the alterations in the expression of PIK3CG, SERP1 and UPP1 were validated by real-time PCR. A significant correlation was also found between circadian functioning and CEBPG and FGF2 expression levels. In summary, our results suggest that lithium treatment induces expression changes in genes associated with the apoptosis pathway in BD LCLs. The more pronounced effects of lithium in patients compared to controls suggest a disease-specific effect of this drug. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  9. Analysis of genome-wide RNA-sequencing data suggests age of the CEPH/Utah (CEU) lymphoblastoid cell lines systematically biases gene expression profiles.

    Science.gov (United States)

    Yuan, Yuan; Tian, Lei; Lu, Dongsheng; Xu, Shuhua

    2015-01-22

    In human, Lymphoblastoid cell lines (LCLs) from the CEPH/CEU (Centre d'Etude du Polymorphisme Humain - Utah) family resource have been extensively used for examining the genetics of gene expression levels. However, we noted that CEU/CEPH cell lines were collected and transformed approximately thirty years ago, much earlier than the other cell lines from the pertaining individuals, which we suspected could potentially affect gene expression, data analysis and results interpretation. In this study, by analyzing RNA sequencing data of CEU and the other three European populations as well as an African population, we systematically examined and evaluated the potential confounding effect of LCL age on gene expression levels and patterns. Our results indicated that gene expression profiles of CEU samples have been biased by the older age of CEU cell lines. Interestingly, most of CEU-specific expressions are associated with functions related to cell proliferation, which are more likely due to older age of cell lines than intrinsic characters of the population. We suggested the results be carefully explained when CEU LCLs are used for transcriptomic data analysis in future studies.

  10. DNA-polymerase induced by Herpesvirus papio (HVP) in cells of lymphoblastoid cultures derived from lymphomatous baboons. Report V.

    Science.gov (United States)

    Djachenko, A G; Lapin, B A

    1981-01-01

    A new DNA-polymerase was found in the cells of suspension lymphoblastoid cultures which produce lymphotropic baboon herpesvirus (HVP). This enzyme was isolated in a partially purified form. Some of its properties vary from those of other cellular DNA-polymerases. HVP-induced DNA-polymerase has a molecule weight of 160,000 and sedimentation coefficient of about 8 S. The enzyme is resistant to high salt concentration and N-ethylmaleimide, but it is very sensitive to phosphonoacetate. It effectively copies "activated" DNA and synthetic deoxyribohomopolymers. Attempts to reveal the DNA-polymerase activity in HVP virions were unsuccessful.

  11. Lymphoblastoids cell lines – Derived iPSC line from a 26-year-old myotonic dystrophy type 1 patient carrying (CTG200 expansion in the DMPK gene: CHUQi001-A

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    Laurie Martineau

    2018-01-01

    Full Text Available Human immortalized Epstein-Barr virus (EBV lymphoblastoids cells line (LCLs from a 26-year- old male affected by an adult form of myotonic dystrophy type 1 (DM1 disease and carrying 200 CTG repeats mutation in the blood was used to generate induced pluripotent stem cells (iPSCs using the Sendai virus expressing KLF4, OCT4, SOX2 and C-MYC. The resulting iPSCs were EBV free, expressed the pluripotency markers, could be differentiated into the three germ layers in vitro, had a normal karyotype, and retained the genetic DM1 mutation. This iPSC line could be useful for the investigation of DM1 mechanisms.

  12. Lymphoblastoids cell lines - Derived iPSC line from a 26-year-old myotonic dystrophy type 1 patient carrying (CTG)200expansion in the DMPK gene: CHUQi001-A.

    Science.gov (United States)

    Martineau, Laurie; Racine, Véronique; Benichou, Siham Ait; Puymirat, Jack

    2017-12-16

    Human immortalized Epstein-Barr virus (EBV) lymphoblastoids cells line (LCLs) from a 26-year- old male affected by an adult form of myotonic dystrophy type 1 (DM1) disease and carrying 200 CTG repeats mutation in the blood was used to generate induced pluripotent stem cells (iPSCs) using the Sendai virus expressing KLF4, OCT4, SOX2 and C-MYC. The resulting iPSCs were EBV free, expressed the pluripotency markers, could be differentiated into the three germ layers in vitro, had a normal karyotype, and retained the genetic DM1 mutation. This iPSC line could be useful for the investigation of DM1 mechanisms. Copyright © 2017. Published by Elsevier B.V.

  13. Gene expression analysis of whole blood, peripheral blood mononuclear cells, and lymphoblastoid cell lines from the Framingham Heart Study.

    Science.gov (United States)

    Joehanes, Roby; Johnson, Andrew D; Barb, Jennifer J; Raghavachari, Nalini; Liu, Poching; Woodhouse, Kimberly A; O'Donnell, Christopher J; Munson, Peter J; Levy, Daniel

    2012-01-18

    Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, there have been few systematic comparisons of various RNA sources in transcriptomic analysis or for biomarker discovery in the context of cardiovascular disease (CVD). As a pilot study of the Systems Approach to Biomarker Research (SABRe) in CVD Initiative, this investigation used Affymetrix Exon arrays to characterize gene expression of three blood-derived RNA sources: lymphoblastoid cell lines (LCL), whole blood using PAXgene tubes (PAX), and peripheral blood mononuclear cells (PBMC). Their performance was compared in relation to identifying transcript associations with sex and CVD risk factors, such as age, high-density lipoprotein, and smoking status, and the differential blood cell count. We also identified a set of exons that vary substantially between participants, but consistently in each RNA source. Such exons are thus stable phenotypes of the participant and may potentially become useful fingerprinting biomarkers. In agreement with previous studies, we found that each of the RNA sources is distinct. Unlike PAX and PBMC, LCL gene expression showed little association with the differential blood count. LCL, however, was able to detect two genes related to smoking status. PAX and PBMC identified Y-chromosome probe sets similarly and slightly better than LCL.

  14. Dominant expansion of a cryptic subclone with an abnormal karyotype in B lymphoblastoid cell lines during culture.

    Science.gov (United States)

    Danjoh, I; Shirota, R; Hiroyama, T; Nakamura, Y

    2013-01-01

    Although B lymphoblastoid cell lines (B-LCLs) are thought to maintain their original genomic structures during long-term culture, there has been considerable disagreement on the actual genomic stability of these cells. This study was initiated to determine whether B-LCLs develop cell populations with abnormal genomes during culture and to search for factors important to the maintenance of the original genome. We established continuous cultures of B-LCLs for more than 6 months and analyzed the cells using array-based comparative genome hybridization (CGH) analysis, conventional karyotyping and analysis of V(D)J recombination in the immunoglobulin (Ig) gene. We found that one B-LCL acquired an extra chromosome 4 without any other genomic rearrangements at passage 16 of continuous culture. At the Ig light- and heavy-chain loci, analysis of the major cell population showed a difference between cultures at early and later passages. Another aneuploid line was detected among B-LCLs established elsewhere and deposited previously into the RIKEN Cell Bank. Our findings indicate that some of the genomic rearrangements in B-LCLs are not caused by gradual accumulation of mutations and rearrangements during the B-LCL establishment processes, but rather as a result of a change in the cell population from clones with a normal genome to clones with de novo rearrangements. It is therefore feasible to maintain B-LCLs with a normal genomic structure by cell cloning or similar treatment. Copyright © 2012 S. Karger AG, Basel.

  15. Different mechanisms of radiation-induced loss of heterozygosity in two human lymphoid cell lines from a single donor

    Science.gov (United States)

    Wiese, C.; Gauny, S. S.; Liu, W. C.; Cherbonnel-Lasserre, C. L.; Kronenberg, A.

    2001-01-01

    Allelic loss is an important mutational mechanism in human carcinogenesis. Loss of heterozygosity (LOH) at an autosomal locus is one outcome of the repair of DNA double-strand breaks (DSBs) and can occur by deletion or by mitotic recombination. We report that mitotic recombination between homologous chromosomes occurred in human lymphoid cells exposed to densely ionizing radiation. We used cells derived from the same donor that express either normal TP53 (TK6 cells) or homozygous mutant TP53 (WTK1 cells) to assess the influence of TP53 on radiation-induced mutagenesis. Expression of mutant TP53 (Met 237 Ile) was associated with a small increase in mutation frequencies at the hemizygous HPRT (hypoxanthine phosphoribosyl transferase) locus, but the mutation spectra were unaffected at this locus. In contrast, WTK1 cells (mutant TP53) were 30-fold more susceptible than TK6 cells (wild-type TP53) to radiation-induced mutagenesis at the TK1 (thymidine kinase) locus. Gene dosage analysis combined with microsatellite marker analysis showed that the increase in TK1 mutagenesis in WTK1 cells could be attributed, in part, to mitotic recombination. The microsatellite marker analysis over a 64-cM region on chromosome 17q indicated that the recombinational events could initiate at different positions between the TK1 locus and the centromere. Virtually all of the recombinational LOH events extended beyond the TK1 locus to the most telomeric marker. In general, longer LOH tracts were observed in mutants from WTK1 cells than in mutants from TK6 cells. Taken together, the results demonstrate that the incidence of radi-ation-induced mutations is dependent on the genetic background of the cell at risk, on the locus examined, and on the mechanisms for mutation available at the locus of interest.

  16. Utility of Lymphoblastoid Cell Lines for Induced Pluripotent Stem Cell Generation

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    Satish Kumar

    2016-01-01

    Full Text Available A large number of EBV immortalized LCLs have been generated and maintained in genetic/epidemiological studies as a perpetual source of DNA and as a surrogate in vitro cell model. Recent successes in reprograming LCLs into iPSCs have paved the way for generating more relevant in vitro disease models using this existing bioresource. However, the overall reprogramming efficiency and success rate remain poor and very little is known about the mechanistic changes that take place at the transcriptome and cellular functional level during LCL-to-iPSC reprogramming. Here, we report a new optimized LCL-to-iPSC reprogramming protocol using episomal plasmids encoding pluripotency transcription factors and mouse p53DD (p53 carboxy-terminal dominant-negative fragment and commercially available reprogramming media. We achieved a consistently high reprogramming efficiency and 100% success rate using this optimized protocol. Further, we investigated the transcriptional changes in mRNA and miRNA levels, using FC-abs ≥ 2.0 and FDR ≤ 0.05 cutoffs; 5,228 mRNAs and 77 miRNAs were differentially expressed during LCL-to-iPSC reprogramming. The functional enrichment analysis of the upregulated genes and activation of human pluripotency pathways in the reprogrammed iPSCs showed that the generated iPSCs possess transcriptional and functional profiles very similar to those of human ESCs.

  17. Individual radiosensitivity does not correlate with radiation-induced apoptosis in lymphoblastoid cell lines or CD{sup 3+} lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Wistop, A.; Keller, U.; Grabenbauer, G.G.; Sauer, R.; Distel, L.V.R. [Dept. of Radiation Oncology, Friedrich Alexander Univ. Erlangen-Nuremberg, Erlangen (Germany); Sprung, C.N. [Div. of Research, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia)

    2005-05-01

    Background and purpose: spontaneous and radiation-induced apoptosis of lymphoblastoid cell lines (LCLs) derived from healthy donors, cancer patients and donors with radiosensitivity syndromes as well as CD{sup 3+} lymphocytes from patients with {>=} grade 3 late toxicity were investigated as a possible marker for the detection of individual radiosensitivity. These investigations are based on the hypothesis that hypersensitive patients have reduced levels of apoptosis after in vitro irradiation as a result of a defect in the signaling pathway. Material and methods: Epstein-Barr virus-(EBV-)transformed LCLs derived from five healthy donors, seven patients with heterozygous or homozygous genotype for ataxia-telangiectasia or Nijmegen breakage syndrome and five patients with {>=} grade 3 late toxicity (RTOG) were investigated. In addition, CD{sup 3+} lymphocytes from 21 healthy individuals and 18 cancer patients including five patients with a proven cellular hypersensitivity to radiation were analyzed. Cells were irradiated in vitro with a dose of 2 and 5 Gy and were incubated for 48 h. Apoptotic rates were measured by the TUNEL assay followed by customized image analysis. Results: four out of seven radiosensitivity syndrome patients were identified to have an increased cellular radiosensitivity as determined by reduced apoptotic rates after irradiation of their respective LCLs. Comparatively, only two of the five hypersensitive cancer patients were clearly identified by reduced apoptotic rates. Spontaneous apoptotic rates were very homogeneous among all 39 samples from controls and patients, while lymphocytes of all cancer patients showed significantly lower radiation-induced rates. Conclusion: only a subgroup of hypersensitive patients may be identified by reduction of radiation-induced apoptotic rate. It is concluded that the hypothesis according to which hypersensitive cells have reduced levels of apoptosis is only conditionally true. The authors suggest that this

  18. In-depth phenotyping of lymphoblastoid cells suggests selective cellular vulnerability in Marinesco-Sjögren syndrome.

    Science.gov (United States)

    Kollipara, Laxmikanth; Buchkremer, Stephan; Coraspe, José Andrés González; Hathazi, Denisa; Senderek, Jan; Weis, Joachim; Zahedi, René P; Roos, Andreas

    2017-09-15

    SIL1 is a ubiquitous protein of the Endoplasmic Reticulum (ER) acting as a co-chaperone for the ER-resident chaperone, BiP. Recessive mutations of the corresponding gene lead to vulnerability of skeletal muscle and central nervous system in man (Marinesco-Sjögren syndrome; MSS) and mouse. However, it is still unclear how loss of ubiquitous SIL1 leads to selective vulnerability of the nervous system and skeletal muscle whereas other cells and organs are protected from clinical manifestations. In this study we aimed to disentangle proteins participating in selective vulnerability of SIL1-deficient cells and tissues: morphological examination of MSS patient-derived lymphoblastoid cells revealed altered organelle structures (ER, nucleus and mitochondria) thus showing subclinical vulnerability. To correlate structural perturbations with biochemical changes and to identify proteins potentially preventing phenotypical manifestation, proteomic studies have been carried out. Results of proteomic profiling are in line with the morphological findings and show affection of nuclear, mitochondrial and cytoskeletal proteins as well as of such responsible for cellular viability. Moreover, expression patterns of proteins known to be involved in neuromuscular disorders or in development and function of the nervous system were altered. Paradigmatic findings were confirmed by immunohistochemistry of splenic lymphocytes and the cerebellum of SIL1-deficient mice. Ataxin-10, identified with increased abundance in our proteome profile, is necessary for the neuronal survival but also controls muscle fiber apoptosis, thus declaring this protein as a plausible candidate for selective tissue vulnerability. Our combined results provide first insights into the molecular causes of selective cell and tissue vulnerability defining the MSS phenotype.

  19. An Epstein-Barr virus isolated from a lymphoblastoid cell line has a 16-kilobase-pair deletion which includes gp350 and the Epstein-Barr virus nuclear antigen 3A.

    Science.gov (United States)

    Lee, W; Hwang, Y H; Lee, S K; Subramanian, C; Robertson, E S

    2001-09-01

    Epstein-Barr virus (EBV) is associated with human cancers, including nasopharyngeal carcinoma, Burkitt's lymphoma, gastric carcinoma and, somewhat controversially, breast carcinoma. EBV infects and efficiently transforms human primary B lymphocytes in vitro. A number of EBV-encoded genes are critical for EBV-mediated transformation of human B lymphocytes. In this study we show that an EBV-infected lymphoblastoid cell line obtained from the spontaneous outgrowth of B cells from a leukemia patient contains a deletion, which involves a region of approximately 16 kbp. This deletion encodes major EBV genes involved in both infection and transformation of human primary B lymphocytes and includes the glycoprotein gp350, the entire open reading frame of EBNA3A, and the amino-terminal region of EBNA3B. A fusion protein created by this deletion, which lies between the BMRF1 early antigen and the EBNA3B latent antigen, is truncated immediately downstream of the junction 21 amino acids into the region of the EBNA3B sequence, which is out of frame with respect to the EBNA3B protein sequence, and indicates that EBNA3B is not expressed. The fusion is from EBV coordinate 80299 within the BMRF1 sequence to coordinate 90998 in the EBNA3B sequence. Additionally, we have shown that there is no detectable induction in viral replication observed when SNU-265 is treated with phorbol esters, and no transformants were detected when supernatant is used to infect primary B lymphocytes after 8 weeks in culture. Therefore, we have identified an EBV genome with a major deletion in critical genes involved in mediating EBV infection and the transformation of human primary B lymphocytes that is incompetent for replication of this naturally occurring EBV isolate.

  20. Adenovirus infection reverses the antiviral state induced by human interferon.

    Science.gov (United States)

    Feduchi, E; Carrasco, L

    1987-04-06

    HeLa cells treated with human lymphoblastoid interferon do not synthesize poliovirus proteins. The antiviral state against poliovirus is reversed if cells are previously infected with adenovirus type 5. A late gene product seems to be involved in this reversion, since no effect is observed at early stages of infection or in the presence of aphidicolin.

  1. Human cell line sensitive to mutation by particle-borne chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Crespi, C.L.; Liber, H.L.; Behymer, T.D.; Hites, R.A.; Thilly, W.G.

    1985-07-01

    A human lymphoblastoid cell line with ability to perform oxidative metabolism of various chemicals is mutated by the direct addition of an intact particulate soot. This experiment demonstrates that materials associated with combustion-generated particulates are biologically available and able to cause genetic changes in metabolically competent human cells.

  2. Use of lymphoblastoid cells for the estimation of environmental insults to DNA. Comprehensive report of the overall activities of the contract during the past three years. Progress report, August 1, 1978-June 31, 1981

    Energy Technology Data Exchange (ETDEWEB)

    None

    1981-01-01

    Research progress is reported on a study to detect chronic low-level exposure of individuals to polycyclic aromatic hydrocarbons by analysis of DNA in cells with low turnover rates. The technique used was to measure the level of excision repair activity in lymphoblastoid and lymphoma cell lines. (ACR)

  3. Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes

    Directory of Open Access Journals (Sweden)

    Lee Norman H

    2006-05-01

    Full Text Available Abstract Background The autism spectrum encompasses a set of complex multigenic developmental disorders that severely impact the development of language, non-verbal communication, and social skills, and are associated with odd, stereotyped, repetitive behavior and restricted interests. To date, diagnosis of these neurologically based disorders relies predominantly upon behavioral observations often prompted by delayed speech or aberrant behavior, and there are no known genes that can serve as definitive biomarkers for the disorders. Results Here we demonstrate, for the first time, that lymphoblastoid cell lines from monozygotic twins discordant with respect to severity of autism and/or language impairment exhibit differential gene expression patterns on DNA microarrays. Furthermore, we show that genes important to the development, structure, and/or function of the nervous system are among the most differentially expressed genes, and that many of these genes map closely in silico to chromosomal regions containing previously reported autism candidate genes or quantitative trait loci. Conclusion Our results provide evidence that novel candidate genes for autism may be differentially expressed in lymphoid cell lines from individuals with autism spectrum disorders. This finding further suggests the possibility of developing a molecular screen for autism based on expressed biomarkers in peripheral blood lymphocytes, an easily accessible tissue. In addition, gene networks are identified that may play a role in the pathophysiology of autism.

  4. Host cell reactivation of uv- and X-ray-damaged herpes simplex virus by Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Henderson, E.E. (Temple Univ. School of Medicine, Philadelphia, PA); Long, W.K.

    1981-12-01

    The efficacy of using an infected centers assay, employing herpes simplex virus-infected, Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) as components, to study host cell reactivation has been explored. Herpes simplex virus type 1 (HSV-1) was shown through the infected centers assay to have detectable but varying ability to lytically infect LCLs established from chromosomal breakage syndromes or closely related genetic disorders. The rate of HSV inactivation by ultraviolet (uv) irradiation was faster in LCLs established from Cockaynes's syndrome than in normal LCLs, and faster still in LCLs established from xeroderma pigmentosum. These results indicate that Cockayne's syndrome, while having what appears to be quantitatively normal levels of uv-induced DNA repair replication, shows decreased ability to host cell reactivated uv-damaged HSV. In direct contrast, X-irradiated HSV showed identical survival when assayed on normal LCLs or LCLs established from ataxia telangiectasia showing increased sensitivity to X irradiation as measured by colony formation. Through the infected centers assay, it has also been possible to demonstrate low levels of multiplicity reactivation of mutagen-damaged HSV in permanently proliferating LCLs.

  5. Identification of the soluble HVP-associated antigen of the lymphoblastoid cell line established from lymphomatous baboon (Papio hamadryas).

    Science.gov (United States)

    Voevodin, A F; Lapin, B A; Agrba, V Z; Timanovskaya, V V

    1978-01-01

    A new technique (indirect double immunodiffusion) for detection of EBV-associated soluble antigen and corresponding antibodies has been developed. This technique includes three steps: 1) simple double immunodiffusion with extracts of Raji cells (or other EBV-genome positive cells) and human sera containing antibodies against EBV-associated soluble antigen; 2) extensive washing and treatment with anti-human globulin; 3) extensive washing and treatment with tannic acid. Using this test it was shown that the soluble antigen indistinguishable from EBV-associated soluble antigen was present in KMPG-1 cells producing HVP.

  6. All-trans Retinoic Acid Upregulates Reduced CD38 Transcription in Lymphoblastoid Cell Lines from Autism Spectrum Disorder

    OpenAIRE

    Riebold, Mathias; Mankuta, David; Lerer, Elad; Israel, Salomon; Zhong, Songfa; Nemanov, Luba; Monakhov, Mikhail V.; Levi, Shlomit; Yirmiya, Nurit; Yaari, Maya; Malavasi, Fabio; Ebstein, Richard P

    2011-01-01

    Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensi...

  7. Induction of epstein-barr virus (EBV lytic cycle in vitro causes lipid peroxidation, protein oxidation and DNA damage in lymphoblastoid B cell lines

    Directory of Open Access Journals (Sweden)

    benmansour Riadh

    2011-07-01

    Full Text Available Abstract Background We investigated the oxidative modifications of lipids, proteins and DNA, potential molecular targets of oxidative stress, in two lymphoblastoid cell lines: B95-8 and Raji, after EBV lytic cycle induction. Conjugated dienes level was measured as biomarker of lipid peroxidation. Malondialdehyde adduct and protein carbonyl levels, as well as protein thiol levels were measured as biomarkers of protein oxidation. DNA fragmentation was evaluated as biomarker of DNA oxidation. Results After 48 h (peak of lytic cycle, a significant increase in conjugated dienes level was observed in B95-8 and Raji cell lines (p = 0.0001 and p = 0.019 respectively. Malondialdehyde adduct, protein carbonyl levels were increased in B95-8 and Raji cell lines after EBV lytic cycle induction as compared to controls (MDA-adduct: p = 0.008 and p = 0.006 respectively; Carbonyl: p = 0.003 and p = 0.0039 respectively. Proteins thiol levels were decreased by induction in B95-8 and Raji cell lines (p = 0.046; p = 0.002 respectively. DNA fragmentation was also detected in B95-8 and Raji cell lines after EBV lytic cycle induction as compared to controls. Conclusion The results of this study demonstrate the presence of increased combined oxidative modifications in lipids, proteins in B95-8 and Raji cells lines after EBV lytic cycle induction. These results suggest that lipid peroxidation, protein oxidation and DNA fragmentation are generally induced during EBV lytic cycle induction and probably contribute to the cytopathic effect of EBV.

  8. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress.

    Science.gov (United States)

    Main, Penelope A E; Thomas, Philip; Esterman, Adrian; Fenech, Michael F

    2013-07-01

    Autism spectrum disorders are a heterogeneous group of neurodevelopmental conditions characterised by impairments in reciprocal social interaction, communication and stereotyped behaviours. As increased DNA damage events have been observed in a range of other neurological disorders, it was hypothesised that they would be elevated in lymphoblastoid cell lines (LCLs) obtained from children with autism compared with their non-autistic siblings. Six case-sibling pairs of LCLs from children with autistic disorder and their non-autistic siblings were obtained from the Autism Genetic Resource Exchange (AGRE) and cultured in standard RPMI-1640 tissue culture medium. Cells were exposed to medium containing either 0, 25, 50, 100 and 200 µM hydrogen peroxide (an oxidative stressor) or 0, 5, 10, 20 and 40 µM s-nitroprusside (a nitric oxide producer) for 1h. Following exposure, the cells were microscopically scored for DNA damage, cytostasis and cytotoxicity biomarkers as measured using the cytokinesis-block micronucleus cytome assay. Necrosis was significantly increased in cases relative to controls when exposed to oxidative and nitrosative stress (P = 0.001 and 0.01, respectively). Nuclear division index was significantly lower in LCLs from children with autistic disorder than their non-autistic siblings when exposed to hydrogen peroxide (P = 0.016), but there was no difference in apoptosis, micronucleus frequency, nucleoplasmic bridges or nuclear buds. Exposure to s-nitroprusside significantly increased the number of micronuclei in non-autistic siblings compared with cases (P = 0.003); however, other DNA damage biomarkers, apoptosis and nuclear division did not differ significantly between groups. The findings of this study show (i) that LCLs from children with autism are more sensitive to necrosis under conditions of oxidative and nitrosative stress than their non-autistic siblings and (ii) refutes the hypothesis that children with autistic disorder are abnormally

  9. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort.

    Science.gov (United States)

    Rose, Shannon; Frye, Richard E; Slattery, John; Wynne, Rebecca; Tippett, Marie; Pavliv, Oleksandra; Melnyk, Stepan; James, S Jill

    2014-01-01

    There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases intracellular reactive oxygen species (ROS). Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32%) of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro

  10. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort.

    Directory of Open Access Journals (Sweden)

    Shannon Rose

    Full Text Available There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs derived from children with autistic disorder (AD as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ, an agent that increases intracellular reactive oxygen species (ROS. Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32% of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and

  11. Unsuitability of lymphoblastoid cell lines as surrogate of cryopreserved isolated lymphocytes for the analysis of DNA double-strand break repair activity

    Energy Technology Data Exchange (ETDEWEB)

    Zijno, Andrea [Department of Environment and Primary Prevention, Istituto Superiore di Sanita, Rome (Italy); Porcedda, Paola [Department of Clinical and Biological Sciences, University of Turin (Italy); Saini, Francesca [Department of Environment and Primary Prevention, Istituto Superiore di Sanita, Rome (Italy); Allione, Alessandra [Institute for Scientific Interchange (ISI) Foundation, Villa Gualino, Turin (Italy); Garofalo, Bruno; Marcon, Francesca [Department of Environment and Primary Prevention, Istituto Superiore di Sanita, Rome (Italy); Guarrera, Simonetta [Institute for Scientific Interchange (ISI) Foundation, Villa Gualino, Turin (Italy); Turinetto, Valentina; Minieri, Valentina [Department of Clinical and Biological Sciences, University of Turin (Italy); Funaro, Ada [Department of Genetics, Biology and Biochemistry, University of Turin (Italy); Crebelli, Riccardo [Department of Environment and Primary Prevention, Istituto Superiore di Sanita, Rome (Italy); Giachino, Claudia [Department of Clinical and Biological Sciences, University of Turin (Italy); Matullo, Giuseppe, E-mail: giuseppe.matullo@unito.it [Institute for Scientific Interchange (ISI) Foundation, Villa Gualino, Turin (Italy); Department of Genetics, Biology and Biochemistry, University of Turin (Italy)

    2010-02-03

    As first task of a comprehensive investigation on DNA repair genotype-phenotype correlations, the suitability of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) as surrogate of cryopreserved peripheral blood mononuclear cells (PBMCs) in DNA repair phenotypic assays was evaluated. To this aim the amount of DNA damage induced by {gamma}-rays and DNA repair capacity were evaluated in unstimulated (G{sub 0}) and mitogen-simulated (G{sub 2}) PBMC from 20 healthy subjects and in EBV-transformed LCL obtained from the same individuals. Phosphorylation of histone H2AX, micronuclei and chromosomal aberrations were the end-points investigated. The results obtained show higher basal frequencies of binucleated cells bearing micronuclei and nucleoplasmic bridge (NPB) in LCL with respect to PBMC, suggesting that EBV transformation may be associated with chromosomal instability. After irradiation, higher levels of micronuclei were induced in G{sub 0}-treated PBMC compared to cycling LCL; conversely, NPB were more frequent in LCL than in PBMC. Moreover, higher levels of chromosomal aberrations were observed in G{sub 2}-treated PBMC compared to LCL. Concerning {gamma}-H2AX measurements, phosphorylation levels 1 h after treatment and dephosphorylation kinetics were basically similar in LCL and in PBMC. However, while Spearman's test showed a strong correlation between the results obtained in replicated experiments with PBMC, high inter-experimental variability and poor reproducibility was observed in the experiments performed with LCL, possibly due to the intrinsic instability of LCL. In summary, both the analysis of {gamma}-H2AX and the evaluation of chromosome damage highlighted a larger inter-experimental variability in the results obtained with LCL compared to PBMC. Noteworthy, the two set of results proved to lack any significant correlation at the individual level. These results indicate that LCL may be unsuitable for investigating genotype

  12. Induction of p16(INK4a is the major barrier to proliferation when Epstein-Barr virus (EBV transforms primary B cells into lymphoblastoid cell lines.

    Directory of Open Access Journals (Sweden)

    Lenka Skalska

    2013-02-01

    Full Text Available To explore the role of p16(INK4a as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the CDKN2A locus encoding p16(INK4a and p14(ARF. Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT, we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs lacking active p16(INK4a protein but expressing a functional 14(ARF-fusion protein (p14/p16. The INK4a locus is epigenetically repressed by EBNA3C--in cooperation with EBNA3A--despite the absence of functional p16(INK4a. Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16(INK4a and growth arrest, EBNA3C inactivation in the p16(INK4a-null LCLs has no impact on the rate of proliferation, establishing that the repression of INK4a is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16(INK4a-Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16(INK4a expression and concomitant block to proliferation 2-4 weeks post-infection. If cells are p16(INK4a-null, functional EBNA3C is dispensable for the outgrowth of LCLs.

  13. A pharmacodynamic model of ganciclovir antiviral effect and toxicity for lymphoblastoid cells suggests a new dosing regimen to treat cytomegalovirus infection.

    Science.gov (United States)

    Janoly-Dumenil, Audrey; Rouvet, Isabelle; Bleyzac, Nathalie; Morfin, Florence; Zabot, Marie-Therese; Tod, Michel

    2012-07-01

    In bone marrow transplantation, the efficacy of ganciclovir in cytomegalovirus (CMV) disease treatment or prophylaxis remains partial. Because its hematological toxicity is dose limiting, optimization of the dosing schedule is required to increase its therapeutic index. The goal of our study was to describe the influence of the ganciclovir concentration and duration of exposure on cell survival and antiviral efficacy. The study was carried out in vitro on cultures of lymphoblastoid cells infected or not with the CMV AD169 reference strain and exposed to ganciclovir at different concentrations for 1, 2, 7, or 14 days. The data were analyzed by a mathematical model that allowed a quantitative characterization of ganciclovir pharmacodynamics and its variability. Simulations of the model were undertaken to determine the optimal concentration profile for maximizing the ganciclovir therapeutic index. Ganciclovir had very little toxic and antiviral effect, even at 20 mg liter(-1), when the duration of exposure was ≤ 7 days. A biologically significant effect was observed only with a 14-day exposure. Complete inhibition of viral replication was obtained at 20 mg liter(-1). The utility function, assuming equal weights for antiviral effect and toxicity, showed that maximal utility was reached around 10 mg liter(-1). The optimal ganciclovir concentration profile consisted of maintaining the concentration at 20 mg liter(-1) at the intervals 0 to 2 days and 7.58 to 9.58 days and a null concentration at other times. This optimal profile could be obtained by intravenous (i.v.) ganciclovir at 10 mg/kg of body weight twice daily (b.i.d.) at days 1, 2, 8.5, and 9.5 in stem cell transplant patients with normal renal function.

  14. Repair of DNA lesions induced by ultraviolet irradiation and aromatic amines in normal and repair-deficient human lymphoblastoid cell lines

    DEFF Research Database (Denmark)

    Stevnsner, Tinna; Frandsen, Henrik; Autrup, Herman

    1995-01-01

    belonging to complementation group B of Cockayne's syndrome (CS-B) showed reduced host cell reactivation. Fibroblasts from CS-B patients have reduced gene-specific DNA repair, but normal total genomic DNA repair, thus our data suggest that the HCR assay measures the capacity for gene-specific DNA repair...

  15. B-lymphoblastoid cell lines from multiple sclerosis patients and a healthy control producing a putative new human retrovirus and Epstein-Barr virus

    DEFF Research Database (Denmark)

    Munch, M; Møller-Larsen, A; Christensen, T

    1995-01-01

    with MS who had a reactivated Epstein-Barr virus (EBV) infection. Both LCLs were found by EM to produce RVLP and EBV particles. Reverse transcriptase (RT) assays were positive in purified viral material from both LCLs. To substantiate these findings we initiated an intensified culturing procedure and were...

  16. Gender differences in the metabolism of 1,3-butadiene to butadiene diepoxide in Sprague-Dawley rats

    Energy Technology Data Exchange (ETDEWEB)

    Thornton-Manning, J.R.; Dahl, A.R.; Bechtold, W.E. [and others

    1995-12-01

    1,3-Butadiene (BD), a gaseous compound used in the production of rubber, is a potent carcinogen in mice and a weak carcinogen in rats. The mechanism of BD-induced carcinogenicity is thought to involve genotoxic effects of its reactive epoxide metabolites butadiene monoepoxide (BDO) and butadiene diepoxide (BDO{sub 2}). Studies in our laboratory have shown that levels of the epoxides, particularly BDO{sub 2}, are greater in mice-the more sensitive species-than rats. While both epoxides are genotoxic in a number of assays, BDO{sub 2} is mutagenic in TK6 human lymphoblastoid cells at concentrations approximately 100-fold lower than BDO. Species differences in carcinogenicity of BD have posed a dilemma to investigators deciding which animal model is most appropriate for BD risk assessment.

  17. Extensive Variation in Chromatin States Across Humans

    KAUST Repository

    Kasowski, M.

    2013-10-17

    The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans.

  18. Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

    Directory of Open Access Journals (Sweden)

    Fry Rebecca C

    2011-04-01

    Full Text Available Abstract Background Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored. Results In this study, we examined the effects of in vitro exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis. Conclusions This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.

  19. Nuclear retention of 18S ribosoma RNA by human myeloma cells

    Energy Technology Data Exchange (ETDEWEB)

    Bynum, J.W. (Southern Illinois Univ., Carbondale); Volkin, E.

    1979-01-01

    Normal quiescent lymphocytes regulate their ribosome content by selectively degrading newly synthesized 18S ribosomal RNA. Unlike actively dividing HeLa cells, lymphocytes retain 18S ribosomal RNA in the nucleus after synthesis instead of immediately transporting it to the cytoplasm. Subcellular fractionation of the highly differentiated human neoplastic lymphocyte RPMI-8226 reveals that this cell line also retains 18S ribosomal RNA in the nucleus, a trait not displayed by the less differentiated human lymphoblastoid cell line RPMI-4265. These observations suggest that neoplastic cells can be phenotypically characterized by their ribosomal RNA processing patterns.

  20. Expression of the chemokine receptors CCR1 and CCR2B is up-regulated in peripheral blood B cells upon EBV infection and in established lymphoblastoid cell lines.

    Science.gov (United States)

    Kholodnyuk, Irina; Rudevica, Zanna; Leonciks, Ainars; Ehlin-Henriksson, Barbro; Kashuba, Elena

    2017-12-01

    In immunocompetent individuals, EBV establishes in B cells an asymptomatic lifelong latent infection controlled by the immune system. Chemokine receptors regulate immune system function. CCR1 and CCR2 share protein sequence similarity and exert responses to multiple chemokines. The role of these receptors in B cells is largely unknown. We show that the mRNA and functional protein expression of CCR1 and CCR2 is induced in ex vivo B cells upon EBV infection and in established lymphoblastoid cell lines (LCLs). The CCR1 and CCR2B ORF transcripts were determined in LCLs. In contrast, in both the EBV-negative and EBV-positive Burkitt lymphoma cell lines, neither the CCR1, CCR2A, and CCR2B ORF transcripts nor their corresponding proteins were detected. Our data suggest that CCR1/CCR2B could be involved in clearing EBV-infected latency III B cells in immunocompetent individuals via directing the migration of these cells and attracting the chemokines-expressing immune cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Assessing the concentration of phthalate esters (PAEs) and bisphenol A (BPA) and the genotoxic potential of treated wastewater (final effluent) in Saudi Arabia.

    Science.gov (United States)

    Al-Saleh, Iman; Elkhatib, Rola; Al-Rajoudi, Tahreer; Al-Qudaihi, Ghofran

    2017-02-01

    Plasticizers such as phthalate esters (PAEs) and bisphenol A (BPA) are highly persistent organic pollutants that tend to bio-accumulate in humans through the soil-plant-animal food chain. Some studies have reported the potential carcinogenic and teratogenic effects in addition to their estrogenic activities. Water resources are scarce in Saudi Arabia, and several wastewater treatment plants (WTPs) have been constructed for agricultural and industrial use. This study was designed to: (1) measure the concentrations of BPA and six PAEs, dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), bis (2-ethylhexyl) phthalate (DEHP) and dioctyl phthalate (DOP), in secondary- and tertiary-treated wastewater collected from five WTPs in three Saudi cities for four to five weeks and (2) test their potential genotoxicity. Three genotoxicological parameters were used: % tail DNA (%T), tail moment (TM) and percentage micronuclei (%MN). Both DBP and DEHP were detected in all treated wastewater samples. DMP, DEP, BBP, DOP, and BPA were found in 83.3, 84.2, 79, 73.7 and 97.4% of the samples, respectively. The levels of DMP (pwastewater than secondary-treated wastewater, perhaps due to the influence of the molecular weight and polarity of the chemicals. Both weekly sampling frequency and WTP locations significantly affected the variability in our data. Treated wastewater from Wadi Al-Araj was able to induce DNA damage (%T and TM) in human lymphoblastoid TK6 cells that was statistically higher than wastewater from all other WTPs and in untreated TK6 cells (negative control). %MN in samples from both Wadi Al-Araj and Manfouah did not differ statistically but was significantly higher than in the untreated TK6 cells. This study also showed that the samples of tertiary-treated wastewater had a higher genotoxicological potential to induce DNA damage than the samples of secondary-treated wastewater. BPA and some PAEs in the treated wastewater

  2. Genotoxicity of silver nanoparticles evaluated using the Ames test and in vitro micronucleus assay.

    Science.gov (United States)

    Li, Yan; Chen, David H; Yan, Jian; Chen, Ying; Mittelstaedt, Roberta A; Zhang, Yongbin; Biris, Alexandru S; Heflich, Robert H; Chen, Tao

    2012-06-14

    Silver nanoparticles (AgNPs) have antimicrobial properties, which have contributed to their widespread use in consumer products. A current issue regarding nanomaterials is the extent to which existing genotoxicity assays are useful for evaluating the risks associated with their use. In this study, the genotoxicity of 5 nm AgNPs was assessed using two standard genotoxicity assays, the Salmonella reverse mutation assay (Ames test) and the in vitro micronucleus assay. Using the preincubation version of the Ames assay, Salmonella strains TA102, TA100, TA1537, TA98, and TA1535 were treated with 0.15-76.8 μg/plate of the AgNPs. Toxicity limited the doses that could be assayed to 2.4-38.4 μg/plate; no increases in mutant frequency over the vehicle control were found for the concentrations that could be assayed. Human lymphoblastoid TK6 cells were treated with 10-30 μg/ml AgNPs, and additional cells were treated with water and 0.73 gy X-rays as vehicle and positive controls. Micronucleus frequency was increased by the AgNP treatment in a dose-dependent manner. At a concentration of 30 μg/ml (with 45.4% relative population doubling), AgNPs induced a significant, 3.17-fold increase with a net increase of 1.60% in micronucleus frequency over the vehicle control, a weak positive response by our criteria. These results demonstrate that the 5 nm AgNP are genotoxic in TK6 cells. Also, the data suggest that the in vitro micronucleus assay may be more appropriate than the Ames test for evaluating the genotoxicity of the AgNPs. Published by Elsevier B.V.

  3. Early embryonic chromosome instability results in stable mosaic pattern in human tissues.

    Directory of Open Access Journals (Sweden)

    Hasmik Mkrtchyan

    Full Text Available The discovery of copy number variations (CNV in the human genome opened new perspectives on the study of the genetic causes of inherited disorders and the aetiology of common diseases. Here, a single-cell-level investigation of CNV in different human tissues led us to uncover the phenomenon of mitotically derived genomic mosaicism, which is stable in different cell types of one individual. The CNV mosaic ratios were different between the 10 individuals studied. However, they were stable in the T lymphocytes, immortalized B lymphoblastoid cells, and skin fibroblasts analyzed in each individual. Because these cell types have a common origin in the connective tissues, we suggest that mitotic changes in CNV regions may happen early during embryonic development and occur only once, after which the stable mosaic ratio is maintained throughout the differentiated tissues. This concept is further supported by a unique study of immortalized B lymphoblastoid cell lines obtained with 20 year difference from two subjects. We provide the first evidence of somatic mosaicism for CNV, with stable variation ratios in different cell types of one individual leading to the hypothesis of early embryonic chromosome instability resulting in stable mosaic pattern in human tissues. This concept has the potential to open new perspectives in personalized genetic diagnostics and can explain genetic phenomena like diminished penetrance in autosomal dominant diseases. We propose that further genomic studies should focus on the single-cell level, to better understand the aetiology of aging and diseases mediated by somatic mutations.

  4. The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases.

    Directory of Open Access Journals (Sweden)

    Andrew J Olaharski

    2005-12-01

    Full Text Available Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC, a compound found in Melilotus officinalis (sweet clover that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.

  5. Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation

    Science.gov (United States)

    Peng, Yuanlin; Zhang, Qinming; Nagasawa, Hatsumi; Okayasu, Ryuichi; Liber, Howard L.; Bedford, Joel S.

    2002-01-01

    Targeted gene silencing in mammalian cells by RNA interference (RNAi) using small interfering RNAs (siRNAs) was recently described by Elbashir et al. (S. M. Elbashir et al., Nature (Lond.), 411: 494-498, 2001). We have used this methodology in several human cell strains to reduce expression of the Prkdc (DNA-PKcs) gene coding for the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) that is involved in the nonhomologous end joining of DNA double-strand breaks. We have also demonstrated a radiosensitization for several phenotypic endpoints of radiation damage. In low-passage normal human fibroblasts, siRNA knock-down of DNA-PKcs resulted in a reduced capacity for restitution of radiation-induced interphase chromosome breaks as measured by premature chromosome condensation, an increased yield of acentric chromosome fragments at the first postirradiation mitosis, and an increased radiosensitivity for cell killing. For three strains of related human lymphoblasts, DNA-PKcs-targeted siRNA transfection resulted in little or no increase in radiosensitivity with respect to cell killing, a 1.5-fold decrease in induced mutant yield in TK6- and p53-null NH32 cells, but about a 2-fold increase in induced mutant yield in p53-mutant WTK1 cells at both the hypoxanthine quanine phosphoribosyl transferase (hprt) and the thymidine kinase loci.

  6. Coating-dependent induction of cytotoxicity and genotoxicity of iron oxide nanoparticles.

    Science.gov (United States)

    Magdolenova, Zuzana; Drlickova, Martina; Henjum, Kristi; Rundén-Pran, Elise; Tulinska, Jana; Bilanicova, Dagmar; Pojana, Giulio; Kazimirova, Alena; Barancokova, Magdalena; Kuricova, Miroslava; Liskova, Aurelia; Staruchova, Marta; Ciampor, Fedor; Vavra, Ivo; Lorenzo, Yolanda; Collins, Andrew; Rinna, Alessandra; Fjellsbø, Lise; Volkovova, Katarina; Marcomini, Antonio; Amiry-Moghaddam, Mahmood; Dusinska, Maria

    2015-05-01

    Surface coatings of nanoparticles (NPs) are known to influence advantageous features of NPs as well as potential toxicity. Iron oxide (Fe3O4) NPs are applied for both medical diagnostics and targeted drug delivery. We investigated the potential cytotoxicity and genotoxicity of uncoated iron oxide (U-Fe3O4) NPs in comparison with oleate-coated iron oxide (OC-Fe3O4) NPs. Testing was performed in vitro in human lymphoblastoid TK6 cells and in primary human blood cells. For cytotoxicity testing, relative growth activity, trypan blue exclusion, (3)H-thymidine incorporation and cytokinesis-block proliferation index were assessed. Genotoxicity was evaluated by the alkaline comet assay for detection of strand breaks and oxidized purines. Particle characterization was performed in the culture medium. Cellular uptake, morphology and pathology were evaluated by electron microscopy. U-Fe3O4 NPs were found not to be cytotoxic (considering interference of NPs with proliferation test) or genotoxic under our experimental conditions. In contrast, OC-Fe3O4 NPs were cytotoxic in a dose-dependent manner, and also induced DNA damage, indicating genotoxic potential. Intrinsic properties of sodium oleate were excluded as a cause of the toxic effect. Electron microscopy data were consistent with the cytotoxicity results. Coating clearly changed the behaviour and cellular uptake of the NPs, inducing pathological morphological changes in the cells.

  7. Analysis of 75 marketed pharmaceuticals using the GADD45a-GFP 'GreenScreen HC' genotoxicity assay.

    Science.gov (United States)

    Hastwell, Paul W; Webster, Thomas W; Tate, Matthew; Billinton, Nicholas; Lynch, Anthony M; Harvey, James S; Rees, Robert W; Walmsley, Richard M

    2009-09-01

    The GADD45a-GFP (GreenScreen HC) reporter assay detects genotoxic damage in the human lymphoblastoid TK6 cell line and gives positive results for all classes of genotoxin, including mutagens, aneugens and clastogens. In this study, a collection of 75 marketed pharmaceuticals were tested in the assay. Compounds in the collection represent a broad range of chemical structures, pharmacologies and therapeutic indications, including neoplasia and viral infection where positive genotoxicity results are often associated with the pharmacological activity. Based on the results of this study, two main conclusions can be drawn: (i) the GreenScreen HC is more predictive of in vivo genotoxicity (88%) and genotoxic carcinogenicity (93%) data than the any of the other regulatory in vitro genotoxicity assay and (ii) no compounds were uniquely positive in the GADD45a-GFP assay. This analysis therefore provides additional evidence to support the use of the GADD45a-GFP assay as an effective tool either in early genotoxic liability identification or non-clinical safety assessment of candidate pharmaceuticals during development.

  8. Large-scale population study of human cell lines indicates that dosage compensation is virtually complete.

    Directory of Open Access Journals (Sweden)

    Colette M Johnston

    2008-01-01

    Full Text Available X chromosome inactivation in female mammals results in dosage compensation of X-linked gene products between the sexes. In humans there is evidence that a substantial proportion of genes escape from silencing. We have carried out a large-scale analysis of gene expression in lymphoblastoid cell lines from four human populations to determine the extent to which escape from X chromosome inactivation disrupts dosage compensation. We conclude that dosage compensation is virtually complete. Overall expression from the X chromosome is only slightly higher in females and can largely be accounted for by elevated female expression of approximately 5% of X-linked genes. We suggest that the potential contribution of escape from X chromosome inactivation to phenotypic differences between the sexes is more limited than previously believed.

  9. Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans

    Science.gov (United States)

    Cenik, Can; Cenik, Elif Sarinay; Byeon, Gun W.; Grubert, Fabian; Candille, Sophie I.; Spacek, Damek; Alsallakh, Bilal; Tilgner, Hagen; Araya, Carlos L.; Tang, Hua; Ricci, Emiliano; Snyder, Michael P.

    2015-01-01

    Elucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control. Combined analysis of RNA expression and ribosome occupancy improves the identification of individual protein level differences. Finally, we identify genetic differences that specifically modulate ribosome occupancy—many of these differences lie close to start codons and upstream ORFs. Our results reveal a new level of gene expression variation among humans and indicate that genetic variants can cause changes in protein levels through effects on translation. PMID:26297486

  10. Population genomics of human gene expression

    Science.gov (United States)

    Stranger, Barbara E.; Nica, Alexandra C.; Forrest, Matthew S.; Dimas, Antigone; Bird, Christine P.; Beazley, Claude; Ingle, Catherine E.; Dunning, Mark; Flicek, Paul; Koller, Daphne; Montgomery, Stephen; Tavaré, Simon; Deloukas, Panagiotis; Dermitzakis, Emmanouil T.

    2009-01-01

    Genetic variation influences gene expression, and this can be efficiently mapped to specific genomic regions and variants. We used gene expression profiling of EBV-transformed lymphoblastoid cell lines of all 270 individuals of the HapMap consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find gene expression levels to be heritable and differentiation between populations in agreement with earlier small-scale studies. A detailed association analysis of over 2.2 million common SNPs per population (5% frequency HapMap) with gene expression identified at least 1348 genes with association signals in cis and at least 180 in trans. Replication in at least one independent population was achieved for 37% of cis- signals and 15% of trans- signals, respectively. Our results strongly support an abundance of cis- regulatory variation in the human genome. Detection of trans- effects is limited but suggests that regulatory variation may be the key primary effect contributing to phenotypic variation in humans. Finally, we explore a variety of methodologies that improve the current state of analysis of gene expression variation. PMID:17873874

  11. Experiment list: SRX188972 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid cell line, Clinically normal; 4 paternal cousins have Cornelia de Lange syndr...sm=human || cell description=lymphoblastoid cell line, Clinically normal; 4 paternal cousins have Cornelia d

  12. Experiment list: SRX189419 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=lymphoblastoid cell line, Clinically normal; 4 paternal cousins have Cornelia de Lange syndrome; 46,...te=1,2 || cell=GM10248 || cell organism=human || cell description=lymphoblastoid cell line, Clinically norma

  13. Experiment list: SRX150361 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=lymphoblastoid, International HapMap Project, Han Chinese in Beijing, China, treatment: Epstein-Barr...| cell organism=human || cell description=lymphoblastoid, International HapMap Project, Han Chinese in Beijin

  14. Experiment list: SRX067520 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Bar...hromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  15. Experiment list: SRX150527 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Japanese in Tokyo, Japan, treatment: Epstein-B...1 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Japanese in Tokyo

  16. Experiment list: SRX067415 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Bar...hromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  17. Experiment list: SRX150470 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion,...ll organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah

  18. Experiment list: SRX111773 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...nism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigre

  19. Experiment list: SRX067523 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Bar...Chromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  20. Experiment list: SRX067459 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Bar...=Chromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  1. Experiment list: SRX189421 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=lymphoblastoid cell line, clinically normal; monozygotic twin sister with Cornelia De Lange syndrome...cell=GM13976 || cell organism=human || cell description=lymphoblastoid cell line, clinically normal; monozyg

  2. Experiment list: SRX150534 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epstein-B...9 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Niger

  3. Experiment list: SRX150359 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epstein-Barr Viru...ll organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera

  4. Experiment list: SRX150402 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epstein-B...cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Niger

  5. Experiment list: SRX150405 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epst...193 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Niger

  6. Experiment list: SRX150353 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epstein-Barr Viru...ll organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera

  7. Experiment list: SRX150404 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epstein-B...cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Niger

  8. Experiment list: SRX150533 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epstein-B...3 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Niger

  9. Experiment list: SRX150403 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Nigera, treatment: Epst...099 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, Niger

  10. Experiment list: SRX150607 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Japanese in Tokyo, Japan, treatment: Epstein-B...cell organism=human || cell description=lymphoblastoid, International HapMap Project, Japanese in Tokyo, Jap

  11. Experiment list: SRX150362 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=lymphoblastoid, International HapMap Project, Han Chinese in Beijing, China, treatment: Epstein-Barr...|| cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in Ibadan, N

  12. Experiment list: SRX150609 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=lymphoblastoid, International HapMap Project, Japanese in Tokyo, Japan, treatment: Epst...951 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Japanese in Tok

  13. Experiment list: SRX111775 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...ism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree

  14. Experiment list: SRX150601 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=lymphoblastoid, International HapMap Project, Han Chinese in Beijing, China, treatment:...=GM18505 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Yoruba in

  15. Experiment list: SRX150469 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus ...nism=human || cell description=lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-B

  16. Experiment list: SRX150529 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion,...ell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Uta

  17. Experiment list: SRX111776 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...nism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree

  18. Experiment list: SRX150604 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Han Chinese in Beijing, China, treatment: Epst...26 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Han Chinese in B

  19. Experiment list: SRX067487 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available tion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Ba...=Chromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  20. Experiment list: SRX080369 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein... || cell=GM12878 || cell organism=Human || cell description=lymphoblastoid, International HapMap Project - C

  1. Experiment list: SRX111774 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...nism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigre

  2. Experiment list: SRX150719 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, tr... || cell=GM12892 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapM

  3. Experiment list: SRX080339 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...aspx?Ref=GM12864 || cell=GM12864 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  4. Experiment list: SRX199864 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...12865 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project,

  5. Experiment list: SRX067518 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available n=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Barr ...atin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International Ha

  6. Experiment list: SRX199857 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...M12873 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project

  7. Experiment list: SRX080333 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst....aspx?Ref=GM12875 || cell=GM12875 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  8. Experiment list: SRX067503 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein...=Chromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  9. Experiment list: SRX111778 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...nism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigre

  10. Experiment list: SRX199861 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...M12872 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project

  11. Experiment list: SRX067509 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available tion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Ba...Chromatin IP Sequencing || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  12. Experiment list: SRX193598 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...2865 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project,

  13. Experiment list: SRX111777 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...nism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigre

  14. Experiment list: SRX080355 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst....aspx?Ref=GM12872 || cell=GM12872 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  15. Experiment list: SRX080349 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst....aspx?Ref=GM12873 || cell=GM12873 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  16. Experiment list: SRX080403 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst....aspx?Ref=GM12865 || cell=GM12865 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  17. Experiment list: SRX080332 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion,...f=GM12878 || cell=GM12878 || cell organism=Human || cell description=lymphoblastoid, International HapMap Pr

  18. Experiment list: SRX150528 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, Han Chinese in Beijing, China, treatment: Epst...18526 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Han Chinese i

  19. Experiment list: SRX150532 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme... || cell=GM12891 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapM

  20. Experiment list: SRX069118 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...&q=GM12864 || cell=GM12864 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  1. Experiment list: SRX150467 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme...l=GM12891 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Proj

  2. Experiment list: SRX150643 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion,...|| cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH

  3. Experiment list: SRX150530 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus trans...ism=human || cell description=lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Ba

  4. Experiment list: SRX080364 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Ba...f=GM12801 || cell=GM12801 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  5. Experiment list: SRX150366 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme...l=GM12892 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Proj

  6. Experiment list: SRX080393 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...aspx?Ref=GM12873 || cell=GM12873 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  7. Experiment list: SRX150603 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available mesoderm|Description=lymphoblastoid, International HapMap Project, Han Chinese in Beijing, China, treatment:...GM18526 || cell organism=human || cell description=lymphoblastoid, International HapMap Project, Han Chinese

  8. Experiment list: SRX080374 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus...1 || cell=GM12801 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International Hap

  9. Experiment list: SRX150557 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein... organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah -

  10. Experiment list: SRX150489 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available iption=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-...n=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International

  11. Experiment list: SRX080425 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst....aspx?Ref=GM12864 || cell=GM12864 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  12. Experiment list: SRX150605 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatment: Epst...GM12891 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Projec

  13. Experiment list: SRX199892 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...M12864 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project

  14. Experiment list: SRX069228 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus... cell=GM06990 || cell organism=Human || cell description=Lymphoblastoid, International HapMap Project, CEPH/

  15. Experiment list: SRX080371 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus...90 || cell=GM06990 || cell organism=Human || cell description=Lymphoblastoid, International HapMap Project,

  16. Experiment list: SRX069105 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...&q=GM12865 || cell=GM12865 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  17. Experiment list: SRX080368 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus...90 || cell=GM06990 || cell organism=Human || cell description=Lymphoblastoid, International HapMap Project,

  18. Experiment list: SRX069151 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus... cell=GM06990 || cell organism=Human || cell description=Lymphoblastoid, International HapMap Project, CEPH/

  19. Experiment list: SRX069154 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatment: Epst...&q=GM12865 || cell=GM12865 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  20. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo.

    Science.gov (United States)

    Zwicker, F; Kirsner, A; Peschke, P; Roeder, F; Debus, J; Huber, P E; Weber, K J

    2013-08-01

    Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. DCA induced tumor-specific radiosensitization in vitro but not in vivo. DCA also induced development of hypoxia in tumor tissue

  1. Inhibition of the SDF-1alpha-CXCR4 axis by the CXCR4 antagonist AMD3100 suppresses the migration of cultured cells from ATL patients and murine lymphoblastoid cells from HTLV-I Tax transgenic mice.

    Science.gov (United States)

    Kawaguchi, Akira; Orba, Yasuko; Kimura, Takashi; Iha, Hidekatsu; Ogata, Masao; Tsuji, Takahiro; Ainai, Akira; Sata, Tetsutaro; Okamoto, Takashi; Hall, William W; Sawa, Hirofumi; Hasegawa, Hideki

    2009-10-01

    Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T lymphotropic virus type I, and presents as an aggressive leukemia with characteristic widespread leukemic cell infiltration into visceral organs and skin. The molecular mechanisms associated with leukemic cell infiltration are poorly understood. We have used mouse models of ATL to investigate the role of chemokines in this process. Transfer of splenic lymphomatous cells from transgenic to SCID mice reproduces a leukemia and lymphoma that is histologically identical to human disease. It could be shown that lymphomatous cells exhibit specific chemotactic activity in response to stromal cell-derived factor-1alpha (SDF-1alpha). Lymphomatous cells exhibited surface expression of CXCR4, the specific receptor of SDF-1alpha. AMD3100, a CXCR4 antagonist, was found to inhibit both SDF-1alpha-induced migration and phosphorylation of extracellular signal-related kinase 1/2. Investigation of cultured cells from human ATL patients revealed identical findings. Using the SCID mouse model, it could be demonstrated that AMD3100 inhibited infiltration of lymphomatous cells into liver and lung tissues in vivo. These results demonstrate the involvement of the SDF-1alpha/CXCR4 interaction as one mechanism of leukemic cell migration and this may provide a novel target as part of combination therapy for ATL.

  2. Isolation of human spontaneous killer lymphocytes by bacterial adherence.

    Science.gov (United States)

    Kleinman, R; De Boer, K P; Teodorescu, M

    1980-01-01

    Human lymphocyte subpopulations (B, T1, T2, T3, and T4 our denomination) have been identified previously by bacterial adherence and differences between them in mitogen responses and specific cytotoxic activity have been found. In this study another aspect has been investigated in order to find functions associated with these subpopulations, namely the spontaneous killing (SK) ability. Freshly isolated human peripheral blood lymphocytes (PBL) were separated into adherent and non-adherent cells following centrifugation against various bact:rial monolayers. The PBL and the resulting subpopulations of PBL were tested alone or in combination as effector cells in a 4 hr cytotoxicity assay against human lymphoblastoid cel- lines of B or T cell origin. The T3 + T4 cells or T4 cells alone showed a significantly higher SK activity against both B and T target cell lines when compared with unseparated PBL, T1 + T2, or T3 cells alone. Whe Fc portion of IgG, contain the lymphocytes responsible for SK activity and that SK cells can be purified by negative selection using bacterial adherence. PMID:7389207

  3. Evaluating the potential genotoxicity of phthalates esters (PAEs) in perfumes using in vitro assays.

    Science.gov (United States)

    Al-Saleh, Iman; Al-Rajudi, Tahreer; Al-Qudaihi, Ghofran; Manogaran, Pulicat

    2017-10-01

    We previously reported high levels of phthalate esters (PAEs) added as solvents or fixatives in 47 brands of perfumes. Diethyl phthalate was the most abundant compound (0.232-23,649 ppm), and 83.3% of the perfumes had levels >1 ppm, the threshold limit cited by a Greenpeace investigation. All samples had dimethyl phthalate levels higher than its threshold limit of 0.1 ppm, and 88, 38, and 7% of the perfumes had benzyl butyl phthalate, di(2-ethylhexyl) phthalate, and dibutyl phthalate levels, respectively, above their threshold limits. The role of PAEs as endocrine disruptors has been well documented, but their effect on genotoxic behavior has received little attention. We used in vitro single-cell gel electrophoresis (comet) and micronucleus (MN) assays with human lymphoblastoid TK6 cells to evaluate the genotoxic potency of 42 of the same perfumes and to determine its association with PAEs. All perfumes induced more DNA damage than a negative control (NEG), ≥ 90% of the samples caused more damage than cells treated with the vehicles possibly used in perfume's preparations such as methanol (ME) and ethanol (ET), and 11.6% of the perfumes caused more DNA damage than a positive control (hydrogen peroxide). Chromosome breakage expressed as MN frequency was higher in cells treated with 71.4, 64.3, 57.1, and 4.8% of the perfumes than in NEG, cells treated with ME or ET, and another positive control (x-rays), respectively. The genotoxic responses in the comet and MN assays were not correlated. The comet assay indicated that the damage in TK6 cells treated with five PAEs at concentrations of 0.05 and 0.2 ppm either individually or as a mixture did not differ significantly from the damage in cells treated with the perfumes. Unlike the comet assay, the sensitivity of the MN assay to PAEs was weak at both low and high concentrations, and MN frequencies were generally low. This study demonstrates for the first time the possible contribution of PAEs in perfumes to DNA

  4. A selection index for gene expression evolution and its application to the divergence between humans and chimpanzees.

    Directory of Open Access Journals (Sweden)

    Maria Warnefors

    Full Text Available The importance of gene regulation in animal evolution is a matter of long-standing interest, but measuring the impact of selection on gene expression has proven a challenge. Here, we propose a selection index of gene expression as a straightforward method for assessing the mode and strength of selection operating on gene expression levels. The index is based on the widely used McDonald-Kreitman test and requires the estimation of four quantities: the within-species and between-species expression variances as well as the sequence heterozygosity and divergence of neutrally evolving sequences. We apply the method to data from human and chimpanzee lymphoblastoid cell lines and show that gene expression is in general under strong stabilizing selection. We also demonstrate how the same framework can be used to estimate the proportion of adaptive gene expression evolution.

  5. Experiment list: SRX100458 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion,...ype description=Chromatin IP Sequencing || cell description=B-lymphocyte, lymphoblastoid, International HapM...ll organism=human || cell description=lymphoblastoid, International HapMap Projec

  6. Experiment list: SRX100481 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion,...type description=Chromatin IP Sequencing || cell description=B-lymphocyte, lymphoblastoid, International Hap...ell organism=human || cell description=lymphoblastoid, International HapMap Proje

  7. A Cellular GWAS Approach to Define Human Variation in Cellular Pathways Important to Inflammation

    Directory of Open Access Journals (Sweden)

    Samuel I. Miller

    2016-04-01

    Full Text Available An understanding of common human diversity in innate immune pathways should be beneficial in understanding autoimmune diseases, susceptibility to infection, and choices of anti-inflammatory treatment. Such understanding could also result in definition of currently unknown components of human inflammation pathways. A cellular genome-wide association studies (GWAS platform, termed Hi-HOST (High-throughput human in vitro susceptibility testing, was developed to assay in vitro cellular phenotypes of infection in genotyped lymphoblastoid cells from genetically diverse human populations. Hi-HOST allows for measurement of multiple host and pathogen parameters of infection/inflammation including: bacterial invasion and intracellular replication, host cell death, and cytokine production. Hi-HOST has been used to successfully define a significant portion of the heritable human diversity in inflammatory cell death in response to Salmonella typhimurium. It also led to the discovery of genetic variants important to protection against systemic inflammatory response syndrome (SIRS and protection against death and bacteremia in individuals with SIRS. Our laboratory is currently using this platform to define human diversity in autophagy and the NLPR3 inflammasome pathways, and to define new components that can impact the expression of phenotypes related to these pathways.

  8. Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture.

    Directory of Open Access Journals (Sweden)

    Alicia R Martin

    2014-08-01

    Full Text Available Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP. The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and

  9. Detection and quantification of 4-ABP adducts in DNA from bladder cancer patients.

    Science.gov (United States)

    Zayas, Beatriz; Stillwell, Sara W; Wishnok, John S; Trudel, Laura J; Skipper, Paul; Yu, Mimi C; Tannenbaum, Steven R; Wogan, Gerald N

    2007-02-01

    We analyzed bladder DNA from 27 cancer patients for dG-C8-4-aminobiphenyl (dG-C8-ABP) adducts using the liquid chromatography tandem mass spectrometry method with a 700 attomol (1 adduct in 10(9) bases) detection limit. Hemoglobin (Hb) 4-aminobiphenyl (4-ABP) adduct levels were measured by gas chromatography-mass spectrometry. After isolation of dG-C8-ABP by immunoaffinity chromatography and further purification, deuterated (d9) dG-C8-ABP (MW=443 Da) was added to each sample. Structural evidence and adduct quantification were determined by selected reaction monitoring, based on the expected adduct ion [M+H+]+1, at m/z 435 with fragmentation to the product ion at m/z 319, and monitoring of the transition for the internal standard, m/z 444-->328. The method was validated by analysis of DNA (100 microg each) from calf thymus; livers from ABP-treated and untreated rats; human placentas; and TK6 lymphoblastoid cells. Adduct was detected at femtomol levels in DNA from livers of ABP-treated rats and calf thymus, but not in other controls. The method was applied to 41 DNA samples (200 microg each) from 27 human bladders; 28 from tumor and 14 from surrounding non-tumor tissue. Of 27 tissues analyzed, 44% (12) contained 5-80 dG-C8-ABP adducts per 10(9) bases; only 1 out of 27 (4%) contained adduct in both tumor and surrounding tissues. The Hb adduct was detected in samples from all patients, at levels of 12-1960 pg per gram Hb. There was no correlation between levels of DNA and Hb adducts. The presence of DNA adducts in 44% of the subjects and high levels of Hb adducts in these non-smokers indicate environmental sources of exposure to 4-ABP.

  10. Genome-wide associations of gene expression variation in humans.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  11. Genome-Wide Associations of Gene Expression Variation in Humans.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  12. Genome-wide DNA methylation analysis in cohesin mutant human cell lines

    Science.gov (United States)

    Liu, Jinglan; Zhang, Zhe; Bando, Masashige; Itoh, Takehiko; Deardorff, Matthew A.; Li, Jennifer R.; Clark, Dinah; Kaur, Maninder; Tatsuro, Kondo; Kline, Antonie D.; Chang, Celia; Vega, Hugo; Jackson, Laird G.; Spinner, Nancy B.; Shirahige, Katsuhiko; Krantz, Ian D.

    2010-01-01

    The cohesin complex has recently been shown to be a key regulator of eukaryotic gene expression, although the mechanisms by which it exerts its effects are poorly understood. We have undertaken a genome-wide analysis of DNA methylation in cohesin-deficient cell lines from probands with Cornelia de Lange syndrome (CdLS). Heterozygous mutations in NIPBL, SMC1A and SMC3 genes account for ∼65% of individuals with CdLS. SMC1A and SMC3 are subunits of the cohesin complex that controls sister chromatid cohesion, whereas NIPBL facilitates cohesin loading and unloading. We have examined the methylation status of 27 578 CpG dinucleotides in 72 CdLS and control samples. We have documented the DNA methylation pattern in human lymphoblastoid cell lines (LCLs) as well as identified specific differential DNA methylation in CdLS. Subgroups of CdLS probands and controls can be classified using selected CpG loci. The X chromosome was also found to have a unique DNA methylation pattern in CdLS. Cohesin preferentially binds to hypo-methylated DNA in control LCLs, whereas the differential DNA methylation alters cohesin binding in CdLS. Our results suggest that in addition to DNA methylation multiple mechanisms may be involved in transcriptional regulation in human cells and in the resultant gene misexpression in CdLS. PMID:20448023

  13. A Metabolic Biofuel Cell: Conversion of Human Leukocyte Metabolic Activity to Electrical Currents

    Directory of Open Access Journals (Sweden)

    Cui X Tracy

    2011-05-01

    Full Text Available Abstract An investigation of the electrochemical activity of human white blood cells (WBC for biofuel cell (BFC applications is described. WBCs isolated from whole human blood were suspended in PBS and introduced into the anode compartment of a proton exchange membrane (PEM fuel cell. The cathode compartment contained a 50 mM potassium ferricyanide solution. Average current densities between 0.9 and 1.6 μA cm-2 and open circuit potentials (Voc between 83 and 102 mV were obtained, which were both higher than control values. Cyclic voltammetry was used to investigate the electrochemical activity of the activated WBCs in an attempt to elucidate the mechanism of electron transfer between the cells and electrode. Voltammograms were obtained for the WBCs, including peripheral blood mononuclear cells (PBMCs - a lymphocyte-monocyte mixture isolated on a Ficoll gradient, a B lymphoblastoid cell line (BLCL, and two leukemia cell lines, namely K562 and Jurkat. An oxidation peak at about 363 mV vs. SCE for the PMA (phorbol ester activated primary cells, with a notable absence of a reduction peak was observed. Oxidation peaks were not observed for the BLCL, K562 or Jurkat cell lines. HPLC confirmed the release of serotonin (5-HT from the PMA activated primary cells. It is believed that serotonin, among other biochemical species released by the activated cells, contributes to the observed BFC currents.

  14. Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling

    Science.gov (United States)

    Raj, Anil; Wang, Sidney H; Shim, Heejung; Harpak, Arbel; Li, Yang I; Engelmann, Brett; Stephens, Matthew; Gilad, Yoav; Pritchard, Jonathan K

    2016-01-01

    Accurate annotation of protein coding regions is essential for understanding how genetic information is translated into function. We describe riboHMM, a new method that uses ribosome footprint data to accurately infer translated sequences. Applying riboHMM to human lymphoblastoid cell lines, we identified 7273 novel coding sequences, including 2442 translated upstream open reading frames. We observed an enrichment of footprints at inferred initiation sites after drug-induced arrest of translation initiation, validating many of the novel coding sequences. The novel proteins exhibit significant selective constraint in the inferred reading frames, suggesting that many are functional. Moreover, ~40% of bicistronic transcripts showed negative correlation in the translation levels of their two coding sequences, suggesting a potential regulatory role for these novel regions. Despite known limitations of mass spectrometry to detect protein expressed at low level, we estimated a 14% validation rate. Our work significantly expands the set of known coding regions in humans. DOI: http://dx.doi.org/10.7554/eLife.13328.001 PMID:27232982

  15. A metabolic biofuel cell: conversion of human leukocyte metabolic activity to electrical currents.

    Science.gov (United States)

    Justin, Gusphyl A; Zhang, Yingze; Cui, X Tracy; Bradberry, Charles W; Sun, Mingui; Sclabassi, Robert J

    2011-05-10

    An investigation of the electrochemical activity of human white blood cells (WBC) for biofuel cell (BFC) applications is described. WBCs isolated from whole human blood were suspended in PBS and introduced into the anode compartment of a proton exchange membrane (PEM) fuel cell. The cathode compartment contained a 50 mM potassium ferricyanide solution. Average current densities between 0.9 and 1.6 μA cm-2 and open circuit potentials (Voc) between 83 and 102 mV were obtained, which were both higher than control values. Cyclic voltammetry was used to investigate the electrochemical activity of the activated WBCs in an attempt to elucidate the mechanism of electron transfer between the cells and electrode. Voltammograms were obtained for the WBCs, including peripheral blood mononuclear cells (PBMCs - a lymphocyte-monocyte mixture isolated on a Ficoll gradient), a B lymphoblastoid cell line (BLCL), and two leukemia cell lines, namely K562 and Jurkat. An oxidation peak at about 363 mV vs. SCE for the PMA (phorbol ester) activated primary cells, with a notable absence of a reduction peak was observed. Oxidation peaks were not observed for the BLCL, K562 or Jurkat cell lines. HPLC confirmed the release of serotonin (5-HT) from the PMA activated primary cells. It is believed that serotonin, among other biochemical species released by the activated cells, contributes to the observed BFC currents.

  16. Patterns of cis regulatory variation in diverse human populations.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    Full Text Available The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for

  17. Sensitive Enzyme Immunoassay for Measuring Plasma and Intracellular Nevirapine Levels in Human Immunodeficiency Virus-Infected Patients

    Science.gov (United States)

    Azoulay, Stéphane; Nevers, Marie-Claire; Créminon, Christophe; Heripret, Laurence; Durant, Jacques; Dellamonica, Pierre; Grassi, Jacques; Guedj, Roger; Duval, Danièle

    2004-01-01

    We have developed an enzyme immunoassay to measure nevirapine (NVP) in plasma and peripheral blood mononuclear cells. Anti-NVP polyclonal antibodies were raised in rabbits by using a synthetic NVP derivative coupled to keyhole limpet hemocyanin as the immunogen, and the enzyme tracer was prepared by chemically coupling the NVP derivative with acetylcholinesterase. These reagents were used to develop a sensitive competitive enzyme immunoassay performed in microtitration plates with a 100-pg ml−1 limit of detection and thus ∼100 times more sensitive than previously published techniques. The plasma assay was performed directly without extraction (in this case, a 500-pg ml−1 limit of detection was observed) on a minimum of 30 μl of plasma. This assay shows good precision and efficiency, since recovery from human plasma and cell extracts spiked with NVP ranged between 87 and 104%, with coefficients of variation of <10%. A pharmacokinetic analysis of plasma NVP was performed for seven patients infected with human immunodeficiency virus (HIV), and it gave results similar to published findings. Intracellular concentrations of NVP were measured in cultured human T-lymphoblastoid cells and peripheral blood mononuclear cells from HIV-infected patients. The results indicated a very low intracellular/extracellular concentration ratio (0.134), thus demonstrating the absence of intracellular drug accumulation. This is the first intracellular assay of a nonnucleoside reverse-transcriptase inhibitor, and this method could be useful in monitoring plasma and intracellular NVP levels in HIV-infected patients. PMID:14693526

  18. A Portrait of Ribosomal DNA Contacts with Hi-C Reveals 5S and 45S rDNA Anchoring Points in the Folded Human Genome.

    Science.gov (United States)

    Yu, Shoukai; Lemos, Bernardo

    2016-12-31

    Ribosomal RNAs (rRNAs) account for >60% of all RNAs in eukaryotic cells and are encoded in the ribosomal DNA (rDNA) arrays. The rRNAs are produced from two sets of loci: the 5S rDNA array resides exclusively on human chromosome 1, whereas the 45S rDNA array resides on the short arm of five human acrocentric chromosomes. The 45S rDNA gives origin to the nucleolus, the nuclear organelle that is the site of ribosome biogenesis. Intriguingly, 5S and 45S rDNA arrays exhibit correlated copy number variation in lymphoblastoid cells (LCLs). Here we examined the genomic architecture and repeat content of the 5S and 45S rDNA arrays in multiple human genome assemblies (including PacBio MHAP assembly) and ascertained contacts between the rDNA arrays and the rest of the genome using Hi-C datasets from two human cell lines (erythroleukemia K562 and lymphoblastoid cells). Our analyses revealed that 5S and 45S arrays each have thousands of contacts in the folded genome, with rDNA-associated regions and genes dispersed across all chromosomes. The rDNA contact map displayed conserved and disparate features between two cell lines, and pointed to specific chromosomes, genomic regions, and genes with evidence of spatial proximity to the rDNA arrays; the data also showed a lack of direct physical interaction between the 5S and 45S rDNA arrays. Finally, the analysis identified an intriguing organization in the 5S array with Alu and 5S elements adjacent to one another and organized in opposite orientation along the array. Portraits of genome folding centered on the ribosomal DNA array could help understand the emergence of concerted variation, the control of 5S and 45S expression, as well as provide insights into an organelle that contributes to the spatial localization of human chromosomes during interphase. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  19. Rare and common regulatory variation in population-scale sequenced human genomes.

    Directory of Open Access Journals (Sweden)

    Stephen B Montgomery

    2011-07-01

    Full Text Available Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function.

  20. Population and allelic variation of A-to-I RNA editing in human transcriptomes.

    Science.gov (United States)

    Park, Eddie; Guo, Jiguang; Shen, Shihao; Demirdjian, Levon; Wu, Ying Nian; Lin, Lan; Xing, Yi

    2017-07-28

    A-to-I RNA editing is an important step in RNA processing in which specific adenosines in some RNA molecules are post-transcriptionally modified to inosines. RNA editing has emerged as a widespread mechanism for generating transcriptome diversity. However, there remain significant knowledge gaps about the variation and function of RNA editing. In order to determine the influence of genetic variation on A-to-I RNA editing, we integrate genomic and transcriptomic data from 445 human lymphoblastoid cell lines by combining an RNA editing QTL (edQTL) analysis with an allele-specific RNA editing (ASED) analysis. We identify 1054 RNA editing events associated with cis genetic polymorphisms. Additionally, we find that a subset of these polymorphisms is linked to genome-wide association study signals of complex traits or diseases. Finally, compared to random cis polymorphisms, polymorphisms associated with RNA editing variation are located closer spatially to their respective editing sites and have a more pronounced impact on RNA secondary structure. Our study reveals widespread cis variation in RNA editing among genetically distinct individuals and sheds light on possible phenotypic consequences of such variation on complex traits and diseases.

  1. Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Eleonora Turrini

    2016-05-01

    Full Text Available Cancer chemotherapy is characterized by an elevated intrinsic toxicity and the development of drug resistance. Thus, there is a compelling need for new intervention strategies with an improved therapeutic profile. Immunogenic cell death (ICD represents an innovative anticancer strategy where dying cancer cells release damage-associated molecular patterns promoting tumor-specific immune responses. The roots of Withania somnifera (W. somnifera are used in the Indian traditional medicine for their anti-inflammatory, immunomodulating, neuroprotective, and anticancer activities. The present study is designed to explore the antileukemic activity of the dimethyl sulfoxide extract obtained from the roots of W. somnifera (WE. We studied its cytostatic and cytotoxic activity, its ability to induce ICD, and its genotoxic potential on a human T-lymphoblastoid cell line by using different flow cytometric assays. Our results show that WE has a significant cytotoxic and cytostatic potential, and induces ICD. Its proapoptotic mechanism involves intracellular Ca2+ accumulation and the generation of reactive oxygen species. In our experimental conditions, the extract possesses a genotoxic potential. Since the use of Withania is suggested in different contexts including anti-infertility and osteoarthritis care, its genotoxicity should be carefully considered for an accurate assessment of its risk–benefit profile.

  2. Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells.

    Science.gov (United States)

    Turrini, Eleonora; Calcabrini, Cinzia; Sestili, Piero; Catanzaro, Elena; de Gianni, Elena; Diaz, Anna Rita; Hrelia, Patrizia; Tacchini, Massimo; Guerrini, Alessandra; Canonico, Barbara; Papa, Stefano; Valdrè, Giovanni; Fimognari, Carmela

    2016-05-12

    Cancer chemotherapy is characterized by an elevated intrinsic toxicity and the development of drug resistance. Thus, there is a compelling need for new intervention strategies with an improved therapeutic profile. Immunogenic cell death (ICD) represents an innovative anticancer strategy where dying cancer cells release damage-associated molecular patterns promoting tumor-specific immune responses. The roots of Withania somnifera (W. somnifera) are used in the Indian traditional medicine for their anti-inflammatory, immunomodulating, neuroprotective, and anticancer activities. The present study is designed to explore the antileukemic activity of the dimethyl sulfoxide extract obtained from the roots of W. somnifera (WE). We studied its cytostatic and cytotoxic activity, its ability to induce ICD, and its genotoxic potential on a human T-lymphoblastoid cell line by using different flow cytometric assays. Our results show that WE has a significant cytotoxic and cytostatic potential, and induces ICD. Its proapoptotic mechanism involves intracellular Ca(2+) accumulation and the generation of reactive oxygen species. In our experimental conditions, the extract possesses a genotoxic potential. Since the use of Withania is suggested in different contexts including anti-infertility and osteoarthritis care, its genotoxicity should be carefully considered for an accurate assessment of its risk-benefit profile.

  3. Nucleotide, cytogenetic and expression impact of the human chromosome 8p23.1 inversion polymorphism.

    Science.gov (United States)

    Bosch, Nina; Morell, Marta; Ponsa, Immaculada; Mercader, Josep Maria; Armengol, Lluís; Estivill, Xavier

    2009-12-14

    The human chromosome 8p23.1 region contains a 3.8-4.5 Mb segment which can be found in different orientations (defined as genomic inversion) among individuals. The identification of single nucleotide polymorphisms (SNPs) tightly linked to the genomic orientation of a given region should be useful to indirectly evaluate the genotypes of large genomic orientations in the individuals. We have identified 16 SNPs, which are in linkage disequilibrium (LD) with the 8p23.1 inversion as detected by fluorescent in situ hybridization (FISH). The variability of the 8p23.1 orientation in 150 HapMap samples was predicted using this set of SNPs and was verified by FISH in a subset of samples. Four genes (NEIL2, MSRA, CTSB and BLK) were found differentially expressed (pinversion occurred. Moreover, an impact of 8p23.1 inversion on gene expression levels cannot be ruled out, since four genes from this region have statistically significant different expression levels depending on the inversion status. FISH results in lymphoblastoid cell lines suggest the presence of mosaicism regarding the 8p23.1 inversion.

  4. More Human than Human.

    Science.gov (United States)

    Lawrence, David

    2017-07-01

    Within the literature surrounding nonhuman animals on the one hand and cognitively disabled humans on the other, there is much discussion of where beings that do not satisfy the criteria for personhood fit in our moral deliberations. In the future, we may face a different but related problem: that we might create (or cause the creation of) beings that not only satisfy but exceed these criteria. The question becomes whether these are minimal criteria, or hierarchical, such that those who fulfill them to greater degree should be afforded greater consideration. This article questions the validity and necessity of drawing divisions among beings that satisfy the minimum requirements for personhood; considering how future beings-intelligent androids, synthezoids, even alternate-substrate sentiences-might fit alongside the "baseline" human. I ask whether these alternate beings ought to be considered different to us, and why this may or may not matter in terms of a notion of "human community." The film Blade Runner, concerned in large part with humanity and its key synthezoid antagonist Roy Batty, forms a framing touchstone for my discussion. Batty is stronger, faster, more resilient, and more intelligent than Homo sapiens. His exploits, far beyond the capability of normal humans, are contrasted with his frailty and transient lifespan, his aesthetic appreciation of the sights he has seen, and his burgeoning empathy. Not for nothing does his creator within the mythos term him "more human than human."

  5. Experiment list: SRX100527 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme...ChipSeq || datatype description=Chromatin IP Sequencing || cell description=B-lymphocyte, lymphoblastoid, International...SL1783 || labexpid=SL1783 || cell organism=human || cell description=B-Lymphocyte, Lymphoblastoid, Interna...tional HapMap Project, CEPH/Utah pedigree 1463, Treatment: Epstein-Barr Virus trans

  6. Experiment list: SRX100533 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme...hipSeq || datatype description=Chromatin IP Sequencing || cell description=B-lymphocyte, lymphoblastoid, International...L818 || labexpid=SL818 || cell organism=human || cell description=B-Lymphocyte, Lymphoblastoid, Internatio...nal HapMap Project, CEPH/Utah pedigree 1463, Treatment: Epstein-Barr Virus transfor

  7. Experiment list: SRX100512 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme...hipSeq || datatype description=Chromatin IP Sequencing || cell description=B-lymphocyte, lymphoblastoid, International...L1782 || labexpid=SL1782 || cell organism=human || cell description=B-Lymphocyte, Lymphoblastoid, Internat...ional HapMap Project, CEPH/Utah pedigree 1463, Treatment: Epstein-Barr Virus transf

  8. FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia.

    Directory of Open Access Journals (Sweden)

    Yogesh K Chutake

    Full Text Available Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.The humanized mouse model of Friedreich ataxia (YG8sR, which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R. We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.

  9. Experimental Infection of NOD/SCID Mice Reconstituted with Human CD34+ Cells with Epstein-Barr Virus

    Science.gov (United States)

    Islas-Ohlmayer, Miguel; Padgett-Thomas, Angela; Domiati-Saad, Rana; Melkus, Michael W.; Cravens, Petra D.; Martin, Maria del P.; Netto, George; Garcia, J. Victor

    2004-01-01

    Epstein-Barr virus (EBV)-induced lymphoproliferative disease is an important complication in the context of immune deficiency. Impaired T-cell immunity allows the outgrowth of transformed cells with the subsequent production of predominantly B-cell lymphomas. Currently there is no in vivo model that can adequately recapitulate EBV infection and its association with B-cell lymphomas. NOD/SCID mice engrafted with human CD34+ cells and reconstituted mainly with human B lymphocytes may serve as a useful xenograft model to study EBV infection and pathogenesis. We therefore infected reconstituted mice with EBV. High levels of viral DNA were detected in the peripheral blood of all infected mice. All infected mice lost weight and showed decreased activity levels. Infected mice presented large visible tumors in multiple organs, most prominently in the spleen. These tumors stained positive for human CD79a, CD20, CD30, and EBV-encoded RNAs and were light chain restricted. Their characterization is consistent with that of large cell immunoblastic lymphoma. In addition, tumor cells expressed EBNA1, LMP1, and LMP2a mRNAs, which is consistent with a type II latency program. EBV+ lymphoblastoid cell lines expressing human CD45, CD19, CD21, CD23, CD5, and CD30 were readily established from the bone marrow and spleens of infected animals. Finally, we also demonstrate that infection with an enhanced green fluorescent protein (EGFP)-tagged virus can be monitored by the detection of infected EGFP+ cells and EGFP+ tumors. These data demonstrate that NOD/SCID mice that are reconstituted with human CD34+ cells are susceptible to infection by EBV and accurately recapitulate important aspects of EBV pathogenesis. PMID:15564497

  10. Human autoantibodies to lamin B receptor are also anti-idiotypic to certain anti-lamin B antibodies.

    Science.gov (United States)

    Lassoued, K; Danon, F; Brouet, J C

    1991-08-01

    Autoantibodies reactive with nuclear envelope proteins are mainly detected in human sera from patients with liver diseases. Some of these antibodies are directed to lamin B, lamins A and C, or to the lamin B receptor (LBR). We show here that the latter one are anti-idiotypic to certain anti-lamin B antibodies. Using an enzyme-linked immunosorbent assay specific for lamins we found that serum M containing anti-LBR antibodies inhibited the binding to lamins of anti-lamin B autoantibodies from three of five sera tested. Similar results were obtained using patient's M purified IgG. The binding of monoclonal IgM, lambda anti-lamin B antibodies produced by a lymphoblastoid cell line derived from the patient's blood lymphocytes was also inhibited. Absorption of serum M with nuclei abolished the inhibitory activity. No inhibition was recorded with normal sera or sera containing other antinuclear specificities. Anti-LBR antibodies did not alter the binding to lamins of sera containing anti-lamins A and C antibodies. Altogether these findings demonstrate that anti-LBR antibodies are also combining site related anti-idiotypic antibodies (Ab2) to certain anti-lamin B antibodies, provide further evidence for discrete specificities among anti-lamin B antibodies and suggest that the occurrence of autoantibodies to nuclear envelope antigens may be under idiotypic regulation.

  11. Study of the Cytotoxic Effects of the New Synthetic Isothiocyanate CM9 and Its Fullerene Derivative on Human T-Leukemia Cells

    Science.gov (United States)

    De Gianni, Elena; Turrini, Eleonora; Milelli, Andrea; Maffei, Francesca; Carini, Marco; Minarini, Anna; Tumiatti, Vincenzo; Da Ros, Tatiana; Prato, Maurizio; Fimognari, Carmela

    2015-01-01

    One important strategy to develop effective anticancer agents is based on natural products. Many active phytochemicals are in human clinical trials and have been used for a long time, alone and in association with conventional anticancer drugs, for the treatment of various types of cancers. A great number of in vitro, in vivo and clinical reports document the multi-target anticancer activities of isothiocyanates and of compounds characterized by a naphthalenetetracarboxylic diimide scaffold. In order to search for new anticancer agents with a better pharmaco-toxicological profile, we investigated hybrid compounds obtained by inserting isothiocyanate group(s) on a naphthalenetetracarboxylic diimide scaffold. Moreover, since water-soluble fullerene derivatives can cross cell membranes thus favoring the delivery of anticancer therapeutics, we explored the cytostatic and cytotoxic activity of hybrid compounds conjugated with fullerene. We studied their cytostatic and cytotoxic effects on a human T-lymphoblastoid cell line by using different flow cytometric assays. In order to better understand their pharmaco-toxicological potential, we also analyzed their genotoxicity. Our global results show that the synthesized compounds reduced significantly the viability of leukemia cells. However, the conjugation with a non-toxic vector did not increase their anticancer potential. This opens an interesting research pattern for certain fullerene properties. PMID:25679371

  12. Detection of EBV, HBV, HCV, HIV-1, HTLV-I and -II, and SMRV in Human and Other Primate Cell Lines

    Directory of Open Access Journals (Sweden)

    Cord C. Uphoff

    2010-01-01

    Full Text Available The high prevalence of contaminated cell cultures suggests that viral contaminations might be distributed among cultures. We investigated more than 460 primate cell lines for Epstein-Barr (EBV, hepatitis B (HBV, hepatitis C (HCV, human immunodeficiency virus type 1 (HIV-1, human T-cell leukemia/lymphoma virus I and II (HTLV-I/-II, and squirrel monkey retrovirus (SMRV infections for risk assessment. None of the cell lines were infected with HCV, HIV-1, or HTLV-I/-II. However, one cell line displayed reverse transcriptase activity. Thirty-nine cell lines harbored EBV DNA sequences. Studies on the lytic phase of EBV revealed that five cell lines produce EBV particles and six further cell lines produced EBV upon stimulation. One cell line contained an integrated HBV genome fragment but showed no virus production. Six cell lines were SMRV-infected. Newly established cell lines should be tested for EBV infections to detect B-lymphoblastoid cell lines (B-LCL. B-LCLs established with EBV from cell line B95-8 should be tested for SMRV infections.

  13. Study of the Cytotoxic Effects of the New Synthetic Isothiocyanate CM9 and Its Fullerene Derivative on Human T-Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Elena De Gianni

    2015-02-01

    Full Text Available One important strategy to develop effective anticancer agents is based on natural products. Many active phytochemicals are in human clinical trials and have been used for a long time, alone and in association with conventional anticancer drugs, for the treatment of various types of cancers. A great number of in vitro, in vivo and clinical reports document the multi-target anticancer activities of isothiocyanates and of compounds characterized by a naphthalenetetracarboxylic diimide scaffold. In order to search for new anticancer agents with a better pharmaco-toxicological profile, we investigated hybrid compounds obtained by inserting isothiocyanate group(s on a naphthalenetetracarboxylic diimide scaffold. Moreover, since water-soluble fullerene derivatives can cross cell membranes thus favoring the delivery of anticancer therapeutics, we explored the cytostatic and cytotoxic activity of hybrid compounds conjugated with fullerene. We studied their cytostatic and cytotoxic effects on a human T-lymphoblastoid cell line by using different flow cytometric assays. In order to better understand their pharmaco-toxicological potential, we also analyzed their genotoxicity. Our global results show that the synthesized compounds reduced significantly the viability of leukemia cells. However, the conjugation with a non-toxic vector did not increase their anticancer potential. This opens an interesting research pattern for certain fullerene properties.

  14. Vincristine-induced bystander effect in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Testi, Serena; Azzarà, Alessia; Giovannini, Caterina; Lombardi, Sara [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Piaggi, Simona [Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Pisa University, Via Savi 10, 56126 Pisa (Italy); Facioni, Maria Sole [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Scarpato, Roberto, E-mail: roberto.scarpato@unipi.it [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Research Center of Nutraceuticals and Food for Health, University of Pisa, Pisa (Italy)

    2016-07-15

    Highlights: • We studied whether or not vincristine induced a bystander response in human lymphocytes. • Vincristine significantly increased MN frequencies in mononucleated recipient cells. • ROS or soluble proteins (IL-32 and TGF-β) may account for the observed response. - Abstract: Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5 ± 1.41 at 6 μM, 22 ± 2.12 at 12 μM or 28.25 ± 5.13 at 15 μM vs. a control value of 4.75 ± 1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75 ± 0.88 at 0.0 μM, 27.25 ± 2.30 at 0.4 μM, 46.25 ± 1.94 at 0.8 μM, 98.25 ± 7.25 at 1.6 μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the

  15. Phosphonate O-deethylation of [4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester, a lipoprotein lipase-promoting agent, catalyzed by cytochrome P450 2C8 and 3A4 in human liver microsomes.

    Science.gov (United States)

    Morioka, Yujiro; Otsu, Makiko; Naito, Shinsaku; Imai, Teruko

    2002-03-01

    NO-1886 ([4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester) increases lipoprotein lipase activity, resulting in a reduction in plasma triglycerides and an increase in high-density lipoprotein cholesterol. The metabolism of NO-1886 in human liver was investigated in the present study. Ester cleavage of NO-1886 from diethyl phosphonate to monoethyl phosphonate was the major metabolic pathway catalyzed by cytochrome P450. In addition, the minor metabolic pathway in human liver was the hydrolysis of the amide bond of NO-1886 by a specific cytosolic esterase. Eadie-Hofstee plots of phosphonate O-deethylation of NO-1886 in human liver microsomes showed a biphasic curve, indicating low- and high-K(m) components. Inhibition experiments with chemical inhibitors and antibodies against various cytochrome P450 isoforms suggested the involvement of CYP2C8 and CYP3A in the phosphonate O-deethylation. Recombinant CYP3A4 and CYP2C8 expressed in baculovirus-infected insect cells and human lymphoblastoid cells exhibited a high activity for phosphonate O-deethylation of NO-1886. The recombinant cytochrome P450 enzymes indicated that CYP2C8 and CYP3A4 were responsible for the low- and high-K(m) components in human liver microsomes, respectively. The selectivity of CYP2C8 in catalyzing phosphonate O-deethylation indicates that coadministration of drugs that are metabolized by the same enzyme requires careful consideration.

  16. MicroRNA Expression Profiles in Cultured Human Fibroblasts in Space

    Science.gov (United States)

    Wu, Honglu; Lu, Tao; Jeevarajan, John; Rohde, Larry; Zhang, Ye

    2014-01-01

    Microgravity, or an altered gravity environment from the static 1g, has been shown to influence global gene expression patterns and protein levels in living organisms. However, it is unclear how these changes in gene and protein expressions are related to each other or are related to other factors regulating such changes. A different class of RNA, the small non-coding microRNA (miRNA), can have a broad effect on gene expression networks by mainly inhibiting the translation process. Previously, we investigated changes in the expression of miRNA and related genes under simulated microgravity conditions on the ground using the NASA invented bioreactor. In comparison to static 1 g, simulated microgravity altered a number of miRNAs in human lymphoblastoid cells. Pathway analysis with the altered miRNAs and RNA expressions revealed differential involvement of cell communication and catalytic activity, as well as immune response signaling and NGF activation of NF-kB pathways under simulated microgravity condition. The network analysis also identified several projected networks with c- Rel, ETS1 and Ubiquitin C as key factors. In a flight experiment on the International Space Station (ISS), we will investigate the effects of actual spaceflight on miRNA expressions in nondividing human fibroblast cells in mostly G1 phase of the cell cycle. A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for tissues, and plays a critical role in wound healing and other functions. In addition to miRNA expressions, we will investigate the effects of spaceflight on the cellular response to DNA damages from bleomycin treatment.

  17. Human rights

    NARCIS (Netherlands)

    Gaay Fortman, B. de

    2006-01-01

    Human rights reflect a determined effort to protect the dignity of each and every human being against abuse of power. This endeavour is as old as human history. What is relatively new is the international venture for the protection of human dignity through internationally accepted legal standards

  18. The convertases furin and PC1 can both cleave the human immunodeficiency virus (HIV)-1 envelope glycoprotein gp160 into gp120 (HIV-1 SU) and gp41 (HIV-I TM).

    Science.gov (United States)

    Decroly, E; Vandenbranden, M; Ruysschaert, J M; Cogniaux, J; Jacob, G S; Howard, S C; Marshall, G; Kompelli, A; Basak, A; Jean, F

    1994-04-22

    Intracellular proteolytic processing of human immunodeficiency virus envelope glycoprotein precursor (gp160) is an essential step for virus infectivity. Northern blot analysis provided evidence that furin and PC1, but not PC2, are expressed in the CD4+ human lymphoblastoid H9 cell line, suggesting the possible participation of these convertases in human immunodeficiency virus (HIV) gp160 proteolytic processing. Purified PC1 and furin cleaved specifically in vitro gp160 into gp120 (HIV-I SU) and gp41 (HIV-I TM). NH2-terminal sequence analysis of the produced gp41 (HIV-I TM) demonstrated that the cleavage occurred within the sequence Arg-Glu-Lys-Arg decreases Ala-Val-Gly-Ile, which is identical to the bond cleaved in vivo. Transition state analog peptides were designed and tested in vitro for their ability to inhibit the PC1- or furin-mediated gp160 cleavage. The best inhibitor was decanoyl-Arg-Lys-Arg-Arg-psi [CH2NH]-Phe-Leu-Gly-Phe-NH2.

  19. Human Rights, Human Needs, Human Development, Human Security

    OpenAIRE

    Gasper, D.R.

    2007-01-01

    Human rights, human development and human security form increasingly important, partly interconnected, partly competitive and misunderstood ethical and policy discourses. Each tries to humanize a pre-existing and unavoidable major discourse of everyday life, policy and politics; each has emerged within the United Nations world; each relies implicitly on a conceptualisation of human need; each has specific strengths. Yet mutual communication, understanding and co-operation are deficient, espec...

  20. Experiment list: SRX189995 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available tion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Ba...rnational HapMap Project - CEPH/Utah - European Caucasio...ype description=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, Inte

  1. Experiment list: SRX150396 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available =mesoderm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Cauc...national HapMap Project - CEPH/Utah - European Caucasion...pe description=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, Inter

  2. Experiment list: SRX150410 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein...ocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucas...atype description=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymph

  3. Experiment list: SRX189979 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available tion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Ba...rnational HapMap Project - CEPH/Utah - European Caucasio...ype description=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, Inte

  4. Experiment list: SRX150531 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1463, treatme...| cell=GM12892 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedig...ree 1463, treatment: Epstein-Barr Virus transformed || c

  5. Experiment list: SRX189962 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ion=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Barr Virus tra...ocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstei...atype description=Chromatin IP Sequencing || cell=GM06990 || cell organism=human || cell description=B-lymph

  6. Experiment list: SRX080394 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah, treatment: Epstein-Ba...f=GM06990 || cell=GM06990 || cell organism=Human || cell description=Lymphoblastoid, International HapMap Pr

  7. Experiment list: SRX069213 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein... cell=GM12878 || cell organism=Human || cell description=lymphoblastoid || cell karyotype=relatively normal || cell lineage=Internati...onal HapMap Project - CEPH/Utah - European Caucasion; Epstein-Barr Virus || cell se

  8. Experiment list: SRX069089 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein...cell=GM12878 || cell organism=Human || cell description=lymphoblastoid || cell karyotype=relatively normal || cell lineage=Internatio...nal HapMap Project - CEPH/Utah - European Caucasion; Epstein-Barr Virus || cell sex

  9. Experiment list: SRX080348 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatme...Detail.aspx?Ref=GM12873 || cell=GM12873 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  10. Experiment list: SRX189971 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ion=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Bar...ernational HapMap Project - CEPH/Utah - European Caucasi...type description=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymphocyte, lymphoblastoid, Int

  11. Experiment list: SRX150586 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ription=B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein...ocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucas...atype description=Chromatin IP Sequencing || cell=GM12878 || cell organism=human || cell description=B-lymph

  12. Experiment list: SRX080440 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatme...Detail.aspx?Ref=GM12865 || cell=GM12865 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  13. Experiment list: SRX080405 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatme...Detail.aspx?Ref=GM12874 || cell=GM12874 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  14. Experiment list: SRX080428 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatme...Detail.aspx?Ref=GM12872 || cell=GM12872 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  15. Experiment list: SRX080387 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatme..._Detail.aspx?Ref=GM12875 || cell=GM12875 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  16. Experiment list: SRX080417 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available erm|Description=B-lymphocyte, lymphoblastoid, International HapMap Project, CEPH/Utah pedigree 1459, treatme...Detail.aspx?Ref=GM12864 || cell=GM12864 || cell organism=Human || cell description=B-Lymphocyte, Lymphoblastoid, International

  17. Vincristine-induced bystander effect in human lymphocytes.

    Science.gov (United States)

    Testi, Serena; Azzarà, Alessia; Giovannini, Caterina; Lombardi, Sara; Piaggi, Simona; Facioni, Maria Sole; Scarpato, Roberto

    2016-07-01

    Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5±1.41 at 6μM, 22±2.12 at 12μM or 28.25±5.13 at 15μM vs. a control value of 4.75±1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75±0.88 at 0.0μM, 27.25±2.30 at 0.4μM, 46.25±1.94 at 0.8μM, 98.25±7.25 at 1.6μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the bystander effect induced by VCR. In fact, we observed an increased level of ROS, IL-32 and TGF-β in the CM from VCR treated cultures, not present in MMC treated cultures. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans.

    Science.gov (United States)

    Fresnay, Stephanie; McArthur, Monica A; Magder, Laurence; Darton, Thomas C; Jones, Claire; Waddington, Claire S; Blohmke, Christoph J; Angus, Brian; Levine, Myron M; Pollard, Andrew J; Sztein, Marcelo B

    2016-03-01

    Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates.

  19. Human Monkeypox

    National Research Council Canada - National Science Library

    Wilson, Mary E; Hughes, James M; McCollum, Andrea M; Damon, Inger K

    2014-01-01

    Human monkeypox is found primarily in forested areas of Central Africa. This article provides a basic review of the clinical, epidemiological, and biological factors that contribute to human disease...

  20. Human microbiomics

    OpenAIRE

    Rajendhran, J.; Gunasekaran, P.

    2010-01-01

    The sequencing of the human genome has driven the study of human biology in a significant way and enabled the genome-wide study to elucidate the molecular basis of complex human diseases. Recently, the role of microbiota on human physiology and health has received much attention. The influence of gut microbiome (the collective genomes of the gut microbiota) in obesity has been demonstrated, which may pave the way for new prophylactic and therapeutic strategies such as bacteriotherapy. The sig...

  1. Human Development

    NARCIS (Netherlands)

    D.R. Gasper (Des)

    2009-01-01

    textabstract‘Human development’ language spread gradually in circles of national and international development policy and planning from the 1970s and acquired a definitive form in the 1990s in the United Nations Development Programme’s Human Development Reports (HDRs). Human development was defined

  2. Human Smuggling

    NARCIS (Netherlands)

    Siegel - Rozenblit, Dina|info:eu-repo/dai/nl/152524096; Zaitch, Damian|info:eu-repo/dai/nl/183348486

    2014-01-01

    Human smuggling is based on a consensus between smuggler, smuggled, and his/her family (which usually guarantees or effectuates payment). However, unauthorized immigrants are violating immigration laws and human smugglers are profiting from enabling illegal immigration. Both human smuggling and its

  3. Chromosome damage evolution after low and high LET irradiation

    Science.gov (United States)

    Andreev, Sergey; Eidelman, Yuri

    Ionizing radiation induces DNA and chromatin lesions which are converted to chromosome lesions detected in the first post-irradiation mitosis by classic cytogenetic techniques as chromosomal aberrations (CAs). These techniques allow to monitor also delayed aberrations observed after many cell generations post-irradiation - the manifestation of chromosomal instability phenotype (CIN). The problem discussed is how to predict time evolution from initial to delayed DNA/chromosome damage. To address this question, in the present work a mechanistic model of CIN is elaborated which integrates pathways of (*) DNA damage induction and its conversion to chromosome lesions (aberrations), (**) lesion transmission and generation through cell cycles. Delayed aberrations in subsequent cycles are formed in the model owing to two pathways, DNA damage generation de novo as well as CA transmission from previous cycles. DNA damage generation rate is assumed to consist of bystander and non-bystander components. Bystander signals impact all cells roughly equally, whereas non-bystander DSB generation rate differs for the descendants of unirradiated and irradiated cells. Monte Carlo simulation of processes underlying CIN allows to predict the time evolution of initial radiation-induced damage - kinetics curve for delayed unstable aberrations (dicentrics) together with dose response and RBE as a function of time after high vs low LET irradiation. The experimental data for radiation-induced CIN in TK6 lymphoblastoid cells and human lymphocytes irradiated with low (gamma) and high (Fe, C) LET radiation are analyzed on the basis of the proposed model. One of the conclusions is that without bystander signaling, just taking into account the initial DNA damage and non-bystander DSB generation, it is impossible to describe the available experimental data for high-LET-induced CIN. The exact contribution of bystander effects for high vs low LET remains unknown, but the relative contribution may be

  4. In vitro genotoxicity testing of four reference metal nanomaterials, titanium dioxide, zinc oxide, cerium oxide and silver: towards reliable hazard assessment.

    Science.gov (United States)

    El Yamani, Naouale; Collins, Andrew R; Rundén-Pran, Elise; Fjellsbø, Lise Marie; Shaposhnikov, Sergey; Zienolddiny, Shanbeh; Dusinska, Maria

    2017-01-01

    There is serious concern about the potential harmful effects of certain nanomaterials (NMs), on account of their ability to penetrate cell membranes and the increased reactivity that results from their increased surface area compared with bulk chemicals. To assess the safety of NMs, reliable tests are needed. We have investigated the possible genotoxicity of four representative NMs, derived from titanium dioxide, zinc oxide, cerium oxide and silver, in two human cell lines, A549 alveolar epithelial cells and lymphoblastoid TK6 cells. A high-throughput version of the comet assay was used to measure DNA strand beaks (SBs) as well as oxidised purines (converted to breaks with the enzyme formamidopyrimidine DNA glycosylase). In parallel, cytotoxicity was measured with the alamarBlue® assay, and the ability of NM-treated cells to survive was assessed by their colony-forming efficiency. TiO2 and CeO2 NMs were only slightly cytotoxic by the alamarBlue® test, and had no long-term effect on colony-forming efficiency. However, both induced DNA damage at non-cytotoxic concentrations; the damage decreased from 3 to 24-h exposure, except in the case of CeO2-treated A549 cells. ZnO and Ag NMs affected cell survival, and induced high levels of DNA damage at cytotoxic concentrations. At lower concentrations, there was significant damage, which tended to persist over 24 h. The implication is that all four reference metal NMs tested-whether cytotoxic or not-are genotoxic. A full assessment of NM toxicity should include tests on different cell types, different times of incubation and a wide range of (especially non-cytotoxic) concentrations; a test for cell viability should be performed in parallel. Inclusion of Fpg in the comet assay allows detection of indirect genotoxic effects via oxidative stress. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Human Technology and Human Affects

    DEFF Research Database (Denmark)

    Fausing, Bent

    2009-01-01

    Human Technology and Human Affects  This year Samsung introduced a mobile phone with "Soul". It was made with a human touch and included itself a magical touch. Which function does technology and affects get in everyday aesthetics like this, its images and interactions included this presentation...... will ask and try to answer. The mobile phone and its devices are depicted as being able to make a unique human presence, interaction, and affect. The medium, the technology is a necessary helper to get towards this very special and lost humanity. Without the technology, no special humanity - soul...... - is the prophecy. This personification or anthropomorphism is important for the branding of new technology. The technology is seen as creating a technotranscendens towards a more qualified humanity, which is in contact with the fundamental human values like intuition, vision, and sensing; all the qualities...

  6. MicroRNA-138 is a potential regulator of memory performance in humans

    Directory of Open Access Journals (Sweden)

    Julia eSchröder

    2014-07-01

    Full Text Available Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate memory genes, these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1,318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA hsa-mir-138-5p (rs9882688, P-value = 7.8x10-9. Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines (P-value = 5x10-4. In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3' untranslated region (3'UTR of DCP1B, a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3'UTR reporter constructs in two human cell lines (HEK293: P-value = 0.0470; SH-SY5Y: P-value = 0.0866. Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo. In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory

  7. Human Parvoviruses.

    Science.gov (United States)

    Qiu, Jianming; Söderlund-Venermo, Maria; Young, Neal S

    2017-01-01

    Parvovirus B19 (B19V) and human bocavirus 1 (HBoV1), members of the large Parvoviridae family, are human pathogens responsible for a variety of diseases. For B19V in particular, host features determine disease manifestations. These viruses are prevalent worldwide and are culturable in vitro, and serological and molecular assays are available but require careful interpretation of results. Additional human parvoviruses, including HBoV2 to -4, human parvovirus 4 (PARV4), and human bufavirus (BuV) are also reviewed. The full spectrum of parvovirus disease in humans has yet to be established. Candidate recombinant B19V vaccines have been developed but may not be commercially feasible. We review relevant features of the molecular and cellular biology of these viruses, and the human immune response that they elicit, which have allowed a deep understanding of pathophysiology. Copyright © 2016 American Society for Microbiology.

  8. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

    Directory of Open Access Journals (Sweden)

    Alexandra C Nica

    2011-02-01

    Full Text Available While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL, skin, and fat. The samples (156 LCL, 160 skin, 166 fat were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes. In addition, we apply factor analysis (FA to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes. The unique study design (Matched Co-Twin Analysis--MCTA permits immediate replication of eQTLs using co-twins (93%-98% and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20% have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

  9. Neutron Exposures in Human Cells: Bystander Effect and Relative Biological Effectiveness

    Science.gov (United States)

    Seth, Isheeta; Schwartz, Jeffrey L.; Stewart, Robert D.; Emery, Robert; Joiner, Michael C.; Tucker, James D.

    2014-01-01

    Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (pneutrons do not induce a bystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0±0.13 for micronuclei and 5.8±2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety. PMID:24896095

  10. Neutron exposures in human cells: bystander effect and relative biological effectiveness.

    Science.gov (United States)

    Seth, Isheeta; Schwartz, Jeffrey L; Stewart, Robert D; Emery, Robert; Joiner, Michael C; Tucker, James D

    2014-01-01

    Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (pbystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0 ± 0.13 for micronuclei and 5.8 ± 2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety.

  11. Human Rights/Human Needs.

    Science.gov (United States)

    Canning, Cynthia

    1978-01-01

    The faculty of Holy Names High School developed an interdisciplinary human rights program with school-wide activities focusing on three selected themes: the United Nations Universal Declaration of Human Rights, in conjunction with Human Rights Week; Food; and Women. This article outlines major program activities. (SJL)

  12. Digital Humanities

    DEFF Research Database (Denmark)

    Brügger, Niels

    2016-01-01

    Digital humanities is an umbrella term for theories, methodologies, and practices related to humanities scholarship that use the digital computer as an integrated and essential part of its research and teaching activities. The computer can be used for establishing, finding, collecting......, and preserving material to study, as an object of study in its own right, as an analytical tool, or for collaborating, and for disseminating results. The term "digital humanities" was coined around 2001, and gained currency within academia in the following years. However, computers had been used within...... the humanities for decades, starting with research fields such as humanities computing or computational linguistics in the 1950s, and later new media studies and internet studies. The historical development of digital humanities has been characterized by a focus on three successive, but co-existing types...

  13. DNA excision repair in cell extracts from human cell lines exhibiting hypersensitivity to DNA-damaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Hansson, J.; Keyse, S.M.; Lindahl, T.; Wood, R.D. (Imperial Cancer Research Fund, South Mimms, (United Kingdom))

    1991-07-01

    Whole cell extracts from human lymphoid cell lines can perform in vitro DNA repair synthesis in plasmids damaged by agents including UV or cis-diamminedichloroplatinum(II) (cis-DDP). Extracts from xeroderma pigmentosum (XP) cells are defective in repair synthesis. We have now studied in vitro DNA repair synthesis using extracts from lymphoblastoid cell lines representing four human hereditary syndromes with increased sensitivity to DNA-damaging agents. Extracts of cell lines from individuals with the sunlight-sensitive disorders dysplastic nevus syndrome or Cockayne's syndrome (complementation groups A and B) showed normal DNA repair synthesis in plasmids with UV photoproducts. This is consistent with in vivo measurements of the overall DNA repair capacity in such cell lines. A number of extracts were prepared from two cell lines representing the variant form of XP (XP-V). Half of the extracts prepared showed normal levels of in vitro DNA repair synthesis in plasmids containing UV lesions, but the remainder of the extracts from the same cell lines showed deficient repair synthesis, suggesting the possibility of an unusually labile excision repair protein in XP-V. Fanconi's anemia (FA) cells show cellular hypersensitivity to cross-linking agents including cis-DDP. Extracts from cell lines belonging to two different complementation groups of FA showed normal DNA repair synthesis in plasmids containing cis-DDP or UV adducts. Thus, there does not appear to be an overall excision repair defect in FA, but the data do not exclude a defect in the repair of interstrand DNA cross-links.

  14. Space experiment "Rad Gene"-report 1; p53-Dependent gene expression in human cultured cells exposed to space environment

    Science.gov (United States)

    Takahashi, Akihisa; Ohnishi, Takeo; Suzuki, Hiromi; Omori, Katsunori; Seki, Masaya; Hashizume, Toko; Shimazu, Toru; Ishioka, Noriaki

    The space environment contains two major biologically significant influences: space radiations and microgravity. A p53 tumor suppressor protein plays a role as a guardian of the genome through the activity of p53-centered signal transduction pathways. The aim of this study was to clarify the biological effects of space radiations, microgravity and a space environment on the gene and protein expression of p53-dependent regulated genes. Space experiments were performed with two human cultured lymphoblastoid cell lines: one cells line (TSCE5) bears a wild-type p53 gene status, and another cells line (WTK1) bears a mutated p53 gene status. Un-der one gravity or microgravity condition, the cells were grown in the cell biology experimental facility (CBEF) of the International Space Station (ISS) for 8 days without experiencing the stress during launching and landing because the cells were frozen during these periods. Ground control samples also were cultured for 8 days in the CBEF on the ground during the same periods as space flight. Gene and protein expression was analyzed by using DNA chip (a 44k whole human genome microarray, Agilent Technologies Inc.) and protein chip (PanoramaTM Ab MicroArray, Sigma-Aldrich Co.), respectively. In addition, we analyzed the gene expression in cultured cells after space flight during 133 days with frozen condition. We report the results and discussion from the viewpoint of the functions of the up-regulated and down-regulated genes after an exposure to space radiations and/or microgravity. The initial goal of this space experiment was completely achieved. It is expected that data from this type of work will be helpful in designing physical protection from the deleterious effects of space radiations during long term stays in space.

  15. Human evolution

    DEFF Research Database (Denmark)

    Llamas, Bastien; Willerslev, Eske; Orlando, Ludovic Antoine Alexandre

    2017-01-01

    The field of human ancient DNA (aDNA) has moved from mitochondrial sequencing that suffered from contamination and provided limited biological insights, to become a fully genomic discipline that is changing our conception of human history. Recent successes include the sequencing of extinct hominins......, and true population genomic studies of Bronze Age populations. Among the emerging areas of aDNA research, the analysis of past epigenomes is set to provide more new insights into human adaptation and disease susceptibility through time. Starting as a mere curiosity, ancient human genetics has become...

  16. Human Rights, Human Needs, Human Development, Human Security - Relationships between four international human discourses.

    NARCIS (Netherlands)

    D.R. Gasper (Des)

    2007-01-01

    markdownabstractAbstract: Human rights, human development and human security form increasingly important, partly interconnected, partly competitive and misunderstood ethical and policy discourses. Each tries to humanize a pre-existing and unavoidable major discourse of everyday life, policy and

  17. Human Rights and Human Nature

    Directory of Open Access Journals (Sweden)

    Vittorio Possenti

    2013-11-01

    Full Text Available There seems to be two different versions of human rights in Western tradition: say Rationalistic and Christian; the former adopted in revolutionary France, the latter highly developed in Renaissance Spain. Current relativistic criticisms attempt to deny the universality of human rights alleging that this theory has been created in Western countries or it has no strong justification, and therefore cannot have universal approach; but this objection can be dismissed with an alternative justification of human rights.

  18. Think Human

    DEFF Research Database (Denmark)

    Nielsen, Charlotte Marie Bisgaard

    2013-01-01

    years' campaigns suggests that the theory of communication underlying the campaign has its basis in mechanical action rather than in human communication. The practice of 'Communication design' is investigated in relation to this metaphorical 'machine thinking' model of communication and contrasted...... with the human-centered theory of communication advocated by integrationism....

  19. Human trichuriasis

    DEFF Research Database (Denmark)

    Betson, Martha; Søe, Martin Jensen; Nejsum, Peter

    2015-01-01

    Human trichuriasis is a neglected tropical disease which affects hundreds of millions of people worldwide and is particularly prevalent among children living in areas where sanitation is poor. This review examines the current knowledge on the taxonomy, genetics and phylogeography of human Trichuris...

  20. Human kapital

    DEFF Research Database (Denmark)

    Grosen, Anders; Nielsen, Peder Harbjerg

    2007-01-01

    finansiel og human kapital. Den traditionelle rådgivnings snævre synsvinkel kan føre til forkerte investeringsråd. Der skal derfor opfordres til, at de finansielle virksomheder i tilrettelæggelsen af deres rådgivning af private kunder systematisk inddrager den humane kapitals størrelse og karakteristika i...

  1. Human Computation

    CERN Multimedia

    CERN. Geneva

    2008-01-01

    What if people could play computer games and accomplish work without even realizing it? What if billions of people collaborated to solve important problems for humanity or generate training data for computers? My work aims at a general paradigm for doing exactly that: utilizing human processing power to solve computational problems in a distributed manner. In particular, I focus on harnessing human time and energy for addressing problems that computers cannot yet solve. Although computers have advanced dramatically in many respects over the last 50 years, they still do not possess the basic conceptual intelligence or perceptual capabilities...

  2. Human phantom

    CERN Multimedia

    CERN PhotoLab

    1973-01-01

    This human phantom has been received by CERN on loan from the State Committee of the USSR for the Utilization of Atomic Energy. It is used by the Health Physics Group to study personel radiation doses near the accelerators.

  3. Human expunction

    Science.gov (United States)

    Klee, Robert

    2017-10-01

    Thomas Nagel in `The Absurd' (Nagel 1971) mentions the future expunction of the human species as a `metaphor' for our ability to see our lives from the outside, which he claims is one source of our sense of life's absurdity. I argue that the future expunction (not to be confused with extinction) of everything human - indeed of everything biological in a terran sense - is not a mere metaphor but a physical certainty under the laws of nature. The causal processes by which human expunction will take place are presented in some empirical detail, so that philosophers cannot dismiss it as merely speculative. I also argue that appeals to anthropic principles or to forms of mystical cosmology are of no plausible avail in the face of human expunction under the laws of physics.

  4. Human brucellosis

    NARCIS (Netherlands)

    Franco, María Pía; Mulder, Maximilian; Gilman, Robert H.; Smits, Henk L.

    2007-01-01

    Human brucellosis still presents scientists and clinicians with several challenges, such as the understanding of pathogenic mechanisms of Brucella spp, the identification of markers for disease severity, progression, and treatment response, and the development of improved treatment regimens.

  5. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    This chapter reviews the human toxicological impacts of chemicals and how to assess these impacts in life cycle impact assessment (LCIA), in order to identify key processes and pollutants. The complete cause-effect pathway – from emissions of toxic substances up to damages on human health...... on characterisation factors means that results should by default be reported and interpreted in log scales when comparing scenarios or substance contribution! We conclude by outlining future trends in human toxicity modelling for LCIA, with promising developments for (a) better estimates of degradation halflives, (b......) the inclusion of ionization of chemicals in human exposure including bioaccumulation, (c) metal speciation, (d) spatialised models to differentiate the variability associated with spatialisation from the uncertainty, and (e) the assessment of chemical exposure via consumer products and occupational settings...

  6. Human ehrlichiosis

    Directory of Open Access Journals (Sweden)

    Đokić Milomir

    2006-01-01

    Full Text Available Background. Human ehrlichiosis is a newly recognized disease. It is a tick-borne disease caused by several bacterial species of the genhus Erlichia. These are small gram-negative pleomorphic cocci, that are obligatory intracellular bacteria. Tick Ixodes is the principle vector in Europe, and Amblyomma americanum in the United States. Bacterial organisms replicate in a tick, and are transmited from infected cells in a vector to the blood cells of animals or humans. Human ehrlichiosis is a name for a group of diseases caused by different species of Ehrlichia. One of them is the disease named human monocytic ehrlichiosis, caused by Ehrlichia chaffeensis, and the other is a human granulocytic ehrlichiosis caused by Anaplasma phagocytophilia. Case report. We reported a 23-year-old patient admitted for the clinical treatment with the symptoms of high febrility (above 40 °C, headache, vomiting, general weakness and exhaustion, but without data on a tick bite. The patient was treated with trimetoprim-sulfamethoxazole for a week when Ehrlichia chaffeensis was confirmed by the immunofluoroscence test, and the therapy contimed with doxacyclin. Conclusion. Human ehrlichiosis is also present in our country, so this disease should be considered everyday, especially in infectology practice.

  7. Allele-specific, age-dependent and BMI-associated DNA methylation of human MCHR1.

    Directory of Open Access Journals (Sweden)

    Stefanie Stepanow

    Full Text Available BACKGROUND: Melanin-concentrating hormone receptor 1 (MCHR1 plays a significant role in regulation of energy balance, food intake, physical activity and body weight in humans and rodents. Several association studies for human obesity showed contrary results concerning the SNPs rs133072 (G/A and rs133073 (T/C, which localize to the first exon of MCHR1. The variations constitute two main haplotypes (GT, AC. Both SNPs affect CpG dinucleotides, whereby each haplotype contains a potential methylation site at one of the two SNP positions. In addition, 15 CpGs in close vicinity of these SNPs constitute a weak CpG island. Here, we studied whether DNA methylation in this sequence context may contribute to population- and age-specific effects of MCHR1 alleles in obesity. PRINCIPAL FINDINGS: We analyzed DNA methylation of a 315 bp region of MCHR1 encompassing rs133072 and rs133073 and the CpG island in blood samples of 49 individuals by bisulfite sequencing. The AC haplotype shows a significantly higher methylation level than the GT haplotype. This allele-specific methylation is age-dependent. In young individuals (20-30 years the difference in DNA methylation between haplotypes is significant; whereas in individuals older than 60 years it is not detectable. Interestingly, the GT allele shows a decrease in methylation status with increasing BMI, whereas the methylation of the AC allele is not associated with this phenotype. Heterozygous lymphoblastoid cell lines show the same pattern of allele-specific DNA methylation. The cell line, which exhibits the highest difference in methylation levels between both haplotypes, also shows allele-specific transcription of MCHR1, which can be abolished by treatment with the DNA methylase inhibitor 5-aza-2'-deoxycytidine. CONCLUSIONS: We show that DNA methylation at MCHR1 is allele-specific, age-dependent, BMI-associated and affects transcription. Conceivably, this epigenetic regulation contributes to the age- and

  8. [Humanized childbirth].

    Science.gov (United States)

    Kuo, Su-Chen

    2005-06-01

    Childbirth is a major event in a family. The expectant parent's perception of the childbirth experience influences his or her development as a parent. Making childbirth a positive and satisfying experience for women is the responsibility of health care providers. Women want to have physical and emotional privacy during labor and delivery, and to experience both in a friendly, comfortable environment. For women expected to undergo normal deliveries, humanized childbirth is one accessible approach. This article explores the definition and evolution of humanized childbirth and the care practice that it involves. It also explores birth plans and birth experiences, and the improvements necessary to routine labor practices to enable women to participate in decision making about their childbirth experiences. The author emphasizes that when health-care providers recognize the value of humanized childbirth and make changes accordingly, the dignity of women's childbirth experiences will be enhanced.

  9. Human monkeypox.

    Science.gov (United States)

    McCollum, Andrea M; Damon, Inger K

    2014-01-01

    Human monkeypox is a zoonotic Orthopoxvirus with a presentation similar to smallpox. Clinical differentiation of the disease from smallpox and varicella is difficult. Laboratory diagnostics are principal components to identification and surveillance of disease, and new tests are needed for a more precise and rapid diagnosis. The majority of human infections occur in Central Africa, where surveillance in rural areas with poor infrastructure is difficult but can be accomplished with evidence-guided tools and educational materials to inform public health workers of important principles. Contemporary epidemiological studies are needed now that populations do not receive routine smallpox vaccination. New therapeutics and vaccines offer hope for the treatment and prevention of monkeypox; however, more research must be done before they are ready to be deployed in an endemic setting. There is a need for more research in the epidemiology, ecology, and biology of the virus in endemic areas to better understand and prevent human infections.

  10. Validation of microarray data in human lymphoblasts shows a role of the ubiquitin-proteasome system and NF-kB in the pathogenesis of Down syndrome.

    Science.gov (United States)

    Granese, Barbara; Scala, Iris; Spatuzza, Carmen; Valentino, Anna; Coletta, Marcella; Vacca, Rosa Anna; De Luca, Pasquale; Andria, Generoso

    2013-07-05

    Down syndrome (DS) is a complex disorder caused by the trisomy of either the entire, or a critical region of chromosome 21 (21q22.1-22.3). Despite representing the most common cause of mental retardation, the molecular bases of the syndrome are still largely unknown. To better understand the pathogenesis of DS, we analyzed the genome-wide transcription profiles of lymphoblastoid cell lines (LCLs) from six DS and six euploid individuals and investigated differential gene expression and pathway deregulation associated with trisomy 21. Connectivity map and PASS-assisted exploration were used to identify compounds whose molecular signatures counteracted those of DS lymphoblasts and to predict their therapeutic potential. An experimental validation in DS LCLs and fetal fibroblasts was performed for the most deregulated GO categories, i.e. the ubiquitin mediated proteolysis and the NF-kB cascade. We show, for the first time, that the level of protein ubiquitination is reduced in human DS cell lines and that proteasome activity is increased in both basal conditions and oxidative microenvironment. We also provide the first evidence that NF-kB transcription levels, a paradigm of gene expression control by ubiquitin-mediated degradation, is impaired in DS due to reduced IkB-alfa ubiquitination, increased NF-kB inhibitor (IkB-alfa) and reduced p65 nuclear fraction. Finally, the DSCR1/DYRK1A/NFAT genes were analysed. In human DS LCLs, we confirmed the presence of increased protein levels of DSCR1 and DYRK1A, and showed that the levels of the transcription factor NFATc2 were decreased in DS along with a reduction of its nuclear translocation upon induction of calcium fluxes. The present work offers new perspectives to better understand the pathogenesis of DS and suggests a rationale for innovative approaches to treat some pathological conditions associated to DS.

  11. Bioenergetic and Antiapoptotic Properties of Mitochondria from Cultured Human Prostate Cancer Cell Lines PC-3, DU145 and LNCaP

    Science.gov (United States)

    Panov, Alexander; Orynbayeva, Zulfiya

    2013-01-01

    The purpose of this work was to reveal the metabolic features of mitochondria that might be essential for inhibition of apoptotic potential in prostate cancer cells. We studied mitochondria isolated from normal prostate epithelial cells (PrEC), metastatic prostate cancer cell lines LNCaP, PC-3, DU145; and non-prostate cancer cells - human fibrosarcoma HT1080 cells; and normal human lymphoblastoid cells. PrEC cells contained 2 to 4 times less mitochondria per gram of cells than the three PC cell lines. Respiratory activities of PrEC cell mitochondria were 5-20-fold lower than PC mitochondria, depending on substrates and the metabolic state, due to lower content and lower activity of the respiratory enzyme complexes. Mitochondria from the three metastatic prostate cancer cell lines revealed several features that are distinctive only to these cells: low affinity of Complex I for NADH, 20-30 mV higher electrical membrane potential (ΔΨ). Unprotected with cyclosporine A (CsA) the PC-3 mitochondria required 4 times more Ca2+ to open the permeability transition pore (mPTP) when compared with the PrEC mitochondria, and they did not undergo swelling even in the presence of alamethicin, a large pore forming antibiotic. In the presence of CsA, the PC-3 mitochondria did not open spontaneously the mPTP. We conclude that the low apoptotic potential of the metastatic PC cells may arise from inhibition of the Ca2+-dependent permeability transition due to a very high ΔΨ and higher capacity to sequester Ca2+. We suggest that due to the high ΔΨ, mitochondrial metabolism of the metastatic prostate cancer cells is predominantly based on utilization of glutamate and glutamine, which may promote development of cachexia. PMID:23951286

  12. Bioenergetic and antiapoptotic properties of mitochondria from cultured human prostate cancer cell lines PC-3, DU145 and LNCaP.

    Directory of Open Access Journals (Sweden)

    Alexander Panov

    Full Text Available The purpose of this work was to reveal the metabolic features of mitochondria that might be essential for inhibition of apoptotic potential in prostate cancer cells. We studied mitochondria isolated from normal prostate epithelial cells (PrEC, metastatic prostate cancer cell lines LNCaP, PC-3, DU145; and non-prostate cancer cells - human fibrosarcoma HT1080 cells; and normal human lymphoblastoid cells. PrEC cells contained 2 to 4 times less mitochondria per gram of cells than the three PC cell lines. Respiratory activities of PrEC cell mitochondria were 5-20-fold lower than PC mitochondria, depending on substrates and the metabolic state, due to lower content and lower activity of the respiratory enzyme complexes. Mitochondria from the three metastatic prostate cancer cell lines revealed several features that are distinctive only to these cells: low affinity of Complex I for NADH, 20-30 mV higher electrical membrane potential (ΔΨ. Unprotected with cyclosporine A (CsA the PC-3 mitochondria required 4 times more Ca²⁺ to open the permeability transition pore (mPTP when compared with the PrEC mitochondria, and they did not undergo swelling even in the presence of alamethicin, a large pore forming antibiotic. In the presence of CsA, the PC-3 mitochondria did not open spontaneously the mPTP. We conclude that the low apoptotic potential of the metastatic PC cells may arise from inhibition of the Ca²⁺-dependent permeability transition due to a very high ΔΨ and higher capacity to sequester Ca²⁺. We suggest that due to the high ΔΨ, mitochondrial metabolism of the metastatic prostate cancer cells is predominantly based on utilization of glutamate and glutamine, which may promote development of cachexia.

  13. MiRNA Profiles in Lymphoblastoid Cell Lines of Finnish Prostate Cancer Families.

    Directory of Open Access Journals (Sweden)

    Daniel Fischer

    Full Text Available Heritable factors are evidently involved in prostate cancer (PrCa carcinogenesis, but currently, genetic markers are not routinely used in screening or diagnostics of the disease. More precise information is needed for making treatment decisions to distinguish aggressive cases from indolent disease, for which heritable factors could be a useful tool. The genetic makeup of PrCa has only recently begun to be unravelled through large-scale genome-wide association studies (GWAS. The thus far identified Single Nucleotide Polymorphisms (SNPs explain, however, only a fraction of familial clustering. Moreover, the known risk SNPs are not associated with the clinical outcome of the disease, such as aggressive or metastasised disease, and therefore cannot be used to predict the prognosis. Annotating the SNPs with deep clinical data together with miRNA expression profiles can improve the understanding of the underlying mechanisms of different phenotypes of prostate cancer.In this study microRNA (miRNA profiles were studied as potential biomarkers to predict the disease outcome. The study subjects were from Finnish high risk prostate cancer families. To identify potential biomarkers we combined a novel non-parametrical test with an importance measure provided from a Random Forest classifier. This combination delivered a set of nine miRNAs that was able to separate cases from controls. The detected miRNA expression profiles could predict the development of the disease years before the actual PrCa diagnosis or detect the existence of other cancers in the studied individuals. Furthermore, using an expression Quantitative Trait Loci (eQTL analysis, regulatory SNPs for miRNA miR-483-3p that were also directly associated with PrCa were found.Based on our findings, we suggest that blood-based miRNA expression profiling can be used in the diagnosis and maybe even prognosis of the disease. In the future, miRNA profiling could possibly be used in targeted screening, together with Prostate Specific Antigene (PSA testing, to identify men with an elevated PrCa risk.

  14. MiRNA Profiles in Lymphoblastoid Cell Lines of Finnish Prostate Cancer Families.

    Science.gov (United States)

    Fischer, Daniel; Wahlfors, Tiina; Mattila, Henna; Oja, Hannu; Tammela, Teuvo L J; Schleutker, Johanna

    2015-01-01

    Heritable factors are evidently involved in prostate cancer (PrCa) carcinogenesis, but currently, genetic markers are not routinely used in screening or diagnostics of the disease. More precise information is needed for making treatment decisions to distinguish aggressive cases from indolent disease, for which heritable factors could be a useful tool. The genetic makeup of PrCa has only recently begun to be unravelled through large-scale genome-wide association studies (GWAS). The thus far identified Single Nucleotide Polymorphisms (SNPs) explain, however, only a fraction of familial clustering. Moreover, the known risk SNPs are not associated with the clinical outcome of the disease, such as aggressive or metastasised disease, and therefore cannot be used to predict the prognosis. Annotating the SNPs with deep clinical data together with miRNA expression profiles can improve the understanding of the underlying mechanisms of different phenotypes of prostate cancer. In this study microRNA (miRNA) profiles were studied as potential biomarkers to predict the disease outcome. The study subjects were from Finnish high risk prostate cancer families. To identify potential biomarkers we combined a novel non-parametrical test with an importance measure provided from a Random Forest classifier. This combination delivered a set of nine miRNAs that was able to separate cases from controls. The detected miRNA expression profiles could predict the development of the disease years before the actual PrCa diagnosis or detect the existence of other cancers in the studied individuals. Furthermore, using an expression Quantitative Trait Loci (eQTL) analysis, regulatory SNPs for miRNA miR-483-3p that were also directly associated with PrCa were found. Based on our findings, we suggest that blood-based miRNA expression profiling can be used in the diagnosis and maybe even prognosis of the disease. In the future, miRNA profiling could possibly be used in targeted screening, together with Prostate Specific Antigene (PSA) testing, to identify men with an elevated PrCa risk.

  15. Human mimicry

    NARCIS (Netherlands)

    Chartrand, T.L.; Baaren, R.B. van

    2009-01-01

    Human mimicry is ubiquitous, and often occurs without the awareness of the person mimicking or the person being mimicked. First, we briefly describe some of the major types of nonconscious mimicry—verbal, facial, emotional, and behavioral—and review the evidence for their automaticity. Next, we

  16. Practicing Humanities

    DEFF Research Database (Denmark)

    Gimmler, Antje

    2016-01-01

    and self-reflective democracy. Contemporary humanities have adopted a new orientation towards practices, and it is not clear how this fits with the ideals of ‘Bildung’ and ‘pure science’. A possible theoretical framework for this orientation towards practices could be found in John Dewey’s pragmatic...

  17. Human waste

    NARCIS (Netherlands)

    Amin, Md Nurul; Kroeze, Carolien; Strokal, Maryna

    2017-01-01

    Many people practice open defecation in south Asia. As a result, lot of human waste containing nutrients such as nitrogen (N) and phosphorus (P) enter rivers. Rivers transport these nutrients to coastal waters, resulting in marine pollution. This source of nutrient pollution is, however, ignored in

  18. Human Parasites

    OpenAIRE

    Davis, Ryan S.; Hodgson, Erin W.

    2008-01-01

    Entomologists often get “bug” samples for identification, including those that accidentally infest residences. In the United States, we are fortunate to have very few arthropods (e.g., insects, spiders, mites, ticks, etc.) that actually infest or feed on humans.

  19. Human steroidogenesis

    DEFF Research Database (Denmark)

    Andersen, Claus Y; Ezcurra, Diego

    2014-01-01

    reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis...

  20. Human Parechoviruses

    DEFF Research Database (Denmark)

    Fischer, Thea Kølsen; Harvala, Heli; Midgley, Sofie

    2017-01-01

    Infections with human parechoviruses (HPeV) are highly prevalent, particularly in neonates, where they may cause substantial morbidity and mortality. The clinical presentation of HPeV infection is often indistinguishable from that of enterovirus (EV) infection and may vary from mild disease...

  1. Nothing Human

    Science.gov (United States)

    Wharram, C. C.

    2014-01-01

    In this essay C. C. Wharram argues that Terence's concept of translation as a form of "contamination" anticipates recent developments in philosophy, ecology, and translation studies. Placing these divergent fields of inquiry into dialogue enables us read Terence's well-known statement "I am a human being--I deem nothing…

  2. Human Trafficking

    Science.gov (United States)

    Wilson, David McKay

    2011-01-01

    The shadowy, criminal nature of human trafficking makes evaluating its nature and scope difficult. The U.S. State Department and anti-trafficking groups estimate that worldwide some 27 million people are caught in a form of forced servitude today. Public awareness of modern-day slavery is gaining momentum thanks to new abolitionist efforts. Among…

  3. Human monkeypox.

    Science.gov (United States)

    Jezek, Z; Gromyko, A I; Szczeniowski, M V

    1983-01-01

    Human monkeypox, occurring in the tropical rainforest of west and central Africa, is regarded as the most important orthopoxvirus infection for epidemiological surveillance during the post-smallpox era. This disease, first recognized in Zaïre in 1970 resembles smallpox clinically but differs epidemiologically. Clinical features, their evolution and sequelae of monkeypox could be compared with discrete ordinary or modified type of smallpox. A case-fatality rate of 14% has been observed but some cases can be exceedingly mild or atypical and may easily remain undetected and unreported. Pronounced lymphadenopathy has been the only clinical feature found commonly in monkeypox but not in smallpox. Fifty-seven cases of human monkeypox have occurred since 1970, in the tropical rainforests in six west and central African countries, the majority of them (45) being reported from Zaïre. The disease appears to be more frequent in dry season. Children below ten years of age comprise 84% of the cases. Smallpox vaccination protects against monkeypox. Clusters of cases have been observed in certain areas within countries and within affected households. Human-to-human spread has possibly occurred seven times. No cases of possible tertiary spread were observed. The secondary attack rate among susceptible close household contacts was 10%, among all susceptible contacts 5%. This is much lower than that occurring with smallpox, which is between 25-40%. The limited avidity of monkeypox virus for human beings indicates that monkeypox is probably a zoonosis, although the animal reservoir(s) have not yet been identified. The low transmissibility, resulting in low frequency of disease in man indicates that monkeypox is not a public health problem. Human monkeypox has been a relatively newly recognized disease. Studies are in progress to identify the natural cycle of monkeypox virus and to define better its clinical and epidemiological characteristics. Special surveillance is maintained in

  4. Human Rights, Human Needs, Human Development, Human Security : Relationships between four international 'human' discourses

    NARCIS (Netherlands)

    D.R. Gasper (Des)

    2007-01-01

    textabstractHuman rights, human development and human security form increasingly important, partly interconnected, partly competitive and misunderstood ethical and policy discourses. Each tries to humanize a pre-existing and unavoidable major discourse of everyday life, policy and politics; each

  5. Human Development Report 2000: Human Rights and Human Development

    OpenAIRE

    United Nations Development Programme, UNDP

    2000-01-01

    The Human Development Report 2000 looks at human rights as an intrinsic part of development—and at development as a means to realizing human rights. It shows how human rights bring principles of accountability and social justice to the process of human development.

  6. Human Rights in the Humanities

    Science.gov (United States)

    Harpham, Geoffrey

    2012-01-01

    Human rights are rapidly entering the academic curriculum, with programs appearing all over the country--including at Duke, Harvard, Northeastern, and Stanford Universities; the Massachusetts Institute of Technology; the Universities of Chicago, of Connecticut, of California at Berkeley, and of Minnesota; and Trinity College. Most of these…

  7. Genome-wide survey of allele-specific splicing in humans

    Directory of Open Access Journals (Sweden)

    Scheffler Konrad

    2008-06-01

    Full Text Available Abstract Background Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. Many examples of mutations within human splice regulatory regions that alter splicing qualitatively or quantitatively have been reported and allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. However, because the effect of a mutation on the efficiency of mRNA splicing is often difficult to predict, many mutations that cause disease through an effect on splicing are likely to remain undiscovered. Results We have combined a genome-wide scan for sequence polymorphisms likely to affect mRNA splicing with analysis of publicly available Expressed Sequence Tag (EST and exon array data. The genome-wide scan uses published tools and identified 30,977 SNPs located within donor and acceptor splice sites, branch points and exonic splicing enhancer elements. For 1,185 candidate splicing polymorphisms the difference in splicing between alternative alleles was corroborated by publicly available exon array data from 166 lymphoblastoid cell lines. We developed a novel probabilistic method to infer allele-specific splicing from EST data. The method uses SNPs and alternative mRNA isoforms mapped to EST sequences and models both regulated alternative splicing as well as allele-specific splicing. We have also estimated heritability of splicing and report that a greater proportion of genes show evidence of splicing heritability than show heritability of overall gene expression level. Our results provide an extensive resource that can be used to assess the possible effect on splicing of human polymorphisms in putative splice-regulatory sites. Conclusion We report a set of genes showing evidence of allele-specific splicing from an integrated analysis of genomic polymorphisms, EST data and exon array

  8. Human Protothecosis

    Science.gov (United States)

    Lass-Flörl, Cornelia; Mayr, Astrid

    2007-01-01

    Human protothecosis is a rare infection caused by members of the genus Prototheca. Prototheca species are generally considered to be achlorophyllic algae and are ubiquitous in nature. The occurrence of protothecosis can be local or disseminated and acute or chronic, with the latter being more common. Diseases have been classified as (i) cutaneous lesions, (ii) olecranon bursitis, or (iii) disseminated or systemic manifestations. Infections can occur in both immunocompetent and immunosuppressed patients, although more severe and disseminated infections tend to occur in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii have been associated with human disease. Usually, treatment involves medical and surgical approaches; treatment failure is not uncommon. Antifungals such as ketoconazole, itraconazole, fluconazole, and amphotericin B are the most commonly used drugs to date. Among them, amphotericin B displays the best activity against Prototheca spp. Diagnosis is largely made upon detection of characteristic structures observed on histopathologic examination of tissue. PMID:17428884

  9. Human paleoneurology

    CERN Document Server

    2015-01-01

    The book presents an integrative review of paleoneurology, the study of endocranial morphology in fossil species. The main focus is on showing how computed methods can be used to support advances in evolutionary neuroanatomy, paleoanthropology and archaeology and how they have contributed to creating a completely new perspective in cognitive neuroscience. Moreover, thanks to its multidisciplinary approach, the book addresses students and researchers approaching human paleoneurology from different angles and for different purposes, such as biologists, physicians, anthropologists, archaeologists

  10. Human Cloning

    Science.gov (United States)

    2006-07-20

    research group, headed by Douglas Melton and Kevin Eggan, submitted their proposal to a Harvard committee composed of ethicists, scientists and public...United States. Although the company offered no proof of its claim, Dr . Brigette Boisselier, Managing Director of Clonaid, stated that genetic tests would...a year of the Dolly announcement, concerns over human cloning were heightened when Dr . Richard Seed, a Chicago scientist, announced on January 7

  11. Human universe

    CERN Document Server

    Cox, Brian

    2014-01-01

    Human life is a staggeringly strange thing. On the surface of a ball of rock falling around a nuclear fireball in the blackness of a vacuum the laws of nature conspired to create a naked ape that can look up at the stars and wonder where it came from. What is a human being? Objectively, nothing of consequence. Particles of dust in an infinite arena, present for an instant in eternity. Clumps of atoms in a universe with more galaxies than people. And yet a human being is necessary for the question itself to exist, and the presence of a question in the universe - any question - is the most wonderful thing. Questions require minds, and minds bring meaning. What is meaning? I don't know, except that the universe and every pointless speck inside it means something to me. I am astonished by the existence of a single atom, and find my civilisation to be an outrageous imprint on reality. I don't understand it. Nobody does, but it makes me smile. This book asks questions about our origins, our destiny, and our place i...

  12. Human Being Human: Culture and the Soul

    OpenAIRE

    Hauke, Chris

    2005-01-01

    Human Being Human explores the classical question 'What is a human being?'\\ud \\ud In examining our human being, Christopher Hauke challenges the notion of human nature, questions the assumed superiority of human consciousness and rational thinking and pays close attention to the contradiction of living simultaneously as an autonomous individual and a member of the collective community. The main chapters include:\\ud \\ud who's in charge here?\\ud knowledge power and human being\\ud that thinking ...

  13. Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine NF1-haploinsufficiency

    Directory of Open Access Journals (Sweden)

    Stewart Douglas R

    2010-03-01

    Full Text Available Abstract Background Neurofibromatosis type 1 (NF1 is a common monogenic tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Haploinsufficiency of NF1 fosters a permissive tumorigenic environment through changes in signalling between cells, however the intracellular mechanisms for this tumor-promoting effect are less clear. Most primary human NF1+/- cells are a challenge to obtain, however lymphoblastoid cell lines (LCLs have been collected from large NF1 kindreds. We hypothesized that the genetic effects of NF1-haploinsufficiency may be discerned by comparison of genome-wide transcriptional profiling in somatic, non-tumor cells (LCLs from NF1-affected and -unaffected individuals. As a cross-species filter for heterogeneity, we compared the results from two human kindreds to whole-genome transcriptional profiling in spleen-derived B lymphocytes from age- and gender-matched Nf1+/- and wild-type mice, and used gene set enrichment analysis (GSEA, Onto-Express, Pathway-Express and MetaCore tools to identify genes perturbed in NF1-haploinsufficiency. Results We observed moderate expression of NF1 in human LCLs and of Nf1 in CD19+ mouse B lymphocytes. Using the t test to evaluate individual transcripts, we observed modest expression differences in the transcriptome in NF1-haploinsufficient LCLs and Nf1-haploinsuffiicient mouse B lymphocytes. However, GSEA, Onto-Express, Pathway-Express and MetaCore analyses identified genes that control cell cycle, DNA replication and repair, transcription and translation, and immune response as the most perturbed in NF1-haploinsufficient conditions in both human and mouse. Conclusions Haploinsufficiency arises when loss of one allele of a gene is sufficient to give rise to disease. Haploinsufficiency has traditionally been viewed as a passive state. Our observations of perturbed, up-regulated cell cycle and DNA repair pathways may functionally contribute to NF1

  14. Introduction: Digital Humanities, Public Humanities

    Directory of Open Access Journals (Sweden)

    Alex Christie

    2014-07-01

    Full Text Available NANO: New American Notes Online: An Interdisciplinary Academic Journal for Big Ideas in a Small World. This special issue shows how both public and digital humanities research can be rendered more persuasive through engagement with cultures beyond the academy. More specifically, the aim of this special issue is to demonstrate how investments in technologies and computation are not necessarily antithetical to investments in critical theory and social justice.

  15. Human Computing, Virtual Humans and Artificial Imperfection

    NARCIS (Netherlands)

    Ruttkay, Z.M.; Reidsma, Dennis; Nijholt, Antinus; Quek, F.; Yang, Y.

    2006-01-01

    In this paper we raise the issue whether imperfections, characteristic of human-human communication, should be taken into account when developing virtual humans. We argue that endowing virtual humans with the imperfections of humans can help making them more ‘comfortable’ to interact with. That is,

  16. Human Capital, (Human) Capabilities and Higher Education

    Science.gov (United States)

    Le Grange, L.

    2011-01-01

    In this article I initiate a debate into the (de)merits of human capital theory and human capability theory and discuss implications of the debate for higher education. Human capital theory holds that economic growth depends on investment in education and that economic growth is the basis for improving the quality of human life. Human capable…

  17. Humanizing Architecture

    DEFF Research Database (Denmark)

    Toft, Tanya Søndergaard

    2015-01-01

    The article proposes the urban digital gallery as an opportunity to explore the relationship between ‘human’ and ‘technology,’ through the programming of media architecture. It takes a curatorial perspective when proposing an ontological shift from considering media facades as visual spectacles...... agency and a sense of being by way of dematerializing architecture. This is achieved by way of programming the symbolic to provide new emotional realizations and situations of enlightenment in the public audience. This reflects a greater potential to humanize the digital in media architecture....

  18. Think Human

    DEFF Research Database (Denmark)

    Nielsen, Charlotte Marie Bisgaard

    2013-01-01

    The paper probes the background of the dire rhetoric of the Danish National Health Board’s 40 week anti-alcohol consumption campaign, in particular the model of communication implied by the campaign's strategy. Contrasting the campaign's strategy in 2011 with the results of evaluations of previous...... years' campaigns suggests that the theory of communication underlying the campaign has its basis in mechanical action rather than in human communication. The practice of 'Communication design' is investigated in relation to this metaphorical 'machine thinking' model of communication and contrasted...

  19. Bubble-seq analysis of the human genome reveals distinct chromatin-mediated mechanisms for regulating early- and late-firing origins

    Science.gov (United States)

    Mesner, Larry D.; Valsakumar, Veena; Cieślik, Marcin; Pickin, Rebecca; Hamlin, Joyce L.; Bekiranov, Stefan

    2013-01-01

    We have devised a method for isolating virtually pure and comprehensive libraries of restriction fragments that contained replication initiation sites (bubbles) in vivo. We have now sequenced and mapped the bubble-containing fragments from GM06990, a near-normal EBV-transformed lymphoblastoid cell line, and have compared origin distributions with a comprehensive replication timing study recently published for this cell line. We find that early-firing origins, which represent ∼32% of all origins, overwhelmingly represent zones, associate only marginally with active transcription units, are localized within large domains of open chromatin, and are significantly associated with DNase I hypersensitivity. Origin “density” falls from early- to mid-S-phase, but rises again in late S-phase to levels only 17% lower than in early S-phase. Unexpectedly, late origin density calculated on the 1-Mb scale increases as a function of increasing chromatin compaction. Furthermore, the median efficiency of origins in late-replicating, heterochromatic domains is only 25% lower than in early-replicating euchromatic loci. Thus, the activation of early- and late-firing origins must be regulated by quintessentially different mechanisms. The aggregate data can be unified into a model in which initiation site selection is driven almost entirely by epigenetic factors that fashion both the long-range and local chromatin environments, with underlying DNA sequence and local transcriptional activity playing only minor roles. Importantly, the comprehensive origin map we have prepared for GM06990 overlaps moderately well with origin maps recently reported for the genomes of four different human cell lines based on the distributions of small nascent strands. PMID:23861383

  20. Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin's lymphoma xenografts.

    Directory of Open Access Journals (Sweden)

    Paola Secchiero

    Full Text Available BACKGROUND: Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL, significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM mesenchymal stem cells (MSC on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL. METHODOLOGY/PRINCIPAL FINDINGS: The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV(- Burkitt-type BJAB, median survival = 46 days and an aggressive (EBV(+ B lymphoblastoid SKW6.4, median survival = 27 days behavior in nude-SCID mice. Intra-peritoneal (i.p. injection of MSC (4 days after i.p. injection of lymphoma cells significantly increased the overall survival at an optimal MSC:lymphoma ratio of 1:10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days. Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL.

  1. Identification of a novel first exon in the human dystrophin gene and of a new promoter located more than 500 kb upstream of the nearest known promoter

    Energy Technology Data Exchange (ETDEWEB)

    Yanagawa, H.; Nishio, H.; Takeshima, Y. [Kobe Univ. School of Medicine (Japan)] [and others

    1994-09-01

    The dystrophin gene, which is muted in patients with Duchenne and Becker muscular dystrophies, is the largest known human gene. Five alternative promoters have been characterized until now. Here we show that a novel dystrophin isoform with a different first exon can be produced through transcription initiation at a previously-unidentified alternative promoter. The case study presented is that of patient with Duchenne muscular dystrophy who had a deletion extending from 5{prime} end of the dystrophin gene to exon 2, including all promoters previously mapped in the 5{prime} part of the gene. Transcripts from lymphoblastoid cells were found to contain sequences corresponding to exon 3, indicating the presence of new promoter upstream of this exon. The nucleotide sequence of amplified cDNA corresponding to the 5{prime} end of the new transcript indicated that the 5{prime} end of exon 3 was extended by 9 codons, only the last (most 3{prime}) of which codes for methionine. The genomic nucleotide sequence upstream from the new exon, as determined using inverse polymerase chain reaction, revealed the presence of sequences similar to a TATA box, an octamer motif and an MEF-2 element. The identified promoter/exon did not map to intron 2, as might have been expected, but to a position more than 500 kb upstream of the most 5{prime} of the previously-identified promoters, thereby adding 500 kb to the dystrophin gene. The sequence of part of the new promoter region is very similar to that of certain medium reiteration frequency repetitive sequences. These findings may help us understand the molecular evolution of the dystrophin gene.

  2. Neutron exposures in human cells: bystander effect and relative biological effectiveness.

    Directory of Open Access Journals (Sweden)

    Isheeta Seth

    Full Text Available Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy, and irradiated-cell conditioned media (ICCM was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control, 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (p<0.0001. These data indicate that neutrons do not induce a bystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0 ± 0.13 for micronuclei and 5.8 ± 2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety.

  3. Exprtarget: an integrative approach to predicting human microRNA targets.

    Directory of Open Access Journals (Sweden)

    Eric R Gamazon

    2010-10-01

    Full Text Available Variation in gene expression has been observed in natural populations and associated with complex traits or phenotypes such as disease susceptibility and drug response. Gene expression itself is controlled by various genetic and non-genetic factors. The binding of a class of small RNA molecules, microRNAs (miRNAs, to mRNA transcript targets has recently been demonstrated to be an important mechanism of gene regulation. Because individual miRNAs may regulate the expression of multiple gene targets, a comprehensive and reliable catalogue of miRNA-regulated targets is critical to understanding gene regulatory networks. Though experimental approaches have been used to identify many miRNA targets, due to cost and efficiency, current miRNA target identification still relies largely on computational algorithms that aim to take advantage of different biochemical/thermodynamic properties of the sequences of miRNAs and their gene targets. A novel approach, ExprTarget, therefore, is proposed here to integrate some of the most frequently invoked methods (miRanda, PicTar, TargetScan as well as the genome-wide HapMap miRNA and mRNA expression datasets generated in our laboratory. To our knowledge, this dataset constitutes the first miRNA expression profiling in the HapMap lymphoblastoid cell lines. We conducted diagnostic tests of the existing computational solutions using the experimentally supported targets in TarBase as gold standard. To gain insight into the biases that arise from such an analysis, we investigated the effect of the choice of gold standard on the evaluation of the various computational tools. We analyzed the performance of ExprTarget using both ROC curve analysis and cross-validation. We show that ExprTarget greatly improves miRNA target prediction relative to the individual prediction algorithms in terms of sensitivity and specificity. We also developed an online database, ExprTargetDB, of human miRNA targets predicted by our approach

  4. Human Factors Planning Guidelines

    Science.gov (United States)

    1996-01-01

    To ensure human factors considerations are fully incorporated in the system : development, the Integrated Product Team (IPT) or Program Manager initiates a : Human Factors Program (HFP) that addresses the human performance and human : resource parame...

  5. The Digital Humanities as a Humanities Project

    Science.gov (United States)

    Svensson, Patrik

    2012-01-01

    This article argues that the digital humanities can be seen as a humanities project in a time of significant change in the academy. The background is a number of scholarly, educational and technical challenges, the multiple epistemic traditions linked to the digital humanities, the potential reach of the field across and outside the humanities,…

  6. NATO Human View Architecture and Human Networks

    Science.gov (United States)

    Handley, Holly A. H.; Houston, Nancy P.

    2010-01-01

    The NATO Human View is a system architectural viewpoint that focuses on the human as part of a system. Its purpose is to capture the human requirements and to inform on how the human impacts the system design. The viewpoint contains seven static models that include different aspects of the human element, such as roles, tasks, constraints, training and metrics. It also includes a Human Dynamics component to perform simulations of the human system under design. One of the static models, termed Human Networks, focuses on the human-to-human communication patterns that occur as a result of ad hoc or deliberate team formation, especially teams distributed across space and time. Parameters of human teams that effect system performance can be captured in this model. Human centered aspects of networks, such as differences in operational tempo (sense of urgency), priorities (common goal), and team history (knowledge of the other team members), can be incorporated. The information captured in the Human Network static model can then be included in the Human Dynamics component so that the impact of distributed teams is represented in the simulation. As the NATO militaries transform to a more networked force, the Human View architecture is an important tool that can be used to make recommendations on the proper mix of technological innovations and human interactions.

  7. Digital Humanities

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørn

    2015-01-01

    overgangen fra trykkekultur til digital kultur. For det første problemstillingen omkring digitalisering af litterær kulturarv med fokus på kodning og tagging af teksten samt organisering i hypertekststrukturer. For det andet reorganiseringen af det digitale dokument i dataelementer og database. For det......Artiklen præsenterer først nogle generelle problemstillinger omkring Digital Humanities (DH) med det formål at undersøge dem nærmere i relation til konkrete eksempler på forskellige digitaliseringsmåder og ændringer i dokumentproduktion. I en nærmere afgrænsning vælger artiklen den tendens i DH......, der betragter DH som forbundet med "making" og "building" af digitale objekter og former. Dette kan også karakteriseres som DH som praktisk-produktiv vending. Artiklen har valgt tre typer af digitalisering. De er valgt ud fra, at de skal repræsentere forskellige måder at håndtere digitaliseringen på...

  8. Human Rhinoviruses

    Science.gov (United States)

    Lamson, Daryl M.; St. George, Kirsten; Walsh, Thomas J.

    2013-01-01

    Human rhinoviruses (HRVs), first discovered in the 1950s, are responsible for more than one-half of cold-like illnesses and cost billions of dollars annually in medical visits and missed days of work. Advances in molecular methods have enhanced our understanding of the genomic structure of HRV and have led to the characterization of three genetically distinct HRV groups, designated groups A, B, and C, within the genus Enterovirus and the family Picornaviridae. HRVs are traditionally associated with upper respiratory tract infection, otitis media, and sinusitis. In recent years, the increasing implementation of PCR assays for respiratory virus detection in clinical laboratories has facilitated the recognition of HRV as a lower respiratory tract pathogen, particularly in patients with asthma, infants, elderly patients, and immunocompromised hosts. Cultured isolates of HRV remain important for studies of viral characteristics and disease pathogenesis. Indeed, whether the clinical manifestations of HRV are related directly to viral pathogenicity or secondary to the host immune response is the subject of ongoing research. There are currently no approved antiviral therapies for HRVs, and treatment remains primarily supportive. This review provides a comprehensive, up-to-date assessment of the basic virology, pathogenesis, clinical epidemiology, and laboratory features of and treatment and prevention strategies for HRVs. PMID:23297263

  9. 3-aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone, forms DNA adducts after metabolic activation by human and rat liver microsomes: evidence for activation by cytochrome P450 1A1 and P450 1A2.

    Science.gov (United States)

    Arlt, Volker M; Hewer, Alan; Sorg, Bernd L; Schmeiser, Heinz H; Phillips, David H; Stiborova, Marie

    2004-08-01

    3-Nitrobenzanthrone (3-NBA) is a suspected human carcinogen found in diesel exhaust and ambient air pollution. The main metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), was recently detected in the urine of salt mining workers occupationally exposed to diesel emissions. Determining the capability of humans to metabolize 3-ABA and understanding which human enzymes are involved in its activation are important in the assessment of individual susceptibility. We compared the ability of eight human hepatic microsomal samples to catalyze DNA adduct formation by 3-ABA. Using the (32)P-postlabeling method, we found that all hepatic microsomes were competent to activate 3-ABA. DNA adduct patterns with multiple adducts, qualitatively similar to those formed in vivo in rats treated with 3-ABA, were observed. These patterns were also similar to those formed by the nitroaromatic counterpart 3-NBA and which derive from reductive metabolites of 3-NBA bound to purine bases in DNA. The role of specific cytochrome P450s (P450s) in the human hepatic microsomal samples in 3-ABA activation was investigated by correlating the P450-linked catalytic activities in each microsomal sample with the level of DNA adducts formed by the same microsomes. On the basis of this analysis, most of the hepatic microsomal activation of 3-ABA was attributable to P450 1A1 and 1A2 enzyme activity. Inhibition of DNA adduct formation in human liver microsomes by alpha-naphthoflavone and furafylline, inhibitors of P450 1A1 and 1A2, and P450 1A2 alone, respectively, supported this finding. Using recombinant human P450 1A1 and 1A2 expressed in Chinese hamster V79 cells and microsomes of baculovirus-transfected insect cells (Supersomes), we confirmed the participation of these enzymes in the formation of 3-ABA-derived DNA adducts. Moreover, essentially the same DNA adduct pattern found in microsomes was detected in metabolically competent human lymphoblastoid MCL-5 cells expressing P450 1A1 and 1A2. Using rat

  10. Human Factors in Human-Systems Integration

    Science.gov (United States)

    Fitts, David J.; Sandor, Aniko; Litaker, Harry L., Jr.; Tillman, Barry

    2008-01-01

    Any large organization whose mission is to design and develop systems for humans, and train humans needs a well-developed integration and process plan to deal with the challenges that arise from managing multiple subsystems. Human capabilities, skills, and needs must be considered early in the design and development process, and must be continuously considered throughout the development lifecycle. This integration of human needs within system design is typically formalized through a Human-Systems Integration (HSI) program. By having an HSI program, an institution or organization can reduce lifecycle costs and increase the efficiency, usability, and quality of its products because human needs have been considered from the beginning.

  11. Humane Education: An Overview.

    Science.gov (United States)

    Whitlock, Eileen S.; Westerlund, Stuart R.

    This booklet traces the historical development of human education as it has been instilled into the young people of America from colonial times to the present and provides a future prognosis of humaneness in the schools. Humane education promotes humane behavior and is an important part of the humane movement in the United States, although until…

  12. In vitro-isolated human cytotoxic T-lymphocyte clones detect variations in serologically defined HLA antigens

    NARCIS (Netherlands)

    Spits, H.; Breuning, M.; Ivanyi, P.; Russo, C.; de Vries, J. E.

    1982-01-01

    T cells of two donors, JR (HLA-A23,29;B7,7;C-;DRw5) and HG (HLA-A2,23;B40,w44;Cw4), were stimulated with cells from an HLA homozygous lymphoblastoid cell line JY (HLA-A2,2;B7,7,C-,DRw4,6) and cloned by limiting dilution after the third stimulation. Two cytotoxic T-cell (CTL) clones, JR-2-16 (from

  13. IVI human factors strategy

    Science.gov (United States)

    1999-11-01

    This document focuses on human factors research that supports the Intelligent Vehicle Initiative (IVI). The status of the problem areas within categories used often by the human factors community to organize human factors process is discussed. A simi...

  14. Human Factors Job Aid

    Science.gov (United States)

    1996-12-09

    The purpose of this Human Factors Job Aid is to serve as a desk reference for : human factors integration during system acquisition. The first chapter contains : an overview of the FAA human factors process in system acquisitions. The : remaining eig...

  15. The golden triangle of human dignity: human security, human development and human rights

    NARCIS (Netherlands)

    Gaay Fortman, B. de

    2004-01-01

    The success or failure of processes of democratization cannot be detached from processes of development related to the aspirations of people at the grassroots. Human rights, in a more theoretical terminology, require human development in order to enhance human security.

  16. Human-machine interactions

    Science.gov (United States)

    Forsythe, J Chris [Sandia Park, NM; Xavier, Patrick G [Albuquerque, NM; Abbott, Robert G [Albuquerque, NM; Brannon, Nathan G [Albuquerque, NM; Bernard, Michael L [Tijeras, NM; Speed, Ann E [Albuquerque, NM

    2009-04-28

    Digital technology utilizing a cognitive model based on human naturalistic decision-making processes, including pattern recognition and episodic memory, can reduce the dependency of human-machine interactions on the abilities of a human user and can enable a machine to more closely emulate human-like responses. Such a cognitive model can enable digital technology to use cognitive capacities fundamental to human-like communication and cooperation to interact with humans.

  17. Isolation, production and characterization of fully human monoclonal antibodies directed to Plasmodium falciparum MSP10.

    Science.gov (United States)

    Maskus, Dominika J; Bethke, Susanne; Seidel, Melanie; Kapelski, Stephanie; Addai-Mensah, Otchere; Boes, Alexander; Edgü, Güven; Spiegel, Holger; Reimann, Andreas; Fischer, Rainer; Barth, Stefan; Klockenbring, Torsten; Fendel, Rolf

    2015-07-16

    Semi-immunity against the malaria parasite is defined by a protection against clinical episodes of malaria and is partially mediated by a repertoire of inhibitory antibodies directed against the blood stage of Plasmodium falciparum, in particular against surface proteins of merozoites, the invasive form of the parasite. Such antibodies may be used for preventive or therapeutic treatment of P. falciparum malaria. Here, the isolation and characterization of novel human monoclonal antibodies (humAbs) for such applications is described. B lymphocytes had been selected by flow cytometry for specificity against merozoite surface proteins, including the merozoite surface protein 10 (MSP10). After Epstein-Barr virus (EBV) transformation and identification of promising resulting lymphoblastoid cell lines (LCLs), human immunoglobulin heavy and light chain variable regions (Vh or Vl regions) were secured, cloned into plant expression vectors and transiently produced in Nicotiana benthamiana in the context of human full-size IgG1:κ. The specificity and the affinity of the generated antibodies were assessed by ELISA, dotblot and surface plasmon resonance (SPR) spectroscopy. The growth inhibitory activity was evaluated based on growth inhibition assays (GIAs) using the parasite strain 3D7A. Supernatants from two LCLs, 5E8 and 5F6, showed reactivity against the second (5E8) or first (5F6) epidermal growth factor (EGF)-like domain of MSP10. The isolated V regions were recombinantly expressed in their natural pairing as well as in combination with each other. The resulting recombinant humAbs showed affinities of 9.27 × 10(-7) M [humAb10.1 (H5F6:κ5E8)], 5.46 × 10(-9) M [humAb10.2 (H5F6:κ5F6)] and 4.34 × 10(-9) M [humAb10.3 (H5E8:κ5E8)]. In GIAs, these antibodies exhibited EC50 values of 4.1 mg/ml [95% confidence interval (CI) 2.6-6.6 mg/ml], 6.9 mg/ml (CI 5.5-8.6 mg/ml) and 9.5 mg/ml (CI 5.5-16.4 mg/ml), respectively. This report describes a platform for the isolation of

  18. Special Section: Human Rights

    Science.gov (United States)

    Frydenlund, Knut; And Others

    1978-01-01

    Eleven articles examine human rights in Europe. Topics include unemployment, human rights legislation, role of the Council of Europe in promoting human rights, labor unions, migrant workers, human dignity in industralized societies, and international violence. Journal available from Council of Europe, Directorate of Press and Information, 67006…

  19. Genetic variation is the major determinant of individual differences in leukocyte endothelial adhesion.

    Science.gov (United States)

    Grassi, Michael A; Rao, Vidhya; Winkler, Kathryn P; Zhang, Wei; Bogaard, Joseph D; Chen, Siquan; LaCroix, Bonnie; Lenkala, Divya; Rehman, Jalees; Malik, Asrar B; Cox, Nancy J; Huang, R Stephanie

    2014-01-01

    To determine the genetic contribution to leukocyte endothelial adhesion. Leukocyte endothelial adhesion was assessed through a novel cell-based assay using human lymphoblastoid cell lines. A high-throughput screening method was developed to evaluate the inter-individual variability in leukocyte endothelial adhesion using lymphoblastoid cell lines derived from different donors. To assess heritability, ninety-two lymphoblastoid cell lines derived from twenty-three monozygotic twin pairs and twenty-three sibling pairs were compared. These lymphoblastoid cell lines were plated with the endothelial cell line EA.hy926 and labeled with Calcein AM dye. Fluorescence was assessed to determine endothelial cell adhesion to each lymphoblastoid cell line. Intra-pair similarity was determined for monozygotic twins and siblings using Pearson pairwise correlation coefficients. A leukocyte endothelial adhesion assay for lymphoblastoid cell lines was developed and optimized (CV = 8.68, Z'-factor = 0.67, SNR = 18.41). A higher adhesion correlation was found between the twins than that between the siblings. Intra-pair similarity for leukocyte endothelial adhesion in monozygotic twins was 0.60 compared to 0.25 in the siblings. The extent to which these differences are attributable to underlying genetic factors was quantified and the heritability of leukocyte endothelial adhesion was calculated to be 69.66% (p-valuegenetic predisposition plays a significant role in inter-individual variability of leukocyte endothelial adhesion.

  20. ISS Payload Human Factors

    Science.gov (United States)

    Ellenberger, Richard; Duvall, Laura; Dory, Jonathan

    2016-01-01

    The ISS Payload Human Factors Implementation Team (HFIT) is the Payload Developer's resource for Human Factors. HFIT is the interface between Payload Developers and ISS Payload Human Factors requirements in SSP 57000. ? HFIT provides recommendations on how to meet the Human Factors requirements and guidelines early in the design process. HFIT coordinates with the Payload Developer and Astronaut Office to find low cost solutions to Human Factors challenges for hardware operability issues.

  1. Human Dignity, Three Human Rights, and Pedagogy.

    Science.gov (United States)

    Vandenberg, Donald

    1986-01-01

    A general theory of value is outlined to show that moral agency is necessary to human dignity and that liberty, equality, and fraternity are necessary to moral agency. These ideals can be implemented in schools and human dignity can be at the core of the professional ethics of teaching. (MT)

  2. Human dignity, bioethics, and human rights.

    Science.gov (United States)

    Häyry, Matti; Takala, Tuija

    2005-09-01

    The authors analyse and assess the Universal Draft Declaration on Bioethics and Human Rights published by UNESCO. They argue that the Draft has two main weaknesses. It unnecessarily confines the scope of bioethics to life sciences and their practical applications. And it fails to spell out the intended role of human dignity in international ethical regulation.

  3. [Humanization in health care].

    Science.gov (United States)

    Oliveira, Beatriz Rosana Gonçalves de; Collet, Neusa; Viera, Cláudia Silveira

    2006-01-01

    This study aims to reflect on humanization in health care, recovering the history of understanding about mankind, the human and humanity, until humanization in humanity and health. We discuss the national humanization program in hospital care and reflect on this proposal and on the issue of humanization in Brazilian health care nowadays. Communication is indispensable to establish humanization, as well as technical and material conditions. Both users and health professionals need to be heard, building a network of dialogues to think and promote singular humanization actions. For this process to take effect, there is a need to involve the whole that makes up the health service. This group involves different professionals, such as managers, public policy makers, professional councils and education institutions.

  4. Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

    Directory of Open Access Journals (Sweden)

    Ciervo Alessandra

    2007-10-01

    Full Text Available Abstract Background Treatment of feline immunodeficiency virus (FIV infection has been hampered by the absence of a specific combination antiretroviral treatment (ART. Integrase strand transfer inhibitors (INSTIs are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs. Methods Phylogenetic analysis of lentiviral integrase (IN sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD. Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR. Results The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810. Conclusion We report a drug class (other than nucleosidic reverse transcriptase inhibitors that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound

  5. Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: Prediction of in vivo drug interactions

    Science.gov (United States)

    Ohyama, K; Nakajima, M; Suzuki, M; Shimada, N; Yamazaki, H; Yokoi, T

    2000-01-01

    Aims To predict the drug interactions of amiodarone and other drugs, the inhibitory effects and inactivation potential for human cytochrome P450 (CYP) enzymes by amiodarone and its N-dealkylated metabolite, desethylamiodarone were examined. Methods The inhibition or inactivation potency of amiodarone and desethylamiodarone for human CYP activities were investigated using microsomes from B-lymphoblastoid cell lines expressing CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The in vivo drug interactions of amiodarone and desethylamiodarone were predicted in vitro using the 1+Iu/Ki values. Results Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4-mediated activities with Ki values of 45.1–271.6 μm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 (Ki = 4.5 μm) and noncompetitively inhibited CYP2A6 (Ki = 13.5 μm), CYP2B6 (Ki = 5.4 μm), and CYP3A4 (Ki = 12.1 μm). The catalytic activities of CYP1A1 (Ki = 1.5 μm, α = 5.7), CYP1A2 (Ki = 18.8 μm, α = 2.6), CYP2C9 (Ki = 2.3 μm, α = 5.9), and CYP2C19 (Ki = 15.7 μm, α = 4.5) were inhibited by desethylamiodarone with mixed type. The 1+Iu/Ki values of desethylamiodarone were higher than those of amiodarone. Amiodarone inactivated CYP3A4, while desethylamiodarone inactivated CYP1A1, CYP1A2, CYP2B6, and CYP2D6. Conclusions The interactions between amiodarone and other drugs might occur via the inhibition of CYP activities by its N-dealkylated metabolite, desethylamiodarone, rather than by amiodarone itself. In addition, the inactivation of CYPs by desethylamiodarone as well as by amiodarone would also contribute to the drug interactions. PMID:10718780

  6. Global Law: Humanism and Human Rights

    Directory of Open Access Journals (Sweden)

    Leilane Serratine Grubba

    2016-06-01

    Full Text Available This article discusses the ideal of human rights before globalizatórios inflows. It begins with a general statement about the legal globalization, comparing it with the Global Law in the political and economic implications. Later, it approaches the ideal predicted with transnationalism. Proposes a reflection on the present Human Rights. Also, rethinks the lines of the complex web of Global Law, its institutions and its actors, which circulate between the public and private plans. There is no sense in space maintenance of the ideal of human rights only in the state or territory in international treaties originally linked to the states.

  7. Human Resource Accounting System

    Science.gov (United States)

    Cerullo, Michael J.

    1974-01-01

    Main objectives of human resource accounting systems are to satisfy the informational demands made by investors and by operating managers. The paper's main concern is with the internal uses of a human asset system. (Author)

  8. Telling the Human Story.

    Science.gov (United States)

    Richardson, Miles

    1987-01-01

    Proposes that one of the fundamental human attributes is telling stories. Explores the debate on whether Neanderthals possessed language ability. Discusses the role of the "human story" in teaching anthropology. (DH)

  9. Human Use Index (Future)

    Data.gov (United States)

    U.S. Environmental Protection Agency — Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the...

  10. Human Use Index

    Data.gov (United States)

    U.S. Environmental Protection Agency — Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the...

  11. Immunology Taught by Humans

    OpenAIRE

    Davis, Mark M

    2012-01-01

    After a half-century of mouse-dominated research, human immunology is making a comeback. Informed by mouse studies and powered by new techniques, human immune research is both advancing disease treatment and providing new insights into basic biology.

  12. Human Papillomavirus (HPV) Screening

    Science.gov (United States)

    ... Search Form Controls Cancel Submit Search The CDC Human Papillomavirus (HPV) Note: Javascript is disabled or is ... 6348 Email CDC-INFO U.S. Department of Health & Human Services HHS/Open USA.gov TOP

  13. Human Papillomavirus (HPV)

    Science.gov (United States)

    ... Listen Español Text Size Email Print Share HPV (Human Papillomavirus) Vaccine: What You Need to Know (VIS) ... Why get vaccinated? HPV vaccine prevents infection with human papillomavirus (HPV) types that are associated with many ...

  14. Human Papillomavirus (HPV) Vaccine

    Science.gov (United States)

    Why get vaccinated?HPV vaccine prevents infection with human papillomavirus (HPV) types that are associated with cause ... at http://www.cdc.gov/hpv. HPV Vaccine (Human Papillomavirus) Information Statement. U.S. Department of Health and ...

  15. Human Parainfluenza Viruses

    Science.gov (United States)

    ... Search Form Controls Cancel Submit Search The CDC Human Parainfluenza Viruses (HPIVs) Note: Javascript is disabled or ... CDC.gov . Recommend on Facebook Tweet Share Compartir Human parainfluenza viruses (HPIVs) commonly cause respiratory illnesses in ...

  16. Human bites (image)

    Science.gov (United States)

    Human bites present a high risk of infection. Besides the bacteria which can cause infection, there is ... the wound extends below the skin. Anytime a human bite has broken the skin, seek medical attention.

  17. HPV (Human Papillomavirus)

    Science.gov (United States)

    ... Consumers Consumer Information by Audience For Women HPV (human papillomavirus) Share Tweet Linkedin Pin it More sharing ... Español In Chamorro In Urdu In Vietnamese HPV (human papillomavirus) is a sexually transmitted virus. It is ...

  18. Humane Education in Action.

    Science.gov (United States)

    Savesky, Kathy

    1981-01-01

    Provides a brief history and description of a field test in the United States and Canada of the National Association for the Advancement of Humane Education's humane education curriculum guide for grades 1-6. (CS)

  19. Human papillomavirus molecular biology.

    Science.gov (United States)

    Harden, Mallory E; Munger, Karl

    Human papillomaviruses are small DNA viruses with a tropism for squamous epithelia. A unique aspect of human papillomavirus molecular biology involves dependence on the differentiation status of the host epithelial cell to complete the viral lifecycle. A small group of these viruses are the etiologic agents of several types of human cancers, including oral and anogenital tract carcinomas. This review focuses on the basic molecular biology of human papillomaviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Human Resource Management System

    OpenAIRE

    Navaz, A. S. Syed; Fiaz, A. S. Syed; Prabhadevi, C.; Sangeetha, V.; Gopalakrishnan, S.

    2013-01-01

    The paper titled HUMAN RESOURCE MANAGEMENT SYSTEM is basically concerned with managing the Administrator of HUMAN RESOURCE Department in a company. A Human Resource Management System, refers to the systems and processes at the intersection between human resource management and information technology. It merges HRM as a discipline and in particular its basic HR activities and processes with the information technology field, whereas the programming of data processing systems evolved into standa...

  1. Has Human Evolution Stopped?

    Directory of Open Access Journals (Sweden)

    Alan R. Templeton

    2010-07-01

    Full Text Available It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important implications for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool, thereby enhancing the potential for human evolution. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences.

  2. International Human Rights Kit.

    Science.gov (United States)

    Woito, Robert, Ed.

    Designed for students, educators, and citizens interested in human rights, the booklet presents resources for learning about the facts, perspectives, and existing procedures and institutions to promote human rights. Chapter one explores the relationship between human rights and war. Chapter two presents a self-survey to help readers clarify…

  3. Human Machine Learning Symbiosis

    Science.gov (United States)

    Walsh, Kenneth R.; Hoque, Md Tamjidul; Williams, Kim H.

    2017-01-01

    Human Machine Learning Symbiosis is a cooperative system where both the human learner and the machine learner learn from each other to create an effective and efficient learning environment adapted to the needs of the human learner. Such a system can be used in online learning modules so that the modules adapt to each learner's learning state both…

  4. Humanities Review Journal

    African Journals Online (AJOL)

    Humanities Review Journal is published in June and December by Humanities Research Forum. The Journal publishes original, well-researched papers, review essays, interviews, resume, and commentaries, which offer new insights into the various disciplines in the Humanities. The focus is on issues about Africa.

  5. A Human Rights Glossary.

    Science.gov (United States)

    Flowers, Nancy

    1998-01-01

    Presents a human rights glossary that includes definitions of basic terms, treaties, charters, and groups/organizations that have been featured in previous articles in this edition of "Update on Law-Related Education"; the human rights terms have been compiled as part of the celebration of the Universal Declaration of Human Rights…

  6. Esprit: A Humanities Magazine.

    Science.gov (United States)

    Parker, Donald G.; Capella, Barry John

    In March 1984, the first issue of "Esprit," a semi-annual humanities magazine for the 56 two-year colleges in New York State, was published. The magazine seeks to confront the apparent decline of student interest in the humanities, community doubts about the relevance of the humanities, and the seeming indifference to the special truths…

  7. Visible Human Project

    Science.gov (United States)

    ... NLM Mobile Gallery Site Navigation Home The Visible Human Project ® Overview The Visible Human Project ® is an outgrowth of the NLM's 1986 ... dimensional representations of the normal male and female human bodies. Acquisition of transverse CT, MR and cryosection ...

  8. Modeling Human Leukemia Immunotherapy in Humanized Mice

    Directory of Open Access Journals (Sweden)

    Jinxing Xia

    2016-08-01

    Full Text Available The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL, which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI, a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.

  9. From Human Past to Human Future

    Directory of Open Access Journals (Sweden)

    Robert G. Bednarik

    2013-01-01

    Full Text Available This paper begins with a refutation of the orthodox model of final Pleistocene human evolution, presenting an alternative, better supported account of this crucial phase. According to this version, the transition from robust to gracile humans during that period is attributable to selective breeding rather than natural selection, rendered possible by the exponential rise of culturally guided volitional choices. The rapid human neotenization coincides with the development of numerous somatic and neural detriments and pathologies. Uniformitarian reasoning based on ontogenic homology suggests that the cognitive abilities of hominins are consistently underrated in the unstable orthodoxies of Pleistocene archaeology. A scientifically guided review establishes developmental trajectories defining recent changes in the human genome and its expressions, which then form the basis of attempts to extrapolate from them into the future. It is suggested that continuing and perhaps accelerating unfavorable genetic changes to the human species, rather than existential threats such as massive disasters, pandemics, or astrophysical events, may become the ultimate peril of humanity.

  10. Human Beings And Water

    OpenAIRE

    Pakpahan, Putra Andika

    2016-01-01

    The writer of this paper on this writing is talking about the human beings and water. Water is one of the very fundamentally things that human beings need to keep their lives. Human beings sometimes do not realise that the water is very important for them because they actually cannot live their lives without the present of water. Human beings can keep their lives without rice, but cannot without water. For instances the use of water for human beings are domestic use, cooking, washing, bathing...

  11. Rethinking medical humanities.

    Science.gov (United States)

    Chiapperino, Luca; Boniolo, Giovanni

    2014-12-01

    This paper questions different conceptions of Medical Humanities in order to provide a clearer understanding of what they are and why they matter. Building upon former attempts, we defend a conception of Medical Humanities as a humanistic problem-based approach to medicine aiming at influencing its nature and practice. In particular, we discuss three main conceptual issues regarding the overall nature of this discipline: (i) a problem-driven approach to Medical Humanities; (ii) the need for an integration of Medical Humanities into medicine; (iii) the methodological requirements that could render Medical Humanities an effective framework for medical decision-making.

  12. Situating Human Sexual Conditioning.

    Science.gov (United States)

    Hoffmann, Heather

    2017-11-01

    Conditioning is often thought of as a basic, automatic learning process that has limited applicability to higher-level human behavior. In addition, conditioning is seen as separable from, and even secondary to, "innate" processes. These ideas involve some misconceptions. The aim of this article is to provide a clearer, more refined sense of human sexual conditioning. After providing some background information and reviewing what is known from laboratory conditioning studies, human sexual conditioning is compared to sexual conditioning in nonhumans, to "innate" sexual responding, and to other types of human learning processes. Recommendations for moving forward in human sexual conditioning research are included.

  13. BDNF and DYRK1A are variable and inversely correlated in lymphoblastoid cell lines from Down syndrome patients

    NARCIS (Netherlands)

    Tlili, A.; Hoischen, A.; Ripoll, C.; Benabou, E.; Badel, A.; Ronan, A.; Touraine, R.; Grattau, Y.; Stora, S.; Bon, B. van; Vries, B. de; Menten, B.; Bockaert, N.; Gecz, J.; Antonarakis, S.E.; Campion, D.; Potier, M.C.; Blehaut, H.; Delabar, J.M.; Janel, N.

    2012-01-01

    Down syndrome or trisomy 21 is the most common genetic disorder leading to mental retardation. One feature is impaired short- and long-term spatial memory, which has been linked to altered brain-derived neurotrophic factor (BDNF) levels. Mouse models of Down syndrome have been used to assess

  14. The mode of lymphoblastoid cell death in response to gas phase cigarette smoke is dose-dependent

    Directory of Open Access Journals (Sweden)

    Baltatzis George E

    2009-09-01

    Full Text Available Abstract Background Cigarette smoke (CS is the main cause in the development of chronic obstructive pulmonary disease (COPD, the pathogenesis of which is related to an extended inflammatory response. In this study, we investigated the effect of low and high doses of gas phase cigarette smoke (GPS on cultured lymphocyte progenitor cells, using techniques to assess cell viability and to elucidate whether cells die of apoptosis or necrosis upon exposure to different doses of GPS. Methods In our approach we utilised a newly-established system of exposure of cells to GPS that is highly controlled, accurately reproducible and simulates CS dosage and kinetics that take place in the smokers' lung. This system was used to study the mode of cell death upon exposure to GPS in conjunction with a range of techniques widely used for cell death studies such as Annexin V staining, activation of caspase -3, cytoplasmic release of cytochrome C, loss of mitochondrial membrane potential and DNA fragmentation. Results Low doses of GPS induced specific apoptotic indexes in CCRF-CEM cells. Specifically, cytochrome C release and cleaved caspase-3 were detected by immunofluorescence, upon treatment with 1-3 puffs GPS. At 4 h post-exposure, caspase-3 activation was observed in western blot analysis, showing a decreasing pattern as GPS doses increased. Concomitant with this behaviour, a dose-dependent change in Δψm depolarization was monitored by flow cytometry 2 h post-exposure, while at 4 h Δψm collapse was observed at the higher doses, indicative of a shift to a necrotic demise. A reduction in DNA fragmentation events produced by 5 puffs GPS as compared to those provoked by 3 puffs GPS, also pointed towards a necrotic response at the higher dose of GPS. Conclusion Collectively, our results support that at low doses gas phase cigarette smoke induces apoptosis in cultured T-lymphocytes, whereas at high doses GPS leads to necrotic death, by-passing the characteristic stage of caspase-3 activation and, thus, the apoptotic route.

  15. Integrated Environmental Modelling: human decisions, human challenges

    Science.gov (United States)

    Glynn, Pierre D.

    2015-01-01

    Integrated Environmental Modelling (IEM) is an invaluable tool for understanding the complex, dynamic ecosystems that house our natural resources and control our environments. Human behaviour affects the ways in which the science of IEM is assembled and used for meaningful societal applications. In particular, human biases and heuristics reflect adaptation and experiential learning to issues with frequent, sharply distinguished, feedbacks. Unfortunately, human behaviour is not adapted to the more diffusely experienced problems that IEM typically seeks to address. Twelve biases are identified that affect IEM (and science in general). These biases are supported by personal observations and by the findings of behavioural scientists. A process for critical analysis is proposed that addresses some human challenges of IEM and solicits explicit description of (1) represented processes and information, (2) unrepresented processes and information, and (3) accounting for, and cognizance of, potential human biases. Several other suggestions are also made that generally complement maintaining attitudes of watchful humility, open-mindedness, honesty and transparent accountability. These suggestions include (1) creating a new area of study in the behavioural biogeosciences, (2) using structured processes for engaging the modelling and stakeholder communities in IEM, and (3) using ‘red teams’ to increase resilience of IEM constructs and use.

  16. Oxytocin and Human Evolution.

    Science.gov (United States)

    Carter, C Sue

    2017-08-16

    A small, but powerful neuropeptide, oxytocin coordinates processes that are central to both human reproduction and human evolution. Also embedded in the evolution of the human nervous system are unique pathways necessary for modern human sociality and cognition. Oxytocin is necessary for facilitating the birth process, especially in light of anatomical restrictions imposed by upright human locomotion, which depends on a fixed pelvis. Oxytocin, by facilitating birth, allowed the development of a large cortex and a protective bony cranium. The complex human brain in turn permitted the continuing emergence of social sensitivity, complex thinking, and language. After birth is complete, oxytocin continues to support human development by providing direct nutrition, in the form of human milk, and emotional and intellectual support through high levels of maternal behavior and selective attachment. Oxytocin also encourages social sensitivity and reciprocal attunement, on the part of both the mother and child, which are necessary for human social behavior and for rearing an emotionally healthy human child. Oxytocin supports growth during development, resilience, and healing across the lifespan. Oxytocin dynamically moderates the autonomic nervous system, and effects of oxytocin on vagal pathways allowing high levels of oxygenation and digestion necessary to support adaptation in a complex environment. Finally, oxytocin has anti-oxidant and anti-inflammatory effects, helping to explain the pervasive adaptive consequences of social behavior for emotional and physical health.

  17. Human Capital and Sustainability

    Directory of Open Access Journals (Sweden)

    Garry Jacobs

    2011-01-01

    Full Text Available A study of sustainability needs to consider the role of all forms of capital—natural, biological, social, technological, financial, cultural—and the complex ways in which they interact. All forms of capital derive their value, utility and application from human mental awareness, creativity and social innovation. This makes human capital, including social capital, the central determinant of resource productivity and sustainability. Humanity has entered the Anthropocene Epoch in which human changes have become the predominant factor in evolution. Humanity is itself evolving from animal physicality to social vitality to mental individuality. This transition has profound bearing on human productive capabilities, adaptability, creativity and values, the organization of economy, public policy, social awareness and life styles that determine sustainability. This article examines the linkages between population, economic development, employment, education, health, social equity, cultural values, energy intensity and sustainability in the context of evolving human consciousness. It concludes that development of human capital is the critical determinant of long-term sustainability and that efforts to accelerate the evolution of human consciousness and emergence of mentally self-conscious individuals will be the most effective approach for ensuring a sustainable future. Education is the primary lever. Human choice matters.

  18. Humanities, Digital Humanities, Media studies, Internet studies

    DEFF Research Database (Denmark)

    Brügger, Niels

    Todays expanding digital landscape constitutes an important research object as well as the research environment for the Humanities at the beginning of the 21st century. Taking this state of affairs as a starting point this inaugural lecture presents a vision for how the digital affects the interp......Todays expanding digital landscape constitutes an important research object as well as the research environment for the Humanities at the beginning of the 21st century. Taking this state of affairs as a starting point this inaugural lecture presents a vision for how the digital affects...... the interplay between four areas which until now to a certain extent have been separated: Traditional Hu- manities, Digital Humanities, Media studies, and Internet studies. The vision is followed by an outline of how it can be unfolded in concrete activities, in the form of research projects, research...

  19. Effects of arsenic exposure on DNA methylation in cord blood samples from newborn babies and in a human lymphoblast cell line

    Directory of Open Access Journals (Sweden)

    Intarasunanont Ponpat

    2012-05-01

    Full Text Available Abstract Background Accumulating evidence indicates that in utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers. Recent studies suggest that arsenic carcinogenesis results from epigenetic changes, particularly in DNA methylation. This study aimed to investigate DNA methylation changes as a result of arsenic exposure in utero and in vitro. Methods For the exposure in utero study, a total of seventy-one newborns (fifty-five arsenic-exposed and sixteen unexposed newborns were recruited. Arsenic concentrations in the drinking water were measured, and exposure in newborns was assessed by measurement of arsenic concentrations in cord blood, nails and hair by Inductively Coupled Plasma Mass Spectrometry (ICP-MS. In the in vitro study, human lymphoblasts were treated with arsenite at 0-100 μM for two, four and eight hours (short-term and at 0, 0.5 and 1.0 μM for eight-weeks period (long-term. DNA methylation was analyzed in cord blood lymphocytes and lymphoblasts treated with arsenite in vitro. Global DNA methylation was determined as LINE-1 methylation using combined bisulfite restriction analysis (COBRA and total 5-methyldeoxycytidine (5MedC content which was determined by HPLC-MS/MS. Methylation of p53 was determined at the promoter region using methylation-specific restriction endonuclease digestion with MspI and HpaII. Results Results showed that arsenic-exposed newborns had significantly higher levels of arsenic in cord blood, fingernails, toenails and hair than those of the unexposed subjects and a slight increase in promoter methylation of p53 in cord blood lymphocytes which significantly correlated with arsenic accumulation in nails (p in vitro arsenite treatment in lymphoblastoid cells clearly demonstrated a significant global hypomethylation, determined as reduction in LINE-1 methylation and total 5-MedC content, and p53 hypermethylation (p in vitro treatment. Conclusions This

  20. Human Performance in Space

    Science.gov (United States)

    Jones, Patricia M.; Fiedler, Edna

    2010-01-01

    Human factors is a critical discipline for human spaceflight. Nearly every human factors research area is relevant to space exploration -- from the ergonomics of hand tools used by astronauts, to the displays and controls of a spacecraft cockpit or mission control workstation, to levels of automation designed into rovers on Mars, to organizational issues of communication between crew and ground. This chapter focuses more on the ways in which the space environment (especially altered gravity and the isolated and confined nature of long-duration spaceflight) affects crew performance, and thus has specific novel implications for human factors research and practice. We focus on four aspects of human performance: neurovestibular integration, motor control and musculo-skeletal effects, cognitive effects, and behavioral health. We also provide a sampler of recent human factors studies from NASA.

  1. Bursty human dynamics

    CERN Document Server

    Karsai, Márton; Kaski, Kimmo

    2018-01-01

    This book provides a comprehensive overview on emergent bursty patterns in the dynamics of human behaviour. It presents common and alternative understanding of the investigated phenomena, and points out open questions worthy of further investigations. The book is structured as follows. In the introduction the authors discuss the motivation of the field, describe bursty phenomena in case of human behaviour, and relate it to other disciplines. The second chapter addresses the measures commonly used to characterise heterogeneous signals, bursty human dynamics, temporal paths, and correlated behaviour. These definitions are first introduced to set the basis for the discussion of the third chapter about the observations of bursty human patterns in the dynamics of individuals, dyadic interactions, and collective behaviour. The subsequent fourth chapter discusses the models of bursty human dynamics. Various mechanisms have been proposed about the source of the heterogeneities in human dynamics, which leads to the in...

  2. Outsourcing in Human Resource

    OpenAIRE

    Oliver Pamelan

    2017-01-01

    The research paper aimed to contribute to the literature of Human Resource Management Planning and employment through the widely used function of the outsourcing human resource. The research paper is based on the description of the process of outsourcing with the reference to the theories of outsourcing management activities. It also explained the effects of this function through measuring the benefits and drawbacks of the outsourcing human resource while planning the employment strategies. T...

  3. The Humanities Matter! Infographic

    OpenAIRE

    Terras, M. M.; Priego, E.; Liu, A.; Rockwell, G.; Sinclair, S.; Henseler, C.; Thomas, L.

    2013-01-01

    The Humanities are academic disciplines that seek to understand and interpret the human experience, from individuals to entire cultures, engaging in the discovery, preservation, and communication of the past and present record to enable a deeper understanding of contemporary society. The Humanities encompass literature, classics, ancient and modern languages, history, philoso - phy, media studies, the fine and performing arts, and other related subjects. It can be a challenge to show the bene...

  4. Human Resource Planning

    OpenAIRE

    Lache Cãtãlina

    2011-01-01

    The objective of human resource planning is to adapt the human capital needed to develop the enterprises’ activities and to accomplish their priority objectives on the medium and/or short term. Human resource planning is a dynamic activity, time being an essential variable, both in what regards the quantitative side (adapting the number of jobs according to the organisation’s evolution in time) and the qualitative side (harmonising the jobs’ complexity with technological changes). The quantit...

  5. Crimes against humanity

    OpenAIRE

    Podlahová, Veronika

    2014-01-01

    57 Resumé "Crimes against humanity" (the thesis title) Crimes against humanity constitute one of the three integral parts of "crimes under international law." At the same time they represent the most severe form of infringement of fundamental human rights that are as the principle value protected by the international community and its peremptory rules. Although these crimes have not emerged during the 20th century for the first time, it was the World War II., which established the term "crime...

  6. Modern Human Capital Management

    OpenAIRE

    Feldberger, Madita

    2008-01-01

    Title: Modern Human Capital Management Seminar date: 30th of May 2008 Course: Master thesis in Business Administration, 15 ECTS Authors: Madita Feldberger Supervisor: Lars Svensson Keywords: Human capital, SWOT Analysis, Strategic Map, Balanced Scorecard Research Problem: Despite of the success of Human Capital Management (HCM) in research it did not arrive yet in the HR departments of many companies. Numerous firms even have problems to set their strategic goals with focus on HR. The HR Bala...

  7. Human hemoglobin genetics

    Energy Technology Data Exchange (ETDEWEB)

    Honig, G.R.; Adams, J.G.

    1986-01-01

    This book contains the following 10 chapters: Introduction; The Human Hemoglobins; The Human Globin Genes; Hemoglobin Synthesis and Globin Gene Expression; The Globin Gene Mutations - A. Mechanisms and Classification; The Globin Gene Mutations - B. Their Phenotypes and Clinical Expression; The Genetics of the Human Globin Gene Loci: Formal Genetics and Gene Linkage; The Geographic Distribution of Globin Gene Variation; Labortory Identification, Screening, Education, and Counseling for Abnormal Hemoglobins and Thalassemias; and Approaches to the Treatment of the Hemoglobin Disorders.

  8. Human Performance Research Center

    Data.gov (United States)

    Federal Laboratory Consortium — Biochemistry:Improvements in energy metabolism, muscular strength and endurance capacity have a basis in biochemical and molecular adaptations within the human body....

  9. Human cloning 2001.

    Science.gov (United States)

    Healy, David L; Weston, Gareth; Pera, Martin F; Rombauts, Luk; Trounson, Alan O

    2002-05-01

    This review summaries human cloning from a clinical perspective. Natural human clones, that is, monozygotic twins, are increasing in the general community. Iatrogenic human clones have been produced for decades in infertile couples given fertility treatment such as ovulation induction. A clear distinction must be made between therapeutic cloning using embryonic stem cells and reproductive cloning attempts. Unlike the early clinical years of in vitro fertilization, with cloning there is no animal model that is safe and dependable. Until there is such a model, 'Dolly'-style human cloning is medically unacceptable.

  10. Robotics for Human Exploration

    Science.gov (United States)

    Fong, Terrence; Deans, Mathew; Bualat, Maria

    2013-01-01

    Robots can do a variety of work to increase the productivity of human explorers. Robots can perform tasks that are tedious, highly repetitive or long-duration. Robots can perform precursor tasks, such as reconnaissance, which help prepare for future human activity. Robots can work in support of astronauts, assisting or performing tasks in parallel. Robots can also perform "follow-up" work, completing tasks designated or started by humans. In this paper, we summarize the development and testing of robots designed to improve future human exploration of space.

  11. [Human physiology: kidney].

    Science.gov (United States)

    Natochin, Iu V

    2010-01-01

    The content of human physiology as an independent part of current physiology is discussed. Substantiated is the point that subjects of human physiology are not only special sections of physiology where functions are inherent only in human (physiology of intellectual activity, speech, labor, sport), but also in peculiarities of functions, specificity of regulation of each of physiological systems. By the example of physiology of kidney and water-salt balance there are shown borders of norm, peculiarities of regulation in human, new chapters of renal physiology which have appeared in connection with achievements of molecular physiology.

  12. Challenges for Virtual Humans in Human Computing

    NARCIS (Netherlands)

    Reidsma, Dennis; Ruttkay, Z.M.; Huang, T; Nijholt, Antinus; Pantic, Maja; Pentland, A.

    The vision of Ambient Intelligence (AmI) presumes a plethora of embedded services and devices that all endeavor to support humans in their daily activities as unobtrusively as possible. Hardware gets distributed throughout the environment, occupying even the fabric of our clothing. The environment

  13. SERUM BETA HUMAN CHORIONIC GONADOTROPHIN IN HUMAN ...

    African Journals Online (AJOL)

    Objectives To determine whether raised levels of serum Beta -HCG) are associated with higher grade and Human Chorionic Gonadotrophin ( -HCG in higher category tumors and whether in patients with raised levels of -HCG their sera the rise (above normal range) and the fall (to normal) in levels would correspond with ...

  14. Developing Human Resources through Actualizing Human Potential

    Science.gov (United States)

    Clarken, Rodney H.

    2012-01-01

    The key to human resource development is in actualizing individual and collective thinking, feeling and choosing potentials related to our minds, hearts and wills respectively. These capacities and faculties must be balanced and regulated according to the standards of truth, love and justice for individual, community and institutional development,…

  15. Skin and the non-human human

    DEFF Research Database (Denmark)

    Rösing, Lilian Munk

    2013-01-01

    ) article 'Visualizing the mind: Looking at Titian's Flaying of Marsyas', addressing features of the painting not commented on by Hart, and supplementing Hart's (Kleinian) theoretical frame by involving Didier Anzieu's 'skin ego', Slavoj Zizek's concept of the 'non-human', Giorgio Agamben's term...

  16. Human Resource Accounting

    Science.gov (United States)

    Woodruff, Robert L., Jr.

    1973-01-01

    An interview is reported which discussed the implications for the hiring, recruiting, screening and development of employees in the light of human resource accounting, here defined as the identification, accumulation and dissemination of information about human resources in dollar terms. (SA)

  17. Human-centred Governance

    DEFF Research Database (Denmark)

    Bason, Christian

    2017-01-01

    Design approaches are now being applied all over the world as a powerful approach to innovating public policies and services. Christian Bason, author of Leading public design: Discovering human-centred governance, argues that by bringing design methods into play, public managers can lead change...... with citizens at the centre, and discover a new model for steering public organisations: human-centred governance....

  18. Human Mind Maps

    Science.gov (United States)

    Glass, Tom

    2016-01-01

    When students generate mind maps, or concept maps, the maps are usually on paper, computer screens, or a blackboard. Human Mind Maps require few resources and little preparation. The main requirements are space where students can move around and a little creativity and imagination. Mind maps can be used for a variety of purposes, and Human Mind…

  19. Dynamics of human movement

    NARCIS (Netherlands)

    Koopman, Hubertus F.J.M.

    2010-01-01

    The part of (bio)mechanics that studies the interaction of forces on the human skeletal system and its effect on the resulting movement is called rigid body dynamics. Some basic concepts are presented: A mathematical formulation to describe human movement and how this relates on the mechanical loads

  20. Biodemography of human ageing

    DEFF Research Database (Denmark)

    Vaupel, James W

    2010-01-01

    Human senescence has been delayed by a decade. This finding, documented in 1994 and bolstered since, is a fundamental discovery about the biology of human ageing, and one with profound implications for individuals, society and the economy. Remarkably, the rate of deterioration with age seems...

  1. the human genome project

    African Journals Online (AJOL)

    Enrique

    have resulted in the biological diversity, both past and present, on this planet. RAJ RAMESAR. MSc, PhD. Professor and Head. Division of Human Genetics. Faculty of Health Sciences. University of Cape Town. Raj Ramesar serves as Director of the MRC. Human Genetics Research Unit and. CANSA's Colorectal Cancer ...

  2. Translating the human microbiome

    NARCIS (Netherlands)

    Brown, J.; Vos, de W.M.; Distefano, P.S.; Doré, J.; Huttenhower, C.; Knight, R.; Lawley, T.D.; Raes, J.; Turnbaugh, P.

    2013-01-01

    Over the past decade, an explosion of descriptive analyses from initiatives, such as the Human Microbiome Project (HMP) and the MetaHIT project, have begun to delineate the human microbiome. Inhabitants of the intestinal tract, nasal passages, oral cavities, skin, gastrointestinal tract and

  3. Damping Effect of Humans

    DEFF Research Database (Denmark)

    Pedersen, Lars

    Passive humans (sitting or standing) might well be present on flooring-systems, footbridges or other structures that carry humans. An active croud of people might generate structural vibrations, and these might be problematic. The passive crowd of people, however, will interact with the structura...

  4. Evaluating the Humanities

    Science.gov (United States)

    Brody, Howard

    2013-01-01

    How can one measure the value of teaching the humanities? The problem of assessment and accountability is prominent today, of course, in secondary and higher education. It is perhaps even more acute for those who teach the humanities in nontraditional settings, such as medical and other professional schools. The public assumes that academes can…

  5. The Humanities' Value

    Science.gov (United States)

    Harpham, Geoffrey Galt

    2009-01-01

    Why should society support the humanities when so many people are suffering from the effects of the economic crisis? What claim do the humanities, or scholarship generally, have on increasingly limited resources? Shouldn't such pursuits be considered luxuries at a time when people should be focusing on essentials? The alleviation of human…

  6. Manage "Human Capital" Strategically

    Science.gov (United States)

    Odden, Allan

    2011-01-01

    To strategically manage human capital in education means restructuring the entire human resource system so that schools not only recruit and retain smart and capable individuals, but also manage them in ways that support the strategic directions of the organization. These management practices must be aligned with a district's education improvement…

  7. Incorporating Human Interindividual Biotransformation ...

    Science.gov (United States)

    The protection of sensitive individuals within a population dictates that measures other than central tendencies be employed to estimate risk. The refinement of human health risk assessments for chemicals metabolized by the liver to reflect data on human variability can be accomplished through (1) the characterization of enzyme expression in large banks of human liver samples, (2) the employment of appropriate techniques for the quantification and extrapolation of metabolic rates derived in vitro, and (3) the judicious application of physiologically based pharmacokinetic (PBPK) modeling. While in vitro measurements of specific biochemical reactions from multiple human samples can yield qualitatively valuable data on human variance, such measures must be put into the perspective of the intact human to yield the most valuable predictions of metabolic differences among humans. For quantitative metabolism data to be the most valuable in risk assessment, they must be tied to human anatomy and physiology, and the impact of their variance evaluated under real exposure scenarios. For chemicals metabolized in the liver, the concentration of parent chemical in the liver represents the substrate concentration in the MichaelisMenten description of metabolism. Metabolic constants derived in vitro may be extrapolated to the intact liver, when appropriate conditions are met. Metabolic capacity Vmax; the maximal rate of the reaction) can be scaled directly to the concentration

  8. Damping Effect of Humans

    DEFF Research Database (Denmark)

    Pedersen, Lars

    Passive humans (sitting or standing) might well be present on flooring-systems, footbridges or other structures that carry humans. An active croud of people might generate structural vibrations, and these might be problematic. The passive crowd of people, however, will interact with the structural...

  9. HUMAN PARAGONIMIASIS IN AFRICA

    African Journals Online (AJOL)

    Emmanuel Ameh

    Abstract. An up-to-date review on human paragonimiasis in Africa was carried out to determine the current geographical distribution of human cases and analyze the animal reservoir, snails and crustaceans which intervene in the local life cycle of Paragonimus species. Two countries, i.e., Cameroon and. Nigeria, were ...

  10. Human Rights, History of

    NARCIS (Netherlands)

    de Baets, Antoon; Wright, James

    2015-01-01

    In this article, six basic debates about human rights are clarified from a historical perspective: the origin of human rights as moral rights connected to the natural law doctrine and opposed to positive rights; the wave of criticism of their abstract and absolute character by nineteenth-century

  11. Modeling human color categorization

    NARCIS (Netherlands)

    van den Broek, Egon; Schouten, Th.E.; Kisters, P.M.F.

    A unique color space segmentation method is introduced. It is founded on features of human cognition, where 11 color categories are used in processing color. In two experiments, human subjects were asked to categorize color stimuli into these 11 color categories, which resulted in markers for a

  12. Fungi that Infect Humans.

    Science.gov (United States)

    Köhler, Julia R; Hube, Bernhard; Puccia, Rosana; Casadevall, Arturo; Perfect, John R

    2017-06-01

    Fungi must meet four criteria to infect humans: growth at human body temperatures, circumvention or penetration of surface barriers, lysis and absorption of tissue, and resistance to immune defenses, including elevated body temperatures. Morphogenesis between small round, detachable cells and long, connected cells is the mechanism by which fungi solve problems of locomotion around or through host barriers. Secretion of lytic enzymes, and uptake systems for the released nutrients, are necessary if a fungus is to nutritionally utilize human tissue. Last, the potent human immune system evolved in the interaction with potential fungal pathogens, so few fungi meet all four conditions for a healthy human host. Paradoxically, the advances of modern medicine have made millions of people newly susceptible to fungal infections by disrupting immune defenses. This article explores how different members of four fungal phyla use different strategies to fulfill the four criteria to infect humans: the Entomophthorales, the Mucorales, the Ascomycota, and the Basidiomycota. Unique traits confer human pathogenic potential on various important members of these phyla: pathogenic Onygenales comprising thermal dimorphs such as Histoplasma and Coccidioides; the Cryptococcus spp. that infect immunocompromised as well as healthy humans; and important pathogens of immunocompromised patients-Candida, Pneumocystis, and Aspergillus spp. Also discussed are agents of neglected tropical diseases important in global health such as mycetoma and paracoccidiomycosis and common pathogens rarely implicated in serious illness such as dermatophytes. Commensalism is considered, as well as parasitism, in shaping genomes and physiological systems of hosts and fungi during evolution.

  13. Businesses’ human rights responsibilities

    Directory of Open Access Journals (Sweden)

    Corinne Lewis

    2012-12-01

    Full Text Available There is no international human rights law standard that expresslyprohibits businesses’ arbitrary displacement of persons. Businessesdo, however, have the responsibility to avoid infringements of humanrights that could lead to displacement and also to take actions toremedy their human rights violations that might lead to displacement.

  14. Global Journal of Humanities

    African Journals Online (AJOL)

    Journal Homepage Image. Global Journal of Humanities is aimed at promoting reasearch in all areas of Humanities including philosophy, languages, linguistics, literature, history, fine/applied arts, theater arts, architecture, etc. Visit the Global Journal Series website here: http://www.globaljournalseries.com/ ...

  15. Human Granulocytic Anaplasmosis, Japan

    Science.gov (United States)

    Gaowa; Wuritu; Kawamori, Fumihiko; Wu, Dongxing; Yoshikawa, Yuko; Chiya, Seizou; Fukunaga, Kazutoshi; Funato, Toyohiko; Shiojiri, Masaaki; Nakajima, Hideki; Hamauzu, Yoshiji; Takano, Ai; Kawabata, Hiroki; Ando, Shuji; Kishimoto, Toshio

    2013-01-01

    We retrospectively confirmed 2 cases of human Anaplasma phagocytophilum infection. Patient blood samples contained unique p44/msp2 for the pathogen, and antibodies bound to A. phagocytophilum antigens propagated in THP-1 rather than HL60 cells. Unless both cell lines are used for serodiagnosis of rickettsiosis-like infections, cases of human granulocytic anaplasmosis could go undetected. PMID:23460988

  16. Humane Education Projects Handbook.

    Science.gov (United States)

    Junior League of Ogden, UT.

    This handbook was developed to promote interest in humane education and to encourage the adoption of humane education projects. Although specifically designed to assist Junior Leagues in developing such projects, the content should prove valuable to animal welfare organizations, zoos, aquariums, nature centers, and other project-oriented groups…

  17. Human migraine models

    DEFF Research Database (Denmark)

    Iversen, Helle Klingenberg

    2001-01-01

    , which is a human experience. A set-up for investigations of experimental headache and migraine in humans, has been evaluated and headache mechanisms explored by using nitroglycerin and other headache-inducing agents. Nitric oxide (NO) or other parts of the NO activated cascade seems to be responsible...

  18. Overophedning af det humane

    DEFF Research Database (Denmark)

    Larsen, Steen Nepper

    2016-01-01

    Anmelder Marius Gudmand-Høyer, Sverre Raffnsøe og Morten Raffnsøe-Møller (red.): "Den humane vending. En antologi", Aarhus Universitetsforlag......Anmelder Marius Gudmand-Høyer, Sverre Raffnsøe og Morten Raffnsøe-Møller (red.): "Den humane vending. En antologi", Aarhus Universitetsforlag...

  19. The Human Technology

    DEFF Research Database (Denmark)

    Fausing, Bent

     Bent Fausing  "The Humane Technology", abstract (for The Two Cultures: Balancing Choices and Effects Oxford University July 20-26, 2008). The paper will investigate the use of technology in everyday aesthetics such as TV-commercials for mobile phones for Nokia, which slogan is, as it is well known...... for as a better humanity.      The paper will investigate how the two cultures are combined in this way in a TV-commercial. Technology points, is the conclusion, towards a forgotten pre-human and not to the often-motioned post-human condition.    ......, "Nokia - connecting people". Which function does this technology get in narratives, images, interactions and affects here?      The mobile phone and its digital camera are depicted as being able to make a unique human presence and interaction. The medium, the technology is a necessary helper to get...

  20. Humanity at the Edge

    DEFF Research Database (Denmark)

    Svendsen, Mette N.; Gjødsbøl, Iben M.; Dam, Mie S.

    2017-01-01

    At the heart of anthropology and the social sciences lies a notion of human existence according to which humans and animals share the basic need for food, but only humans have the capacity for morality. Based on fieldwork in a pig laboratory, a neonatal intensive care unit (NICU), and a dementia...... nursing home, we follow practices of feeding precarious lives lacking most markers of human personhood, including the exercise of moral judgment. Despite the absence of such markers, laboratory researchers and caregivers in these three sites do not abstain from engaging in questions about the moral status...... of the piglets, infants, and people with dementia in their care. They continually negotiate how their charges belong to the human collectivity and thereby challenge the notion of ‘the human’ that is foundational to anthropology. Combining analytical approaches that do not operate with a fixed boundary between...

  1. Refractoriness in human atria

    DEFF Research Database (Denmark)

    Skibsbye, Lasse; Jespersen, Thomas; Christ, Torsten

    2016-01-01

    rhythm and chronic atrial fibrillation tissues and was neither affected by changes in frequency (1 vs. 3Hz). CONCLUSIONS: Our results suggest a preferentially voltage-dependent, rather than time-dependent, effect with respect to refractoriness at physiologically relevant rates in human atria. However...... drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation. This study therefore aims to characterise how sodium channel inactivation affects refractoriness in human atria. METHODS AND RESULTS: Steady......-state activation and inactivation parameters of sodium channels measured in vitro in isolated human atrial cardiomyocytes were used to parameterise a mathematical human atrial cell model. Action potential data were acquired from human atrial trabeculae of patients in either sinus rhythm or chronic atrial...

  2. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogeno...... of the solutions used in the study nor was it present as a residual material in blank HPLC runs. CONCLUSIONS: Morphine is present in human gliomas, suggesting that it may exert an action that effects tumour physiology/pathology.......BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  3. The human cell atlas

    DEFF Research Database (Denmark)

    Regev, Aviv; Teichmann, Sarah A.; Lander, Eric S.

    2017-01-01

    The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international...... collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells...... in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early...

  4. Designing Human Technologies

    DEFF Research Database (Denmark)

    Simonsen, Jesper

    Design is increasingly becoming a part of the university curriculum and research agenda. The keynote present and discuss Designing Human Technologies – an initiative aiming at establishing a design oriented main subject area alongside traditional main subject areas such as Natural Science......, the Humanities, and Social Science. The initiative broadens the perspective of IS and recognize reflections on aesthetics, ethics, values, connections to politics, and strategies for enabling a better future as legitimate parts of the research agenda. Designing Human Technologies is a design-oriented Strategic...... Research Initiative supporting Roskilde University’s new Humanities and Technology bachelor programme (‘HumTek’), and its three dimensions: Design, Humanities, and Technology. The research initiative involves 70 researchers from different departments and research groups at Roskilde University through...

  5. Human Milk Banking.

    Science.gov (United States)

    Haiden, Nadja; Ziegler, Ekhard E

    2016-01-01

    Human milk banks play an essential role by providing human milk to infants who would otherwise not be able to receive human milk. The largest group of recipients are premature infants who derive very substantial benefits from it. Human milk protects premature infants from necrotizing enterocolitis and from sepsis, two devastating medical conditions. Milk banks collect, screen, store, process, and distribute human milk. Donating women usually nurse their own infants and have a milk supply that exceeds their own infants' needs. Donor women are carefully selected and are screened for HIV-1, HIV-2, human T-cell leukemia virus 1 and 2, hepatitis B, hepatitis C, and syphilis. In the milk bank, handling, storing, processing, pooling, and bacterial screening follow standardized algorithms. Heat treatment of human milk diminishes anti-infective properties, cellular components, growth factors, and nutrients. However, the beneficial effects of donor milk remain significant and donor milk is still highly preferable in comparison to formula. © 2017 S. Karger AG, Basel.

  6. Human Power Empirically Explored

    Energy Technology Data Exchange (ETDEWEB)

    Jansen, A.J.

    2011-01-18

    Harvesting energy from the users' muscular power to convert this into electricity is a relatively unknown way to power consumer products. It nevertheless offers surprising opportunities for product designers; human-powered products function independently from regular power infrastructure, are convenient and can be environmentally and economically beneficial. This work provides insight into the knowledge required to design human-powered energy systems in consumer products from a scientific perspective. It shows the developments of human-powered products from the first introduction of the BayGen Freeplay radio in 1995 till current products and provides an overview and analysis of 211 human-powered products currently on the market. Although human power is generally perceived as beneficial for the environment, this thesis shows that achieving environmental benefit is only feasible when the environmental impact of additional materials in the energy conversion system is well balanced with the energy demands of the products functionality. User testing with existing products showed a preference for speeds in the range of 70 to 190 rpm for crank lengths from 32 to 95 mm. The muscular input power varied from 5 to 21 W. The analysis of twenty graduation projects from the Faculty of Industrial Design Engineering in the field of human-powered products, offers an interesting set of additional practice based design recommendations. The knowledge based approach of human power is very powerful to support the design of human-powered products. There is substantial potential for improvements in the domains energy conversion, ergonomics and environment. This makes that human power, when applied properly, is environmentally and economically competitive over a wider range of applications than thought previously.

  7. Genetics of human hydrocephalus.

    Science.gov (United States)

    Zhang, Jun; Williams, Michael A; Rigamonti, Daniele

    2006-10-01

    Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders.A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic components and mechanism of this complex disorder may offer us significant insights into the molecular etiology of impaired brain development and an accumulation of the cerebrospinal fluid in cerebral compartments during the pathogenesis of hydrocephalus. Genetic studies in animal models have started to open the way for understanding the underlying pathology of hydrocephalus. At least 43 mutants/loci linked to hereditary hydrocephalus have been identified in animal models and humans. Up to date, 9 genes associated with hydrocephalus have been identified in animal models. In contrast, only one such gene has been identified in humans. Most of known hydrocephalus gene products are the important cytokines, growth factors or related molecules in the cellular signal pathways during early brain development. The current molecular genetic evidence from animal models indicate that in the early development stage, impaired and abnormal brain development caused by abnormal cellular signaling and functioning, all these cellular and developmental events would eventually lead to the congenital hydrocephalus. Owing to our very primitive knowledge of the genetics and molecular pathogenesis of human hydrocephalus, it is difficult to evaluate whether data gained from animal models can be extrapolated to humans. Initiation of a large population genetics study in humans will certainly provide invaluable information about the molecular and cellular etiology and the developmental mechanisms of human

  8. Human exposure to aluminium.

    Science.gov (United States)

    Exley, Christopher

    2013-10-01

    Human activities have circumvented the efficient geochemical cycling of aluminium within the lithosphere and therewith opened a door, which was previously only ajar, onto the biotic cycle to instigate and promote the accumulation of aluminium in biota and especially humans. Neither these relatively recent activities nor the entry of aluminium into the living cycle are showing any signs of abating and it is thus now imperative that we understand as fully as possible how humans are exposed to aluminium and the future consequences of a burgeoning exposure and body burden. The aluminium age is upon us and there is now an urgent need to understand how to live safely and effectively with aluminium.

  9. Aluminium in human sweat.

    Science.gov (United States)

    Minshall, Clare; Nadal, Jodie; Exley, Christopher

    2014-01-01

    It is of burgeoning importance that the human body burden of aluminium is understood and is measured. There are surprisingly few data to describe human excretion of systemic aluminium and almost no reliable data which relate to aluminium in sweat. We have measured the aluminium content of sweat in 20 healthy volunteers following mild exercise. The concentration of aluminium ranged from 329 to 5329μg/L. These data equate to a daily excretion of between 234 and 7192μg aluminium and they strongly suggest that perspiration is the major route of excretion of systemic aluminium in humans. Copyright © 2013 Elsevier GmbH. All rights reserved.

  10. Wear in human knees

    Directory of Open Access Journals (Sweden)

    M.L. Wang

    2015-06-01

    Full Text Available Wear occurs in natural knee joints and plays a pivotal factor in causing articular cartilage degradation in osteoarthritis (OA processes. Wear particles are produced in the wear process and get involved in inflammation of human knees. This review presents progresses in the mechanical and surface morphological studies of articular cartilages, wear particles analysis techniques for wear studies and investigations of human knee synovial fluid in wear of human knees. Future work is also included for further understanding of OA symptoms and their relations which may shed light on OA causes.

  11. Human Genome Project

    Energy Technology Data Exchange (ETDEWEB)

    Block, S. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Cornwall, J. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Dally, W. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Dyson, F. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Fortson, N. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Joyce, G. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Kimble, H. J. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Lewis, N. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Max, C. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Prince, T. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Schwitters, R. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Weinberger, P. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Woodin, W. H. [The MITRE Corporation, McLean, VA (US). JASON Program Office

    1998-01-04

    The study reviews Department of Energy supported aspects of the United States Human Genome Project, the joint National Institutes of Health/Department of Energy program to characterize all human genetic material, to discover the set of human genes, and to render them accessible for further biological study. The study concentrates on issues of technology, quality assurance/control, and informatics relevant to current effort on the genome project and needs beyond it. Recommendations are presented on areas of the genome program that are of particular interest to and supported by the Department of Energy.

  12. Human Capital and Development

    OpenAIRE

    Rodolfo E. Manuelli

    2015-01-01

    Perhaps no question has attracted as much attention in the economics literature as “Why are some countries richer than others?” In this article, the author revisits the “development problem” and provides some estimates of the importance of human capital in accounting for cross-country differences in output per worker. His results suggest that human capital has a central role in determining the wealth of nations and that the quality of human capital varies systematically with the level of deve...

  13. Human pancreas development.

    Science.gov (United States)

    Jennings, Rachel E; Berry, Andrew A; Strutt, James P; Gerrard, David T; Hanley, Neil A

    2015-09-15

    A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes. © 2015. Published by The Company of Biologists Ltd.

  14. Human dignity and bioethics

    Directory of Open Access Journals (Sweden)

    Marjanović Miloš

    2013-01-01

    Full Text Available By opening the field of bioethics followed a new wave of intense debate on the theological, philosophical and legal significance of the concept of human dignity . Exactly ten years ago (December 2003 American bioethicist Ruth Maclin has proposed to divest ourselves of the concept of human dignity because it is vague, useless and redundant and that, without any loss, we can replace it by the ethical principle of personal autonomy. Her article was followed by harsh reactions and opposite views. What is this term in so broad, almost inflationary and opposite use is not a reason to deprive him, but, on the contrary, it shows how important it is and that it should be determined at least outline. As universal values and general concept, the human dignity has no pre-defined and narrow, precise meaning. It is more an evaluation horizon, the guiding principle and regulatory ideas that must constantly define and codify by many guaranted human rights and fundamental freedoms. As generic notion of each reasonable law, it is their foundation and a common denominator, legitimising basis of natural but also of positive law. As intrinsic and static value which means the humaneness, the humanity it is absolute, inherent to every human being without distinction and conditioning, as a unique and unrepeatable creation. In this meaning, the dignity is the obligation and limitation of the state, society and each of us. As an ethical and dynamic category, it is not given to us, but it is assign to us, and it is not in us, but always before us, as a guide of our actions in accordance with virtues, to treat ourselves, each other and the nature in a human way. The century in which we live is named the century of molecular biology and genetic engineering because of the enormous potential but also risks to human dignity. Because of that human dignity has become a central principle in all international documents relating to the human genome, genetics and bioethics, adopted

  15. Sulfatases and human disease.

    Science.gov (United States)

    Diez-Roux, Graciana; Ballabio, Andrea

    2005-01-01

    Sulfatases are a highly conserved family of proteins that cleave sulfate esters from a wide range of substrates. The importance of sulfatases in human metabolism is underscored by the presence of at least eight human monogenic diseases caused by the deficiency of individual sulfatases. Sulfatase activity requires a unique posttranslational modification, which is impaired in patients with multiple sulfatase deficiency (MSD) due to a mutation of the sulfatase modifying factor 1 (SUMF1). Here we review current knowledge and future perspectives on the evolution of the sulfatase gene family, on the role of these enzymes in human metabolism, and on new developments in the therapy of sulfatase deficiencies.

  16. Propelling medical humanities in China.

    Science.gov (United States)

    Tang, Wei

    2017-05-23

    Advances in the study of the medical humanities and medical humanities education have been made over the past few decades. Many influential journals have published articles examining the role of medical humanities and medical humanities education, the development and evaluation of medical humanities, and the design of a curriculum for medical humanities education in Western countries. However, most articles related to medical humanities in China were published in Chinese, moreover, researchers have worked in relative isolation and published in disparate journals, so their work has not been systematically presented to and evaluated by international readers. The six companion articles featured in this issue describe the current status and challenge of medical humanities and medical humanities education in China in the hope of providing international readers with a novel and meaningful glimpse into medical humanities in China. This Journal is calling for greater publication of research on medical humanities and medical humanities education to propel medical humanities in China.

  17. Human Research Program

    Data.gov (United States)

    National Aeronautics and Space Administration — Strategically, the HRP conducts research and technology development that: 1) enables the development or modification of Agency-level human health and performance...

  18. The human urine metabolome

    National Research Council Canada - National Science Library

    Bouatra, Souhaila; Aziat, Farid; Mandal, Rupasri; Guo, An Chi; Wilson, Michael R; Knox, Craig; Bjorndahl, Trent C; Krishnamurthy, Ramanarayan; Saleem, Fozia; Liu, Philip; Dame, Zerihun T; Poelzer, Jenna; Huynh, Jessica; Yallou, Faizath S; Psychogios, Nick; Dong, Edison; Bogumil, Ralf; Roehring, Cornelia; Wishart, David S

    2013-01-01

    .... Many of these compounds are poorly characterized and poorly understood. In an effort to improve our understanding of this biofluid we have undertaken a comprehensive, quantitative, metabolome-wide characterization of human urine...

  19. The bionic human

    OpenAIRE

    Francalanza, Emmanuel;

    2013-01-01

    Faster, fitter and flawless? What would it take to build a Bionic Human? Emmanuel Francalanza delved into research at the Faculty of Engineering to see how Malta could contribute. 3D Art by Jean Claude Vancell.

  20. Human Resource Planning

    Science.gov (United States)

    Hoffman, W. H.; Wyatt, L. L.

    1977-01-01

    By using the total resource approach, we have focused attention on the need to integrate human resource planning with other business plans and highlighted the importance of a productivity strategy. (Author)

  1. Human factors in aviation

    National Research Council Canada - National Science Library

    Salas, Eduardo; Maurino, Daniel E

    2010-01-01

    .... HFA offers a comprehensive overview of the topic, taking readers from the general to the specific, first covering broad issues, then the more specific topics of pilot performance, human factors...

  2. Extraterritorial Human Rights Obligations

    DEFF Research Database (Denmark)

    Amsinck Boie, Hans Nikolaj; Torp, Kristian

    The book addresses the issue of corporate respect for human rights by examining if and how states are obligated to ensure that corporations originating from their jurisdiction respect human rights when they operate abroad. The existence of such a duty is much debated by academics at national...... and international level, and in an attempt to bring something new to the table, the book examines both if states have extraterritorial obligations in regard to their corporations and what can be required of states under such an obligation. The complex issue of states and corporate respect for human rights cannot...... adequately be addressed without including the approach to the problem taken in practice; Corporate Social Responsibility, CSR. The book therefore draws upon the concept of CSR and the approaches developed here and discusses whether states may utilize the CSR-based concept of human rights due diligence...

  3. Aerospace Human Factors

    Science.gov (United States)

    Jordan, Kevin

    1999-01-01

    The following contains the final report on the activities related to the Cooperative Agreement between the human factors research group at NASA Ames Research Center and the Psychology Department at San Jose State University. The participating NASA Ames division has been, as the organization has changed, the Aerospace Human Factors Research Division (ASHFRD and Code FL), the Flight Management and Human Factors Research Division (Code AF), and the Human Factors Research and Technology Division (Code IH). The inclusive dates for the report are November 1, 1984 to January 31, 1999. Throughout the years, approximately 170 persons worked on the cooperative agreements in one capacity or another. The Cooperative Agreement provided for research personnel to collaborate with senior scientists in ongoing NASA ARC research. Finally, many post-MA/MS and post-doctoral personnel contributed to the projects. It is worth noting that 10 former cooperative agreement personnel were hired into civil service positions directly from the agreements.

  4. Journal of Humanities: Contact

    African Journals Online (AJOL)

    Principal Contact. Dr. Japhet Bakuwa Copy and Production Editor Chancellor College Publications Journal of Humanities Chancellor College Publications PO Box 280 Zomba Malawi Email: jbakuwa@cc.ac.mw ...

  5. Business and Human Rights

    DEFF Research Database (Denmark)

    Buhmann, Karin

    This article analyses the United Nations (UN) Guidelines on Business and Human Rights adopted in 2011 by the UN Human Rights Council from the perspective of Transnational Business Governance Interactions (TBGI) analytical framework (Eberlein et al. 2014). The article identifies and discusses dime...... business governance suggests that this form of governance offers prospects for public institutions as a means towards regulating global sustainability concerns.......This article analyses the United Nations (UN) Guidelines on Business and Human Rights adopted in 2011 by the UN Human Rights Council from the perspective of Transnational Business Governance Interactions (TBGI) analytical framework (Eberlein et al. 2014). The article identifies and discusses...... that the UN Guiding Principles are unique in several respects of relevance to transnational business governance interaction and indicate the relevance of the TBGI approach to public regulatory transnational business governance initiatives. The analysis of the Guiding Principles as interactional transnational...

  6. Human Reliability Program Overview

    Energy Technology Data Exchange (ETDEWEB)

    Bodin, Michael

    2012-09-25

    This presentation covers the high points of the Human Reliability Program, including certification/decertification, critical positions, due process, organizational structure, program components, personnel security, an overview of the US DOE reliability program, retirees and academia, and security program integration.

  7. Human Bond Communication

    DEFF Research Database (Denmark)

    Prasad, Ramjee

    2016-01-01

    Modern dexterous communication technology is progressively enabling humans to communicate their information through them with speech (aural) and media (optical) as underpinning essence. Humans realize this kind of aural and optical information by their optical and auditory senses. However, due...... to certain constraints, the ability to incorporate the other three sensory features namely, olfactory, gustatory, and tactile are still far from reality. Human bond communication is a novel concept that incorporates olfactory, gustatory, and tactile that will allow more expressive and holistic sensory...... information exchange through communication techniques for more human sentiment centric communication. This concept endorses the need of inclusion of other three senses and proposes an innovative approach of holistic communication for future communication network....

  8. Strategic Human Resources Management

    National Research Council Canada - National Science Library

    Marta Muqaj

    2016-01-01

    Strategic Human Resources Management (SHRM) represents an important and sensitive aspect of the functioning and development of a company, business, institution, state, public or private agency of a country...

  9. BIOETHICS AND HUMAN CLONING

    Directory of Open Access Journals (Sweden)

    Željko Kaluđerović

    2011-12-01

    Full Text Available In this paper the authors analyze the process of negotiating and beginning of the United Nations Declaration on Human Cloning as well as the paragraphs of the very Declaration. The negotiation was originally conceived as a clear bioethical debate that should have led to a general agreement to ban human cloning. However, more often it had been discussed about human rights, cultural, civil and religious differences between people and about priorities in case of eventual conflicts between different value systems. In the end, a non-binding Declaration on Human Cloning had been adopted, full of numerous compromises and ambiguous formulations, that relativized the original intention of proposer states. According to authors, it would have been better if bioethical discussion and eventual regulations on cloning mentioned in the following text had been left over to certain professional bodies, and only after the public had been fully informed about it should relevant supranational organizations have taken that into consideration.

  10. Science and Humanism

    Science.gov (United States)

    Auger, Pierre

    1971-01-01

    Science and humanism are separated so completely as to bring about the creation of two cultures quite distinct from each other within contemporary civilization. Pragmatic, rational attitudes are needed on both sides to bring them together. (DF)

  11. Human Capital Tracking Tool -

    Data.gov (United States)

    Department of Transportation — AVS is now required to collect, track, and report on data from the following Flight, Business and Workforce Plan. The Human Resource Management’s Performance Target...

  12. Human Factors Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — Purpose: The purpose of the Human Factors Laboratory is to further the understanding of highway user needs so that those needs can be incorporated in roadway design,...

  13. Human Power Empirically Explored

    NARCIS (Netherlands)

    Jansen, A.J.

    2011-01-01

    Harvesting energy from the users’ muscular power to convert this into electricity is a relatively unknown way to power consumer products. It nevertheless offers surprising opportunities for product designers; human-powered products function independently from regular power infrastructure, are

  14. HUMAN CAPITAL INVESTMENT

    Directory of Open Access Journals (Sweden)

    Ph. D. Student Ioana - Julieta Josan

    2012-05-01

    Full Text Available Once with the development of the human capital theory, the education received an economic value. Leading theorists and specialists in the field have shown that the remarkable economic effects of the investments in education influence the chances of acquiring a job and earnings, demonstrating how the theory justifies such an investment. At the hand, the allocation of resources in human capital brings performance and benefits to companies investing in their employees. Also, the investment in human capital is strategic for any country that seeks to create a knowledge economy. Considering the above arguments, the aim of this paper is to highlight the characteristics of investment in human capital, the types of investment, the factors of education investment and the entities interested in investing and their benefits.

  15. Human female meiosis revised

    DEFF Research Database (Denmark)

    Capalbo, Antonio; Hoffmann, Eva R.; Cimadomo, Danilo

    2017-01-01

    in the female germline is a crucial step towards the development of new diagnostic approaches and, possibly, for the development of therapeutic targets and molecules. Here, we have reviewed emerging mechanisms that may drive human aneuploidy, in particular the maternal age effect. SEARCH METHODS We conducted...... a systematic search in PubMed Central of the primary literature from 1990 through 2016 following the PRISMA guidelines, using MeSH terms related to human aneuploidy. For model organism research, we conducted a literature review based on references in human oocytes manuscripts and general reviews related...... to chromosome segregation in meiosis and mitosis. OUTCOMES Advances in genomic and imaging technologies are allowing unprecedented insight into chromosome segregation in human oocytes. This includes the identification of a novel chromosome segregation error, termed reverse segregation, as well as sister...

  16. Human Assisted Assembly Processes

    Energy Technology Data Exchange (ETDEWEB)

    CALTON,TERRI L.; PETERS,RALPH R.

    2000-01-01

    Automatic assembly sequencing and visualization tools are valuable in determining the best assembly sequences, but without Human Factors and Figure Models (HFFMs) it is difficult to evaluate or visualize human interaction. In industry, accelerating technological advances and shorter market windows have forced companies to turn to an agile manufacturing paradigm. This trend has promoted computerized automation of product design and manufacturing processes, such as automated assembly planning. However, all automated assembly planning software tools assume that the individual components fly into their assembled configuration and generate what appear to be a perfectly valid operations, but in reality the operations cannot physically be carried out by a human. Similarly, human figure modeling algorithms may indicate that assembly operations are not feasible and consequently force design modifications; however, if they had the capability to quickly generate alternative assembly sequences, they might have identified a feasible solution. To solve this problem HFFMs must be integrated with automated assembly planning to allow engineers to verify that assembly operations are possible and to see ways to make the designs even better. Factories will very likely put humans and robots together in cooperative environments to meet the demands for customized products, for purposes including robotic and automated assembly. For robots to work harmoniously within an integrated environment with humans the robots must have cooperative operational skills. For example, in a human only environment, humans may tolerate collisions with one another if they did not cause much pain. This level of tolerance may or may not apply to robot-human environments. Humans expect that robots will be able to operate and navigate in their environments without collisions or interference. The ability to accomplish this is linked to the sensing capabilities available. Current work in the field of cooperative

  17. Pushing Human Frontiers

    Science.gov (United States)

    Zubrin, Robert

    2005-01-01

    With human colonization of Mars, I think you will see a higher standard of civilization, just as America set a higher standard of civilization which then promulgated back into Europe. I think that if you want to maximize human potential, you need a higher standard of civilization, and that becomes an example that benefits everyone. Without an open frontier, closed world ideologies, such as the Malthus Theory, tend to come to the forefront. It is that there are limited resources; therefore, we are all in deadly competition with each other for the limited pot. The result is tyrannical and potentially genocidal regimes, and we've already seen this in the twentieth century. There s no truth in the Malthus Theory, because human beings are the creators of their resources. With every mouth comes a pair of hands and a brain. But if it seems to be true, you have a vector in this direction, and it is extremely unfortunate. It is only in a universe of infinite resources that all humans can be brothers and sisters. The fundamental question which affects humanity s sense of itself is whether the world is changeable or fixed. Are we the makers of our world or just its inhabitants? Some people have a view that they re living at the end of history within a world that s already defined, and there is no fundamental purpose to human life because there is nothing humans can do that matters. On the other hand, if humans understand their own role as the creators of their world, that s a much more healthy point of view. It raises the dignity of humans. Indeed, if we do establish a new branch of human civilization on Mars that grows in time and potency to the point where it cannot really settle Mars, but transforms Mars, and brings life to Mars, we will prove to everyone and for all time the precious and positive nature of the human species and every member of it.

  18. Human-Robot Biodynamics

    OpenAIRE

    Ivancevic, Vladimir G.

    2008-01-01

    This paper presents the scientific body of knowledge behind the Human Biodynamics Engine (HBE), a human motion simulator developed on the concept of Euclidean motion group SE(3), with 270 active degrees of freedom, force-velocity-time muscular mechanics and two-level neural control - formulated in the fashion of nonlinear humanoid robotics. The following aspects of the HBE development are described: geometrical, dynamical, control, physiological, AI, behavioral and complexity, together with s...

  19. Reclaiming human machine nature

    OpenAIRE

    Fass, Didier

    2014-01-01

    International audience; Extending and modifying his domain of life by artifact production is one of the main characteristics of humankind. From the first hominid, who used a wood stick or a stone for extending his upper limbs and augmenting his gesture strength, to current systems engineers who used technologies for augmenting human cognition, perception and action, extending human body capabilities remains a big issue. From more than fifty years cybernetics, computer and cog-nitive sciences ...

  20. Genetics of human hydrocephalus

    OpenAIRE

    Zhang, Jun; Michael A. Williams; Rigamonti, Daniele

    2006-01-01

    Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders. A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic co...

  1. Human ocular anatomy.

    Science.gov (United States)

    Kels, Barry D; Grzybowski, Andrzej; Grant-Kels, Jane M

    2015-01-01

    We review the normal anatomy of the human globe, eyelids, and lacrimal system. This contribution explores both the form and function of numerous anatomic features of the human ocular system, which are vital to a comprehensive understanding of the pathophysiology of many oculocutaneous diseases. The review concludes with a reference glossary of selective ophthalmologic terms that are relevant to a thorough understanding of many oculocutaneous disease processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Evolution and human sexuality.

    Science.gov (United States)

    Gray, Peter B

    2013-12-01

    The aim of this review is to put core features of human sexuality in an evolutionary light. Toward that end, I address five topics concerning the evolution of human sexuality. First, I address theoretical foundations, including recent critiques and developments. While much traces back to Darwin and his view of sexual selection, more recent work helps refine the theoretical bases to sex differences and life history allocations to mating effort. Second, I consider central models attempting to specify the phylogenetic details regarding how hominin sexuality might have changed, with most of those models honing in on transitions from a possible chimpanzee-like ancestor to the slightly polygynous and long-term bonded sociosexual partnerships observed among most recently studied hunter-gatherers. Third, I address recent genetic and physiological data contributing to a refined understanding of human sexuality. As examples, the availability of rapidly increasing genomic information aids comparative approaches to discern signals of selection in sexuality-related phenotypes, and neuroendocrine studies of human responses to sexual stimuli provide insight into homologous and derived mechanisms. Fourth, I consider some of the most recent, large, and rigorous studies of human sexuality. These provide insights into sexual behavior across other national samples and on the Internet. Fifth, I discuss the relevance of a life course perspective to understanding the evolution of human sexuality. Most research on the evolution of human sexuality focuses on young adults. Yet humans are sexual beings from gestation to death, albeit in different ways across the life course, and in ways that can be theoretically couched within life history theory. Copyright © 2013 Wiley Periodicals, Inc.

  3. ELECTRONIC HUMAN RESOURCE MANAGEMENT

    OpenAIRE

    Dr. M. Panneerselvam

    2017-01-01

    Electronic Human Resource Management is an essence the revolution of human resource functions to management and employees. These functions are typically used via intranet and web technology. This helps the organization to improve their standards where they can able to review and forward. All those documents can be viewed within a fraction of second with help of client and server links. The phenomenon of E- HRM deserves closer and more fundamental roots to HR activity. The E-HRM develops and b...

  4. Human motricity and health

    Directory of Open Access Journals (Sweden)

    Manuel Sérgio Vieira e Cunha

    2008-06-01

    Full Text Available If human motricity science intends to study motor conduct (or actions in which the human being pursues transcendence (or surmounting, it inevitably relates to the large realm of health. What are the aspects it evinces? Transdisciplinarity, solidarity among the various knowledge types (including poetical, complexity, (where the physical is integrated but surmounted and the firm belief that to be healthy is to have in ourselves, alive and working, the capacity for surmounting anything.

  5. Human Germline Genome Editing.

    Science.gov (United States)

    Ormond, Kelly E; Mortlock, Douglas P; Scholes, Derek T; Bombard, Yvonne; Brody, Lawrence C; Faucett, W Andrew; Garrison, Nanibaa' A; Hercher, Laura; Isasi, Rosario; Middleton, Anna; Musunuru, Kiran; Shriner, Daniel; Virani, Alice; Young, Caroline E

    2017-08-03

    With CRISPR/Cas9 and other genome-editing technologies, successful somatic and germline genome editing are becoming feasible. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in March 2017. The workgroup included representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counselors. These groups, as well as the American Society for Reproductive Medicine, Asia Pacific Society of Human Genetics, British Society for Genetic Medicine, Human Genetics Society of Australasia, Professional Society of Genetic Counselors in Asia, and Southern African Society for Human Genetics, endorsed the final statement. The statement includes the following positions. (1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy. (2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research. (3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input. Copyright © 2017 American Society of Human Genetics. All rights reserved.

  6. HUMAN CAPITAL INVESTMENT

    OpenAIRE

    Ph. D. Student Ioana - Julieta Josan

    2012-01-01

    Once with the development of the human capital theory, the education received an economic value. Leading theorists and specialists in the field have shown that the remarkable economic effects of the investments in education influence the chances of acquiring a job and earnings, demonstrating how the theory justifies such an investment. At the hand, the allocation of resources in human capital brings performance and benefits to companies investing in their employees. Also, the investment in hu...

  7. Deuteronomy and Human Rights

    Directory of Open Access Journals (Sweden)

    G. Braulik

    1998-08-01

    Full Text Available If one compares the articles of the "Universal Declaration of Human Rights" dated December 10th, 1948, with the regulations of the book of Deuteronomy, one detects a surprising abundance of correspondences, or at least of similar tendencies, between them. As the social theorists of the seventeenth and eighteenth centuries, the architects of the catalogue of Human Rights, knew the Scripture very well. References to Deuteronomy are historically well probable and factually hardly coincidental. Deuteronomy rightly boasts about its social laws (4:8 that are unique in the Ancient Near East. The paper orientates itself to the short formula of Human Rights and at the same time to the normative basic character of each human right, as it is formulated in the first article of the declaration: "liberty", "equality", "fraternity". Each of these basic categories are concretised in terms of several Deuteronomic regulations and prove themselves to be central matters of concern within the YHWH religion. Finally, it is outlined how the connection between Deuteronomy and modem expressions of human rights might be explained, and further it is shown what actually makes up the peculiarity of biblical thinking on human rights.

  8. Proteomics of human mitochondria.

    Science.gov (United States)

    Palmfeldt, Johan; Bross, Peter

    2017-03-01

    Proteomics have passed through a tremendous development in the recent years by the development of ever more sensitive, fast and precise mass spectrometry methods. The dramatically increased research in the biology of mitochondria and their prominent involvement in all kinds of diseases and ageing has benefitted from mitochondrial proteomics. We here review substantial findings and progress of proteomic analyses of human cells and tissues in the recent past. One challenge for investigations of human samples is the ethically and medically founded limited access to human material. The increased sensitivity of mass spectrometry technology aids in lowering this hurdle and new approaches like generation of induced pluripotent cells from somatic cells allow to produce patient-specific cellular disease models with great potential. We describe which human sample types are accessible, review the status of the catalog of human mitochondrial proteins and discuss proteins with dual localization in mitochondria and other cellular compartments. We describe the status and developments of pertinent mass spectrometric strategies, and the use of databases and bioinformatics. Using selected illustrative examples, we draw a picture of the role of proteomic analyses for the many disease contexts from inherited disorders caused by mutation in mitochondrial proteins to complex diseases like cancer, type 2 diabetes and neurodegenerative diseases. Finally, we speculate on the future role of proteomics in research on human mitochondria and pinpoint fields where the evolving technologies will be exploited. Copyright © 2016. Published by Elsevier B.V.

  9. Cytokines in human milk.

    Science.gov (United States)

    Garofalo, Roberto

    2010-02-01

    Epidemiologic studies conducted in the past 30 years to investigate the protective functions of human milk strongly support the notion that breastfeeding prevents infantile infections, particularly those affecting the gastrointestinal and respiratory tracts. However, more recent clinical and experimental observations also suggest that human milk not only provides passive protection, but also can directly modulate the immunological development of the recipient infant. The study of this remarkable defense system in human milk has been difficult because of its biochemical complexity, the small concentration of certain bioactive components, the compartmentalization of some of these agents, the dynamic quantitative and qualitative changes of milk during lactation, and the lack of specific reagents to quantify these agents. However, a host of bioactive substances, including hormones, growth factors, and immunological factors such as cytokines, have been identified in human milk. Cytokines are pluripotent polypeptides that act in autocrine/paracrine fashions by binding to specific cellular receptors. They operate in networks and orchestrate the development and functions of immune system. Several different cytokines and chemokines have been discovered in human milk in the past years, and the list is growing very rapidly. This article will review the current knowledge about the increasingly complex network of chemoattractants, activators, and anti-inflammatory cytokines present in human milk and their potential role in compensating for the developmental delay of the neonate immune system. Copyright 2010. Published by Mosby, Inc.

  10. Human Factors Review Plan

    Energy Technology Data Exchange (ETDEWEB)

    Paramore, B.; Peterson, L.R. (eds.)

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

  11. A WORLD BEYOND HUMAN

    Directory of Open Access Journals (Sweden)

    David Abram

    2013-12-01

    Full Text Available From an initial project to investigate the relationship between magic and traditional medicine as practiced by shamans in Southern rural Asia, the focus of attention gradually shifted to an awareness of the negotiation traditional medicine people or shamans exert between the human community and the larger community of beings. This attentiveness to a more-than-human world does not occur at a supernatural domain above nature or inside her personal self but is the result of the shaman’s special ability to project her consciousness horizontally to other forms of sensibility with which human existence is interwoven. The ecological function of the shaman is to maintain a constant balance between what is taken and what is given from the human community to the larger community. The spirits of indigenous cultures are not defined in opposition to materiality but are essentially those modes of intelligence or awareness that do not possess a human form. By exploring different landscapes, and the sensibility living in them, a new sensitivity is awoken that allows for communication with those intelligences. However, the drowning of these other voices in Western culture, which reduces otherness to an object, creates an uneasiness that is hardly perceived except as an inability to interact with anything more-than-human and its dire consequences in the form of “civilization’s” destructive behavior.

  12. Habitability and Human Factors Contributions to Human Space Flight

    Science.gov (United States)

    Sumaya, Jennifer Boyer

    2011-01-01

    This slide presentation reviews the work of the Habitability and Human Factors Branch in support of human space flight in two main areas: Applied support to major space programs, and Space research. The field of Human Factors applies knowledge of human characteristics for the design of safer, more effective, and more efficient systems. This work is in several areas of the human space program: (1) Human-System Integration (HSI), (2) Orion Crew Exploration Vehicle, (3) Extravehicular Activity (EVA), (4) Lunar Surface Systems, (5) International Space Station (ISS), and (6) Human Research Program (HRP). After detailing the work done in these areas, the facilities that are available for human factors work are shown.

  13. Testing for Human Immunodeficiency Virus

    Science.gov (United States)

    ... education Fact Sheet PFS005: Testing for Human Immunodeficiency Virus AUGUST 2015 • Reasons for Getting Tested • Who Should ... For More Information • Glossary Testing for Human Immunodeficiency Virus Human immunodeficiency virus (HIV) is the virus that ...

  14. Human bites - self-care

    Science.gov (United States)

    Bites - human - self-care ... Human bites can occur in 2 ways: If someone bites you If your hand comes into contact ... bite to express anger or other negative feelings. Human bites may be more dangerous than animal bites. ...

  15. Developing Human Performance Measures

    Energy Technology Data Exchange (ETDEWEB)

    Jeffrey Joe; Bruce Hallbert; Larry Blackwood; Donald Dudehoeffer; Kent Hansen

    2006-05-01

    Through the reactor oversight process (ROP), the U.S. Nuclear Regulatory Commission (NRC) monitors the performance of utilities licensed to operate nuclear power plants. The process is designed to assure public health and safety by providing reasonable assurance that licensees are meeting the cornerstones of safety and designated crosscutting elements. The reactor inspection program, together with performance indicators (PIs), and enforcement activities form the basis for the NRC’s risk-informed, performance based regulatory framework. While human performance is a key component in the safe operation of nuclear power plants and is a designated cross-cutting element of the ROP, there is currently no direct inspection or performance indicator for assessing human performance. Rather, when human performance is identified as a substantive cross cutting element in any 1 of 3 categories (resources, organizational or personnel), it is then evaluated for common themes to determine if follow-up actions are warranted. However, variability in human performance occurs from day to day, across activities that vary in complexity, and workgroups, contributing to the uncertainty in the outcomes of performance. While some variability in human performance may be random, much of the variability may be attributed to factors that are not currently assessed. There is a need to identify and assess aspects of human performance that relate to plant safety and to develop measures that can be used to successfully assure licensee performance and indicate when additional investigation may be required. This paper presents research that establishes a technical basis for developing human performance measures. In particular, we discuss: 1) how historical data already gives some indication of connection between human performance and overall plant performance, 2) how industry led efforts to measure and model human performance and organizational factors could serve as a data source and basis for a

  16. Interaction Between Humans and Structures

    DEFF Research Database (Denmark)

    Pedersen, Lars

    2014-01-01

    On structures two types of humans may be present. (1) Active humans and (2) passive humans (sitting or standing on the structure). The active humans can excite the structure and cause structural vibrations. The mass of the passive humans will interact with the structure and basically it changes...... the structural system (modal characteristics and structural vibration levels). The paper addresses this subject and explores the implications of having passive humans present on the structure....

  17. Towards a better understanding of human smuggling

    OpenAIRE

    Heckmann, Friedrich

    2007-01-01

    Contents: What is human smuggling?; How can we know about human smuggling?; Human smuggling as a migration phenomenon; Human smuggling as a business; The social organizing of human smuggling; Fighting against human smuggling.

  18. Why Geo-Humanities

    Science.gov (United States)

    Graells, Robert Casals i.; Sibilla, Anna; Bohle, Martin

    2016-04-01

    Anthropogenic global change is a composite process. It consists of societal processes (in the 'noosphere') and natural processes (in the 'bio-geosphere'). The 'noosphere' is the ensemble of social, cultural or political insights ('shared subjective mental concepts') of people. Understanding the composite of societal and natural processes ('human geo-biosphere intersections'), which shapes the features of anthropogenic global change, would benefit from a description that draws equally on natural sciences, social sciences and humanities. To that end it is suggested to develop a concept of 'geo-humanities': This essay presents some aspects of its scope, discussing "knowledge that is to manage", "intentions that are to shape", "choices that are to justify" and "complexity that is to handle". Managing knowledge: That people understand anthropogenic global change requires their insights into how 'human geosphere intersections' function. Insights are formed ('processed') in the noosphere by means of interactions between people. Understanding how 'human geosphere intersections' functions combines scientific, engineering and economic studies with studies of the dynamics of the noosphere. Shaping intentions: During the last century anthropogenic global change developed as the collateral outcome of humankind's accumulated actions. It is caused by the number of people, the patterns of their consumption of resources, and the alterations of their environments. Nowadays, anthropogenic global chance is either an intentional negligence or a conscious act. Justifying choices: Humanity has alternatives how to alter Earth at planetary scale consciously. For example, there is a choice to alter the geo-biosphere or to adjust the noosphere. Whatever the choice, it will depend on people's world-views, cultures and preferences. Thus beyond issues whether science and technology are 'sound' overarching societal issues are to tackle, such as: (i) how to appropriate and distribute natural

  19. Humanity and Sustainability

    Directory of Open Access Journals (Sweden)

    Shu-Kun Lin

    2011-09-01

    Full Text Available So far our open access publishing company MDPI (Multidisciplinary Digital Publishing Institute has published mainly science, medicine and technology journals. To become a multidisciplinary publisher, we launched the journal Sustainability [1]. More recently, we started to run several social science journals, including Societies [2], Religions [3], Administrative Sciences [4] and Behavioral Sciences [5]. Today we published the first paper [6] of the inaugural issue of Humanities (ISSN 2076-0787. This will be an international open access journal, publishing scholarly papers of high quality across all humanities disciplines. As a publisher, I would like to publish journals surrounding the topics of sustainability and I believe the humanities as a discipline of academic studies are very important. As a scientist, I believed science and technology will only benefit human beings. I was raised in a small village, living a very primitive life in a peasant family: no electricity, no machines, of course no TV and no refrigerator. Now, the life of my children is completely different. Even my own life has completely changed. I have witnessed very rapid changes: more and more machines are used to consume mineral resources and energy and to pollute the environment, in order to produce more and more powerful machines (we are also launching a journal titled Machines, in which the relationship between Man and machine should be an interesting topic.. Machines are more and more like human individuals consuming resources themselves (we are launching a journal titled Resources. [...

  20. Human milk banking guidelines.

    Science.gov (United States)

    Bharadva, Ketan; Tiwari, Satish; Mishra, Sudhir; Mukhopadhyay, Kanya; Yadav, Balraj; Agarwal, R K; Kumar, Vishesh

    2014-06-01

    WHO and UNICEF state that the use of human milk from other sources should be the first alternative when it is not possible for the mother to breastfeed. Human milk banks should be made available in appropriate situations. The IYCF Chapter is actively concerned about the compelling use of formula feeds in the infants because of the non availability of human breast milk banks. A National Consultative Meet for framing guidelines was summoned by the IYCF Chapter and the Ministry of Health and Family Welfare, Government of India on 30th June, 2013, with representations from various stakeholders. The guidelines were drafted after an extensive literature review and discussions. Though these guidelines are based on the experiences and guidelines from other countries, changes have been made to suit the Indian setup, culture and needs, without compromising scientific evidence. To ensure quality of donated breast milk as a safe end product. Human Milk Banking Association should be constituted, and human milk banks should be established across the country. National coordination mechanism should be developed with a secretariat and technical support to follow-up on action in States. Budgetary provisions should be made available for the activities.